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Plasticity in descending pain modulatory systems
J. Samktihler, B. Bromm and G.F. Gebhart (Ed%) Progress in Brain Research, Vol. 129 0 2000 Elsevier Science B.V. All rights reserved
CHAPTER 16
Plasticity in descending pain modulatory systems Antti Pertovaara* Department
of Physiology,
Institute
of Biomedicine,
University
Introduction The development of experimental animal models of neuropathy and other chronic pain conditions has provided the possibility to study cellular mechanisms underlying pathophysiological pain. The studies performed using these models have provided abundant evidence indicating that various pathophysiological conditions may cause dramatic changes in the transmission and modulation of pain-related information. Recently, we performed a series of studies in which we attempted to characterize changes in central transmission of nociceptive information, and, in particular, descending modulation of nociception, in a rat model of experimental neuropathy caused by unilateral ligation of two spinal nerves (Kim and Chung, 1992). This model produces a robust, long-lasting and highly reproducible allodynia and hyperalgesia to mechanical and cooling stimulation (Kim and Chung, 1992; Rijyttg et al., 1999) without causing distress or measurable anxiety to the animals (Kontinen et al., 1999). Also, heat hyperalgesia has been described following spinal nerve ligation in many laboratories (Kim and Chung, 1992). However, in contrast to hypersensitivity to mechanical and cooling stimulation, heat hyperalgesia in this model has been more variable and it has not been observed in all experimental conditions (Bian et al.,
*Corresponding author: A. Pertovaara, Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. Tel.: +358 (40) 760-7123; Fax: +358 (2) 250-2610; E-mail: [email protected]
of Turku,
Kiinamyllynkatu
IO, FIN-20520
Turku,
Finland
1998; Riiyttg et al., 1999). Concomitant with an increased sensitivity to stimuli activating predominantly thick myelinated fibers, spinal nerve ligation causes a marked reduction in the number of myelinated axons innervating the allodynic skin (R6yttti et al., 1999). This paradoxical finding suggests that spinal nerve ligation induces a central amplification, disinhibition of tactile signals, or both. To determine whether findings with the spinal nerve ligation-induced model of neuropathy can be generalized to other pathophysiological conditions, a parallel series of studies on plasticity of central pain transmission and modulation was performed using an acute model of hyperalgesia and allodynia induced by neurogenic inflammation. Role of supraspinal controls It is well-established that brainstem spinal pathways have an important role in the control of spinal nociceptive responses (Fields and Basbaum, 1999). In general, the influence of the brainstem on spinal nociception has been considered to be predominantly inhibitory. However, there is accumulating evidence indicating that brainstem-spinal pathways may not only attenuate pain, but descending controls may also contribute to facilitation or disinhibition of nociceptive signals at the spinal cord level depending on the submodality of test stimulation, pathophysiological condition and the neural pathway (for reviews, see Maier et al., 1992; Lima et al., 1998; Urban and Gebhart, 1999). Studies addressing the role of supraspinal control in the spinal nerve ligation-induced model of neuropathy have shown that a reversible block of the rostroventromedial medulla
232
INTRACEREBRAL
INJECTION
SYSTEMIC
INJECTION
IO' . ctrl paw post 20 /~g RVM 0 oper paw post 20 pg RVM D oper paw post SAL RVM
lzm
TIME [min]
TIME [mini
(Cl
(W
INTRACEREBRAL
TAIL-FLICK
INJECT.
50 1
SAL RVM
2Ql.N
4oW3
20 P!3
RVM
RVM
PAG
TEST
IO,
I
SAL RVM LIDOCAINE
20 I4 RVM
20 /Jg
PAG
DOSE
Fig. 1. Selective attenuation of tactile allodynia following lidocaine-induced block of the RVM or PAG in rats with a spinal nerve ligation-induced neuropathy. (A) Following lidocaine (20 kg) administration in the RVM the hindlimb withdrawal threshold to monofilament stimulation was elevated in the neuropathic side (oper paw), but not in the contralateral side (ctrl paw). Saline (SAL) administration in the RVM had no influence on tactile allodynia. (B) The selective attenuation of tactile allodynia following supraspinal administration of lidocaine was not due to a systemic effect, since systemic administration of lidocaine at the dose of 40 ug had no influence on tactile ahodynia. (C) The antiallodynic effect of lidocaine in the RVM was dose-related. Lidocaine at the dose of 20 ug produced an equipotent antiallodynia following administration in the RVM and the PAG. (D) An antiallodynic dose of lidocaine in the RVM or PAG did not produce any change in the latency of the radiant heat-induced tail-flick in neuropathic animals. The error bars represent S.E.M. (n = 4-7). *P < 0.05 (reference: in A and B, the corresponding pre-injection threshold; in C and D, the saline group). Adapted from Pertovaara et al. (1996).
(RVM) or periaqueductal gray (PAG) by lidocaine selectively attenuate tactile allodynia (Fig. 1; Pertovaara et al., 1996). In line with this, midthoracic spinalization also selectively attenuated tactile allodynia in neuropathic animals (Fig. 2; Bian et al., 1998; Kauppila et al., 1998). These findings, together with similar findings in other models of hypersensitivity (Herrero and Cervero, 1996; Urban et al.,
1996; Kauppila, 1997; Mans&a and Pertovaara, 1997; Pertovaara, 1998; Sung et al., 1998), suggest that a positive feedback loop involving structures rostra1 to the injured segment contributes to mechanical hypersensitivity at the spinal cord level. However, because mechanical hypersensitivity induced by neurogenic inflammation is not completely abolished by spinalization (Pertovaara, 1998), at least
233
(A)
Monofilament-induced
reflex
(W
100
7.5
z e8 eI_
10
s c 5 2 2.5
g
30
3 1
Ctrl
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5.0 0.0 bh
Heat-induced
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reflex
ClPre I Post
# ?Y*
Ctrl
NP
-
Fig. 2. Effect of spinalization on hindlimb withdrawal reflex response elicited by mechanical stimulation with monofilaments (A) versus radiant heat (B) in rats with no other pathophysiology (CM) and in rats with a spinal nerve ligation-induced neuropathy (Np). Np-ip, neuropathic side; Np-ct, side contralateral to neuropathy; Pre, prior to spinal transection; Post, 10 h after midthoracic transection of the spinal cord. Note a marked elevation of threshold to mechanical stimulation (antiallodynic effect) that is accompanied by a decrease in radiant heat-induced withdrawal latency (hyperalgesic effect) in the neuropathic limb following spinal transection. *P < 0.05 (reference: the corresponding value prior to spinalization; n = 64, #P c 0.05 (reference: the corresponding value in the Ctrl-group). Adapted from Kauppila et al. (1998).
part of the mechanical hypersensitivity observed in spinal dorsal horn neurons is due to spinal segmental mechanisms, which is in line with earlier studies demonstrating central hypersensitivity in spinal preparations (Coderre et al., 1993). In contrast to mechanically evoked responses, heat-evoked responses were enhanced following spinalization (Kauppila et al., 1998), indicating that heat-evoked responses are predominantly under tonic inhibitory controls. The tonic descending inhibition of heat-evoked responses varied depending on the segmental level, being stronger on tail- than limb-evoked responses (Bian et al., 1998; Kauppila et al., 1998), and more distinct in neuropathic than control animals (Fig. 2B; Kauppila et al., 1998). The influence of supraspinal controls on spinal nociception may also vary depending on whether the nociceptive signals originate from the area of primary hyperalgesia (the injured site in which hypersensitivity is predominantly due to peripheral sensitization of nociceptors) or from the area of secondary hyperalgesia (adjacent to the injured site, in which hypersensitivity is mainly due to central mechanisms). That is, brainstem-spinal pathways predominantly facilitate secondary hyperalgesia, but not primary hyperalgesia (Urban et al., 1996, 1999b; Pertovaara, 1998). The complexity of descending modulatory systems is illustrated by the previous findings that at least in some non-neurogenie inflammatory conditions, the descending inhibitory control of ascending nociceptive signals from the inflamed region is enhanced (Schaible et
al., 1991; Ren and Dubner, 1996; Tsuruoka and Willis, 1996). These findings add to the accumulating evidence indicating that various pathophysiological conditions, including experimental neuropathy, may significantly change the brainstem-spinal control of nociceptive signals and that the direction of change may depend on various experimental factors. Dependence of hypersensitivity on maintained injury discharge versus afferent barrage at the time of injury Previous studies indicate that the afferent barrage induced by experimental nerve injury may trigger enhanced pain sensitivity, revealed by the preemptive effect of local lidocaine treatment in some models of neuropathy (e.g. Kauppila and Pertovaara, 1991; Luukko et al., 1994; for a review see Jensen and Nikolajsen, 2000, this volume). The injury discharge may trigger the enhanced responsiveness due to a number of neurochemical changes in the central nervous system and particularly in the spinal dorsal horn; these plastic changes presumably involve an important contribution of N-methyl-D-aspartate (NMDA) receptors (Coderre et al., 1993; see Moore et al., 2000, this volume; Sandktihler et al., 2000, this volume). This is supported in two different spinal nerve ligation-induced models of neuropathy by the finding that a single administration of an NMDA receptor antagonist systemically prior to, but not after, the nerve injury dose-dependently attenuated the
234
(A)
Mechanical
hyperalgesia
Tactile
allodynia
iceiflt---~+~.<~.~.o f ~~~~ dl
cl2 Postoperative
d3
w2
time
dl
d2 Postoperative
d= time
Fig. 3. An NMDA receptor antagonist, MK-801 (1 kg), in the RVM attenuated development of mechanical hyperalgesia (A) and tactile allodynia (B) for weeks when administered 15 min before (MK-801 pre) but not 25 min after (MK-801 post) ligation of spinal nerves. In A, the y-axis indicates the difference between hindlimb withdrawal thresholds to noxious mechanical stimulation (threshold difference ~0 g indicates hyperalgesia of the operated side). In B, the y-axis indicates the hindlimb withdrawal threshold to monofilament stimulation of the operated side. The error bars represent S.E.M. (n = 8 in each group). dl-3, postoperative days 1-3; w2, postoperative days 12-14. *P < 0.05, ** P < 0.01 vs. corresponding value in the saline group. Adapted from Wei and Pertovaara (199913).
development of neuropathic symptoms for several days (Kim et al., 1997; Wei and Pertovaara, 1999a). Microinjection of a single dose of an NMDA receptor antagonist in the rostroventral medulla (RVM) prior to, but not after, the nerve injury also significantly suppressed the development of neuropathic symptoms for 2 weeks (Fig. 3; Wei and Pertovaara, 1999b), indicating that the preemptive effect induced by systemic NMDA receptor antagonists may in part be due to a supraspinal action. In line with this finding, supraspinal administration of NMDA receptor antagonists as well as a nitric oxide synthase inhibitor attenuated hypersensitivity in other pathophysiological models (Coutinho et al., 1999; Urban et al., 1999a,b). It should be noted that this finding does not exclude a contribution of spinal NMDA receptors in the development and maintenance of hypersensitivity. Antihyperalgesic effects by intrathecal NMDA receptor antagonists demonstrated in various pathophysiological models (Coderre et al., 1993), including the spinal nerve ligation-induced model of neuropathy (Leem et al., 1996), indicate that spinal NMDA receptors also play an important role in the maintenance of hypersensitivity. Moreover, these findings do not exclude a contribution of ectopic discharge originating from peripheral nerves (Lee et al., 1999) as an important factor for the maintenance of neuropathic symptoms. Indeed, the attenuation of neuropathic symptoms by dorsal rhizotomy supports the hypothesis that on-going discharge from peripheral nerves is of importance for the maintenance of
neuropathic symptoms induced by spinal nerve ligation (Yoon et al., 1996). The importance of on-going afferent barrage for maintenance of fully developed central hyperalgesia has also been demonstrated in other experimental models of hypersensitivity. For example, the secondary hyperalgesia induced by neurogenic inflammation is distinctly dependent on on-going activity in peripheral nerve fibers as shown by immediate and reversible abolishment of central hyperalgesia by cold block of the injury discharge (e.g. Gronroos and Pertovaara, 1993). Together, these findings suggest that an afferent barrage at the time of spinal nerve ligation may trigger sensitization of a positive feedback loop involving NMDA receptors in the spinal cord and the brainstem. However, this pronociceptive central circuitry may not alone explain the neuropathic symptoms, and an ongoing ectopic discharge from the injured (and possibly neighboring) peripheral nerves is probably also needed to maintain hyperresponsiveness at the spinal cord level. Behavioral effectiveness of centrally acting analgesic compounds in neuropathy, with particular emphasis on drugs influencing descending controls Spinal nerve ligation produces changes in the potency of several analgesic drugs, including those presumably acting on descending controls. Morphine is known to modulate nociception at different levels
235
of the neuraxis, from the periphery to a number of supraspinal sites, and this includes action on various descending pain modulatory pathways (Fields and Basbaum, 1999; see also Ingram, 2000, this volume). Several behavioral studies indicate that the antinociceptive potency of intrathecal morphine in spinal nerve ligation-induced model of neuropathy is considerably reduced (Bian et al., 1995; Lee et al., 1995), and this may be due to upregulation of cholecystokinin (Xu et al., 1993; Nichols et al., 1995). However, supraspinal and systemic morphine seem to have a strong antinociceptive potency following spinal nerve ligation (Bian et al., 1995; Lee et al., 1995; Wei et al., 1998). Following spinal nerve ligation, naloxone, an opioid receptor antagonist, does not modulate skin sensitivity either in rats with tactile allodynia (Wei et al., 1998) or in asymptomatic animals (Xu et al., 1999). This finding indicates that spinal nerve ligation does not activate tonic (descending or spinal segmental) opioidergic controls that would mask neuropathic symptoms. It is well-established that descending noradrenergic pain modulatory systems attenuate pain due to action on spinal clz-adrenoceptors (for a review, see Pertovaara, 1993). The pain-attenuating effect of systemic cl*-adrenoceptor agonists is markedly enhanced in spinal nerve ligation-induced neuropathy (Wei and Pertovaara, 1997), other models of neuropathy (Kayser et al., 1995) and neurogenic inflammation (Mansikka and Pertovaara, 1995). The enhanced effectiveness of q-adrenergic compounds in various pathophysiological conditions can, at least in part, be explained by mechanisms at the spinal cord level (Stanfa and Dickenson, 1994; Mansikka et al., 1996; Wei and Pertovaara, 1997), whereas supraspinally c12-adrenergic compounds may have, if anything, pronociceptive effects in hyperalgesic animals (Fig. 4A,B; Mansikka et al., 1996). This, however, does not exclude the possibility that peripheral az-adrenoceptors might play a role in some pathophysiological conditions. Paradoxically, an a*-adrenoceptor administered in the lateral reticular nucleus of the caudal ventrolateral medulla, but not in the RVM or spinal cord, produced, in animals with a secondary hyperalgesia, a selective antihyperalgesic effect, suggesting that the facilitatory spinal-brainstem-spinal circuitry may involve clz-adrenoceptors at the medullary level (Fig. 4;
(6)
(A) SAL-LRN
MED-LRN
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10'
'; IA
ld
(Cl ,02 ,
(Dl AT’-kRN
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0
10
20
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30
40
Time
Al-PYG
1oQ~ -10
0
10
20
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,
30
40
(mid
Fig. 4. Plasticity in the supraspinal az-adrenergic modulation of secondary hyperalgesia/allodynia following mustard oil-induced neurogenic inflammation in the rat. Medetomi dine (MED; an az-adrenoceptor agonist), atipamezole (ATI; an az-adrenoceptor antagonist) or saline (SAL) were microinjetted into the medullary lateral reticular nucleus (LRN) or raphe magnus nucleus (RMG) at time point -12 min. To produce neurogenic inflammation, the ankle of one hindpaw was treated with mustard oil at time point 0 and the hindlimb withdrawal threshold was determined by applying monofilaments to the paw at a site 2 cm outside the border of neurogenic inflammation (a site with secondary hyperalgesia; open symbols) or to the contralateral paw (control; filled symbols). (A) Mustard oil induced, within a few minutes, a marked threshold decrease for about 30-40 min in the treated side and this effect was not influenced by saline in the LRN. (Bi A low dose of medetomidine (1 ug) in the LRN tended to enhance secondary hyperalgesia without influencing thresholds in the control limb. In contrast, following intrathecal administration, this low dose of medetomidine completely reversed the hyperalgesia without influencing nociception in non-inflamed tissue (shown in the original article). (C) Atipamezole (2.5 ug) in the LRN produced a paradoxical antihyperalgesic effect. (D) The effect of atipamezole (2.5 pg) in the RMG on hyperalgesia was not significant. Neither did intrathecal atipamezole (2.5 p.g) influence hyperalgesia (shown in the original article). The error bars represent S.E.M. (n = 4-7 in each group). Adapted from Mans&a et al. (1996).
Mansikka et al., 1996). Interestingly, it was recently shown that an wz-adrenoceptor antagonist alone administered intrathecally could unmask al-
236 lodynia in asymptomatic animals with a spinal nerve ligation, whereas existing allodynia was not modified by an cl*-adrenoceptor antagonist (Xu et al., 1999). This finding suggests that in some conditions, nerve injury may promote the potency of endogenous oz-adrenergic action, possibly including activation of descending noradrenergic pathways, which contributes to attenuation of neuropathic symptoms due to action on spinal c12-adrenoceptors. Neuropeptide FF in the PAG produced a selective attenuation of tactile allodynia in rats with a spinal nerve ligation-induced neuropathy (Wei et al., 1998). Following intrathecal administration neuropeptide FF attenuates pain responses in neuropathic animals as well in non-neuropathic ones (Panula et al., 1999). Thus, neuropeptide FF has a dual action by selectively attenuating descending facilitatory or disinhibitory influence at the brainstem level and by an accompanying more general attenuation of pain responses at the spinal cord level. Moreover, spinal administration of neuropeptide FF has enhanced the potency of descending inhibitory controls following inflammation (Pertovaara et al., 1998) and neuropathy (Wei and Pertovaara, unpublished). These findings suggest that neuropeptide FF may provide possibilities for selective treatment of neuropathic symptoms due to enhancement of descending inhibitory controls at the spinal cord level and due to an accompanying attenuation of descending facilitation or disinhibition at the brainstem level.
Spontaneous IO.01
Response properties and brainstem-spinal control of nociceptive spinal dorsal horn neurons in neuropathic animals Neurophysiological studies in rats with a spinal nerve ligation-induced neuropathy indicate that a characteristic change in the response properties of spinal dorsal horn wide-dynamic range (WDR) neurons, which are considered to have an important role for pain, is their increased spontaneous activity (Fig. 5A; Pertovaara et al., 1997; Chapman et al., 1998). This may reflect injury-induced ectopic discharge in primary afferent neurons (Lee et al., 1999). Also, an increase in responsivity of spinal dorsal horn WDR neurons to mechanical stimulation has been observed in some (Leem et al., 1995, 1996; Pertovaara et al., 1997) but not all (Chapman et al., 1998) investigations. The responses of spinal WDR neurons to noxious heat have been almost identical with those in non-neuropathic animals (Pertovaara et al., 1997; Chapman et al., 1998). In line with behavioral findings, spinalization or reversible block of the RVM by lidocaine selectively attenuated the enhanced mechanically evoked responses to spinal dorsal horn WDR neurons in animals with neurogenic inflammation (Fig. 6; Pertovaara, 1998), indicating that descending brainstem-spinal pathways contribute to mechanical hyperresponsiveness. The noxious heat-evoked responses to spinal dorsal horn WDR neurons from non-neuropathic skin were markedly attenuated by electrical stimulation of the PAG, whereas the inhibitory effect of PAG-stimulation on heat-evoked responses from the neuropathic
Attenuation of heatevoked responses by PAG stimulation
activity *
1501
Fig. 5. Response characteristics of spinal dorsal horn WDR neurons following spinal nerve ligation-induced neuropathy in the rat. (A) Spontaneous activity ipsilateral to the spinal nerve ligation (Np-ip), contralateral to the spinal nerve ligation (Np-ct) and in unoperated control animals (Ctrl). (B) Effect of electrical stimulation of the PAG on noxious heat-evoked responses from the hindpaw ipsilateral (Np-ip) or contralateral (Np-ct) to the spinal nerve ligation. 100% = the response prior to PAG stimulation. *P < 0.05, **P i 0.01 (reference: Ctrl group in A, the corresponding response without PAG stimulation in B). Adapted from Pertovaara et al. (1997).
237
(4
Heat Mech. Adjacent
SPINAL
Mech. Remote
50 ‘a WDR
46g WDR
4.5 LTM
TRANSECTION
300 -**7 250 t
1
M.O.
+LIDO-RVM
M.O.
+LIDO-RVM
Fig. 6. Response characteristics and supraspinal modulation of spinal dorsal horn neuron responses following mustard oil-induced neurogenic inflammation in rats. (A) Mustard oil (M.O.) applied adjacent to the receptive fields of WDR neurons did not enhance their responses to noxious heat, whereas responses to noxious mechanical stimuli were significantly enhanced. Mustard oil in a remote site (forepaw) did not enhance mechanically evoked responses. (B) Mustard oil adjacent to the receptive field of spinal pain (WDR) neurons produced an equal enhancement of mechanically evoked responses both to low (4 g) and high (46 g) intensity stimuli, whereas responses to spinal dorsal horn mechanoreceptive (LTM) neurons were not influenced. (C) Following spinal transection, mustard oil applied adjacent to the receptive field produced a significant hyperexcitability to mechanical stimuli in WDR neurons that was significantly weaker than that in rats with an intact spinal cord (compare with graph A) and not attenuated by lidocaine (40 ug) in the RVM, rostra1 to the spinal transection. (D) Lidocaine (LIDO; 40 pg) in the RVM significantly attenuated mustard oil-induced hyperexcitability in rats with an intact spinal cord. 100% = the response prior to application of mustard oil. *P < 0.05, **P < 0.01, ***P < 0.005, (reference: the corresponding response prior to mustard oil.) Ns, non-significant. Adapted from Pertovaara (1998).
skin was reduced (Fig. 5B; Pertovaara et al., 1997). This finding resembles the reduction of descending inhibition from the PAG described in animals with neurogenic inflammation (Lin et al., 1997) and it indicates that neuropathy and neurogenic inflammation may significantly attenuate phasic inhibitory controls originating in the midbrain. Response properties of nociceptive medullary neurons presumably involved in descending controls in neuropathic animals At the brainstem level, the RVM is a site that has an important role in modulation of spinal nocicep-
tive signals (Fields and Basbaum, 1999). The RVM neurons can be classified into three main groups: (1) On-cells that fire prior to a nocifensive reflex; (2) Off-cells that pause prior to a nocifensive reflex; and (3) neutral cells that have no nociception-related response (Fields and Basbaum, 1999). According to our recent results, On- or Off-type RVM neurons did not express any marked submodality dependence in their responsivity to noxious heat versus noxious mechanical stimulation in inflammatory or neuropathic conditions (Keski-Vakkuri and Pertovaara, 1999). It was expected that the selective attenuation of mechanical hypersensitivity observed in behavioral studies following spinal transection or lidocaine
238
block of the RVM (Pertovaara et al., 1996; Kauppila et al., 1998) was due to submodality-dependent response properties of RVM neurons. Moreover, following spinal nerve ligation-induced neuropathy, spontaneous activity or evoked responses to noxious mechanical and heat stimulation in nociceptive On-type neurons of the RVM were not significantly changed (Pertovaara and Wei, 2000). This finding suggests that the response properties of nociceptive On-type neurons in the RVM may not explain the hypersensitivity induced by spinal nerve ligation. This result is in line with that observed in another model of neuropathy, the chronic constriction injury of the sciatic nerve (Luukko and Pertovaara, 1993). In contrast, a sciatic transection caused an enhancement of excitatory responses to nociceptive RVM neurons from the hypersensitive skin area adjacent to the denervated area (Pertovaara and Kauppila, 1989). Moreover, the hyperalgesia induced by opioid-abstinence has been correlated with enhanced responsivity of On-type neurons of the RVM (Fields and Basbaum, 1999). Thus, a change in response properties of nociceptive On-neurons in the RVM may contribute to facilitation of spinal reflexes in models of central hyperalgesia induced by opioid-abstinence or transection of the sciatic nerve, but their role in the spinal nerve ligation-induced model of neuropathy is less evident. Since the response properties of On-type RVM neurons (and possibly also Off-type neurons) do not correspond with behavioral changes induced by spinal nerve ligation, the contribution of the RVM to behavioral hypersensitivity in this neuropathy model could be due to a change in discharge properties of other types of RVM neurons (neutral neurons), due to a change in synchronization of descending signals between RVM neurons, or due to a change in synaptic efficacy of spinal terminals of the RVM neurons. The reduced inhibitory effect of PAG stimulation at the spinal cord level under neuropathic conditions (Pertovaara et al., 1997) is in line with the latter hypothesis, since the RVM is an important relay between the PAG and the spinal dorsal horn (Fields and Basbaum, 1999). The response properties of RVM neurons in neuropathic animals have been characterized only after the development of neuropathic symptoms. However, the role of RVM neurons during development and maintenance of neuropathic symptoms may dif-
fer. Evidence for this possibility is the finding that a single administration of an NMDA receptor antagonist in the RVM prior to nerve injury, but not after the injury, attenuated development of neuropathic symptoms for several days (Fig. 3; Wei and Pertovaara, 1999b). This result raises the possibility that the afferent barrage at the time of nerve injury, via activation of a pronociceptive circuitry involving the RVM, causes long-lasting changes in the synaptic efficacy of the spinal terminals of RVM neurons. According to this proposal, a discharge rate of RVM neurons, that is within the same range as in control conditions, could be enough to produce enhanced spinal (facilitatory) actions following development of neuropathy. This hypothesis is compatible with the two seemingly paradoxical findings observed in fully developed neuropathy: lack of marked changes in response properties of nociceptive RVM neurons (Keski-Vakkuri and Pertovaara, 1999; Pertovaara and Wei, 2000) and the attenuation of hyperresponsiveness at the spinal cord level following lidocaine block of the RVM or spinal transection (e.g. Pertovaara et al., 1996; Kauppila et al., 1998). Furthermore, neurophysiological studies are performed under general anesthesia, whereas behavioral studies are performed in awake animals, and this may provide a confounding factor when comparing behavioral findings with electrophysiological results. This caveat applies especially to recordings of supraspinal neuron responses that are known to be sensitive to anesthetic agents (Oliveras et al., 199 1). Possible spinal actions of descending influence Brainstem-spinal pathways may modulate spinal sensory responses due to an action that is pre- or postsynaptic to the spinal dorsal horn neuron, or both, and these influences may involve a number of spinal segmental interneurons. There is previous evidence indicating that following spinalization presynaptic inhibition of A-fiber input to the spinal dorsal horn is enhanced (Quevedo et al., 1993) whereas presynaptic inhibition of C-fiber input is attenuated (Calvillo et al., 1982). Since mechanically evoked responses are predominantly, although not exclusively, mediated by A-fibers and heat-evoked responses by C-fibers, this dissociative effect of supraspinal controls on presynaptic inputs into the spinal cord might
239
provide a mechanism contributing to submodalitydependent descending control of nociceptive input to the spinal cord. This hypothesis is further supported by the finding that spinalization and lidocaine block of the RVM selectively attenuated mechanically evoked responses of spinal dorsal WDR neurons, whereas heat-evoked responses of the same neurons were not attenuated in animals with a mechanical hyperresponsiveness induced by neurogenic inflammation (Fig. 6; Pertovaara, 1998). This electrophysiological finding is in line with the hypothesis that the supraspinal facilitatory influence was due to a selective action presynaptic to the spinal dorsal horn WDR neuron. In addition to excitatory amino acids and in particular their action on NMDA receptors, there are many other neurochemical mediators potentially contributing to descending facilitatory or disinhibitory effects at the spinal cord level. For example, there is evidence indicating that serotonin released from descending axons may lead to unmasking of silent synapses (Zhuo, 2000, this volume). Also, protein kinase C in postsynaptic spinal dorsal horn neurons has an important role in spinal hypersensitivity and attenuation of descending inhibitory effects (Lin et al., 1997; Malmberg, 2000, this volume). The differential descending control of physiological and pathophysiological sensory input to the spinal cord is likely to reflect corresponding differences in neurochemistry. A better understanding of these complex pronociceptive changes may provide possibilities to develop more selective treatments of pathophysiological pain.
injured and possibly neighboring peripheral nerves may be required for the maintenance of hyperalgesia and pain. The analgesic efficacy of various drugs, including those acting on descending controls, is also changed by this model of neuropathy. Neurophysiological studies have revealed increased spontaneous activity and enhanced mechanical responsiveness in the presumed spinal pain-relay neurons. Importantly, spinal nerve ligation may induce significant changes in descending control of spinal nociception as indicated by selective attenuation of mechanical hypersensitivity by blockade of brainstem-spinal pathways. Moreover, phasic descending inhibition of heat-evoked responses is reduced in neuropathic animals. These findings in neuropathic animals, and similar observations in animals with neurogenic inflammation, indicate that nerve injury or neurogenic inflammation may produce selective plastic changes in the brainstem-spinal control of pain. These central changes in endogenous pain control mechanisms may explain, although not fully, some of the neuropathic symptoms. The selectivity of this pathophysiological plasticity in descending controls and its underlying neurochemisty may provide possibilities to develop treatments that attenuate neuropathic symptoms without influencing physiological pain responses. The selective antiallodynia by supraspinally administered neuropeptide FF and enhancement of descending inhibitory controls by spinally administered neuropeptide FF provides just one example demonstrating that this therapeutic approach is, at least experimentally, applicable and deserves to be studied further.
Conclusions
Abbreviations
The spinal nerve ligation-induced model of neuropathy (Kim and Chung, 1992) has proved a highly useful model for investigation of mechanisms underlying neuropathic pain. The nerve ligation produces a number of changes in pain transmission and modulation pathways that may contribute to neuropathic symptoms. The injury discharge at the time of surgery appears to trigger central mechanisms involving glutamatergic NMDA receptors in the brainstem as well as in the spinal cord that contribute to the development and maintenance of hyperalgesia. Additionally, an on-going ectopic discharge from the
NMDA receptor PAG RVM WDR neuron
N-methyl-D-aspartate receptor periaqueductal gray rostroventromedial medulla wide-dynamic range neuron
Acknowledgements The author wishes to thank Drs. H. Wei, T. Kauppila, M.M. H;im&iinen, H. Mansikka, U. Keski-Vakkuri, M. Luukko, P Panula, V.K. Kontinen and E. Mecke for their contributions to the series of studies described. The author’s work was supported by the
240 Academy of Finland, TEKES, and Sigrid JusClius Foundation, Helsinki, Finland. References Bian, D., Nichols, M., Ossipov, M.H., Lai, J. and Porreca, F. (1995) Characterization of the antiallodynic efficacy of morphine in a model of neuropathic pain in rats. NeuroReporr, 6: 1981-1984. Bian, D., Ossipov, M.H., Malan Jr., T.P. and Porreca, F. (1998) Tactile allodynia, but not thermal hyperalgesia, of the hindlimbs is blocked by spinal transection in rats with nerve injury. Neurosci. Let?., 241: 19-82. Calvillo, O., Madrid, J. and Rudomin, P. (1982) Presynaptic depolarization of unmyelinated primary afferent fibers in the spinal cord of the cat. Neuroscience, 7: 1389-1409. Chapman, V.C., Suzuki, R. and Dickenson, A.H. (1998) Electrophysiological characterization of spinal neuronal response properties in anesthetized rats after ligation of spinal nerves L5-L6. J. Physiol., 507(3): 881-894. Coderre, T.J., Katz, J., Vaccarino, A.L. and Melzack, R. (1993) Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain, 53: 1-27. Coutinho, S.V., Urban, M.O. and Gebhart. G.F. (1999) Role of glutamate receptors and nitric oxide in the rostra1 ventromedial medulla in visceral hyperalgesia. Pain, 78: 59-69. Fields, H.L. and Basbaum, A.I. (1999) Central nervous system mechanisms of pain modulation, In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain, 4th Ed. Churchill Livingstone, Hong Kong, pp. 309-329. Griinroos, M. and Pertovaara, A. (1993) Capsaicin-induced central facilitation of a nociceptive flexion reflex in humans. Neurosci. Left., 159: 215-218. Herrero, J.F. and Cervero, F. (1996) Supraspinal influence on the facilitation of rat nociceptive reflexes induced by carrageenan monoarthritis. Neurosci. L&t., 209: 21-24. Ingram, S.L. (2000) Cellular and molecular mechanisms of opioid action. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain, Progress in Brain Research, Vol. 129. Elsevier Science, Amsterdam, pp. 483-492. Jensen, T.S. and Nikolajsen, L. (2000) Pre-emptive analgesiain postamputation pain: an update. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), In: Nervous Sysrem Plasticity and Chronic Pain, Progress in Brain Research, Vol. 129. Elsevier Science, Amsterdam, pp. 493-503. Kauppila, T. (1997) Spinahzation increases the mechanical stimulation-induced withdrawal reflex threshold after a sciatic cut in the rat. Brain Res., 770: 310-312. Kauppila, T. and Pertovaara, A. (1991) Effects of different sensory and behavioral manipulations on autotomy caused by a sciatic lesion in rats. Enp. Neural., 111: 128- 130. Kauppila, T., Kontinen, V.K. and Pertovaara, A. (1998) Influence of spinalization on spinal withdrawal reflex responses varies depending on the submodality of the test stimulus and the experimental pathophysiological condition in the rat. Brain Res., 797: 234-242.
Kayser, V., Desmeules, J. and Guilbaud, G. (1995) Systemic clonidine differentially modulates the abnormal reactions to mechanical and thermal stimuli in rats with peripheral mononeuropathy. Pain, 60: 275-285. Keski-Vakkuri, U. and Pertovaara, A. (1999) Dependence of onand off-responses to nociceptive neurons of the rostroventromedial medulla. Acfa Physiol. Stand., 165: A32-33. Kim, S.H. and Chung, J.M. (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain, 50: 355-363. Kim, Y.I., Na, H.S., Yoon, Y.W., Han, H.C., Ko, K.H. and Hong, S.K. (1997) NMDA receptors are important for both mechanical and thermal allodynia from peripheral nerve injury in rats. NeuroReport, 8: 2149-2153. Kontinen, V.K., Kauppila, T., Paananen, S., Pertovaara, A. and Kalso, E. (1999) Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy. Pain, 80: 341-346. Lee, Y.W., Chaplan, S.R. and Yaksh, T.L. (1995) Systemic and supraspinal, but not spinal, opiates suppress allodynia in a rat neuropathic pain model. Neurosci. Lett., 199: 11 I- 114. Lee, D.H., Kim, H.T., Chung, K. and Chung, J.M. (1999) Receptor subtype mediating the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats. .I. Neurophysiol., 81: 2226-2233. Leem, J.W., Park, ES. and Paik, K.S. (1995) Electrophysiological evidence for the antinociceptive effect of transcutaneous electrical stimulation on mechanically evoked responsiveness of dorsal horn neurons in neuropathic rats. Neurosci. Lett., 192: 197-200. Leem, J.W., Choi, E.J., Park, E.S. and Paik, KS. (1996) N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists differentially suppress dorsal horn neuron responses to mechanical stimuli in rats with peripheral nerve injury. Neurosci. Lett., 211: 37-40. Lima, D., Almeida, A. and Tavares, I. (1998) The endogenous pain control system: facilitating and inhibitory pathways. In S.N. Ayrapetyan and A.V. Apkarian (Eds.), Pain Mechanisms and Management. 10s Press, Amsterdam, pp. 198-211. Lin, Q., Peng, Y.B. and Willis, W.D. (1997) Possible role of protein kinase C in the sensitization of primate spinothalamic tract neurons. J. Neurosci., 16: 3026-3034. Luukko, M. and Pertovaara, A. (1993) Influence of an experimental peripheral mononeuropathy on the responses of medial bulboreticular neurons to noxious skin stimulation and the modulation of the responses by an alpha-2-adrenoceptor agonist in the rat. Exp. Neural., 124: 390-394. Luukko, M., Konttinen, Y., Kemppinen, P. and Pertovaara, A. (1994) Influence of various experimental parameters on the incidence of thermal and mechanical hyperalgesia induced by a constriction mononeuropathy of the sciatic nerve in lightly anesthetized rats. Exp. Neural., 128: 143-154. Maier, S.F., Wiertelak, E.P. and Watkins, L.R. (1992) Endogenous pain facilitatory systems. Am. Pain Sot. J., 1: 191-198. Malmberg, A. (2000) Protein kinase subtypes involved in injury-induced nociception. In J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plastic@ and Chronic
241
Pain, Progress in Brain Research, Vol. 129. Elsevier Science, Amsterdam, pp. 51-59. Mansikka, H. and Pertovaara, A. (1995) Influence of selective alpha-2-adrenergic agents on mustard oil-induced hyperalgesia in rats. Eur J. Pharmacol., 281: 43-48. Mansikka, H. and Pertovaara, A. (1997) Supraspinal influence on hindlimb withdrawal thresholds and mustard oil-induced secondary allodynia in rats. Brain Res. Bull., 42: 359-365. Mansikka, H., Id&rpl&He&kill, J.J. and Pertovaara, A. (1996) Different roles of alpha-2-adrenoceptors of the medulla versus the spinal cord in modulation of mustard oil- induced hyperalgesia in rats. Eur J. Pharmacol., 291: 19-26. Moore, K.A., Baba. H. and Woolf, C.J. (2000) Synaptic transmission and plasticity in the superficial dorsal horn. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain, Progress in Brain Research, Vol. 129. Elsevier Science, Amsterdam, pp. 63-80. Nichols, M.L., Bian, D., Ossipov, M.H., Lai, J. and Porreca, F. (1995) Regulation of antiallodynic efficacy by CCK in a model of neuropathic pain in rats. J. Pharmacol. Exp. Ther, 275: 1339-1345. Oliveras, J.L., Montagne-Clavel, J. and Martin, G. (1991) Drastic changes of ventromedial medulla neuronal properties induced by barbiturate anesthesia. I. Comparison of the single-unit types in the same awake and pentobarbital-treated rats. Brain Res., 563: 241-250. Panula, P., Kalso, E., Nieminen, M.L., Kontinen, V.K., Brandt, A. and Pertovaara, A. (1999) Neuropeptide FF and modulation of pain, Brain Res. Interact., 848: 191-196. Pertovaara, A. (1993) Antinociception induced by alpha-2adrenoceptor agonists, with special emphasis on medetomidine studies. Prog. Neurobiol., 40: 691-709. Pertovaara, A. (1998) A neuronal correlate of secondary hyperalgesia in the rat spinal dorsal horn is submodality selective and facilitated by supraspinal influence. Exp. Neurol., 149: 193-202. Pertovaara, A. and Kauppila, T. (1989) Effect of chronic sciatic nerve cut on saphenous nerve input to midline bulboreticular formation in the rat. Neurosci. Lett., 105: 68-72. Pertovaara, A. and Wei, H. (2000) Attenuation of ascending nociceptive signals to the rostroventromedial medulla induced by a novel alpha-2-adrenoceptor agonist, MPV-2426, following intrathecal application in neuropathic rats. Anesthesiology, 92: 1082-1092. Pertovaara, A., Wei, H. and HPmll&ren, M.M. (1996) Lidocaine in the rostroventromedial medulla and the periaqueductal gray attenuates allodynia in neuropathic rats. Neurosci. Lett., 218: 127-130. Pertovaara, A., Kontinen, V.K. and Kalso, E.A. (1997) Chronic spinal nerve ligation induces changes in response characteristics of nociceptive spinal dorsal horn neurons and in their descending control originating in the periaqueductal gray in the rat. Exp. Neural., 147: 428-436. Pertovaara, A., Hlmalillinen, M.M., Kauppila, T. and Panula, P. (1998) Carrageenan-induced changes in spinal nociception and its modulation by the brainstem. NemoReport, 9: 351-355. Quevedo, J., Eguibar, J.R., Schmidt, R.F. and Rudomin, P (1993)
Primary afferent depolarization of muscle afferents elicited by stimulation of joint afferents in cats with intact neuraxis and during reversible spinalization. J. Neurophysiol., 70: 18991910. Ren, K. and Dubner, R. (1996) Enhanced descending modulation of nociception in rats with persistent hindpaw inflammation. J Neurophysiol., 16: 3025-3037. Riiyttl, M., Wei, H. and Pertovaara, A. (1999) Spinal nerve ligation-induced neuropathy in the rat: sensory disorders and correlation between histology of the peripheral nerves. Pain, 80: 161-170. Sandktihler, J., Benrath, J., Brechtel, C., Ruscheweyh, R. and Heinke, B. (2000) Synaptic mechanisms of hyperalgesia. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain, Progress in Brain Research, Vol. 129. Elsevier Science, Amsterdam, pp. 8 l- 100. Schaible, H.-G., Neugebauer, V., Cervero, F. and Schmidt, R.F. (1991) Changes in tonic descending inhibition of spinal neurons with articular input during the development of acute arthritis in the cat. J. Neurophysiol., 66: 1021-1032. Stanfa, L.C. and Dickenson, A.H. (1994) Enhanced alpha-2 adrenergic controls and spinal morphine potency in inflammation. NemoReport, 5: 469-472. Sung, B., Na, H.S., Kim, Y.I., Yoon, Y.W., Han, H.C., Nam, S.H. and Hong, S.K. (1998) Supraspinal involvement in the production of mechanical allodynia by spinal nerve injury in rats. Neurosci. Lett., 246: 117-119. Tsuruoka, M. and Willis, W.D. (1996) Descending modulation from the region of the locus coeruleus on nociceptive sensitivity in a rat model of inflammatory hyperalgesia. Brain Res., 743: 86-92. Urban, M.O. and Gebhart, G.F. (1999) Supraspinal contribution to hyperalgesia. Proc. Natl. Acad. Sci. U.S.A., 96: 7687-7692. Urban, M.O., Coutinho, S.V. and Gebhart, G.F. (1999a) Involvement of excitatory amino acid receptors and nitric oxide in the rostra1 ventromedial medulla in modulating secondary hyperalgesia produced by mustard oil. Pain, 81: 45-55. Urban, M.O., Jiang, M.C. and Gebhart, G.F. (1996) Participation of central descending nociceptive facilitatory systems in secondary hyperalgesia. Brain Res., 737: 83-91. Urban, M.O., Zahn, PK. and Gebhart, G.F. (1999b) Descending facilitatory influences from the rostra1 medial medulla mediate secondary, but not primary hyperalgesia in the rat. Neuroscience, 90: 349-352. Wei, H. and Pertovaara, A. (1997) Peripherally administered alpha-2-adrenoceptor agonist in the modulation of chronic allodynia induced by spinal nerve ligation in the rat. Anesth. Analg., 85: 1122-I 127. Wei, H. and Pertovaara, A. (1999a) Influence of preemptive treatment with MK-801, an N-methyl-D-aspartate receptor antagonist, on development of neuropathic symptoms induced by spinal nerve ligation in the rat. Anesthesiology, 91: 3 13-3 16. Wei, H. and Pertovaara, A. (1999b) MK-801, an NMDA receptor antagonist, in the rostroventromedial medulla attenuates development of neuropathic symptoms in the rat. NemoReport, 10: 2933-2937. Wei, H., Panula, P and Pertovaara, A. (1998) A differential
242 modulation of allodynia, hyperalgesia and nociception by neuropeptide FF in the periaqueductal gray of neuropathic rats. Neuroscience, 86: 31 l-319. Xu, M., Kontinen, V.K. and Kalso, E. (1999) Endogenous noradrenergic tone controls symptoms of allodynia in the spinal nerve ligation model of neuropathic pain. Eu,: J. Phannacol., 366: 41-45. Xu, X.J., Puke, M.J.C., Verge, V.M.K., Wiesenfeld-Hallin, Z., Hughes, J. and Hokfelt, T. (1993) Up-regulation of cholecystokinin in primary sensory neurons is associated with mor-
phine insensitivity in experimental neuropathic pain in the rat. Lett., 152: 129-132. Yoon, Y.W., Na, H.S. and Chung, J.M. (1996) Contributions of injured and intact afferents to neuropathic pain in an experimental rat model. Pain, 64: 27-36. Zhuo, M. (2000) Silent glutamatergic synapses and long-term facilitation in spinal dorsal horn neurons. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticiry and Chronic Pain, Progress in Bruin Research, Vol. 129. Elsevier Science, Amsterdam, pp. 101-I 13. Neurosci.
CHAPTER 16
Plasticity in descending pain modulatory systems Antti Pertovaara* Department
of Physiology,
Institute
of Biomedicine,
University
Introduction The development of experimental animal models of neuropathy and other chronic pain conditions has provided the possibility to study cellular mechanisms underlying pathophysiological pain. The studies performed using these models have provided abundant evidence indicating that various pathophysiological conditions may cause dramatic changes in the transmission and modulation of pain-related information. Recently, we performed a series of studies in which we attempted to characterize changes in central transmission of nociceptive information, and, in particular, descending modulation of nociception, in a rat model of experimental neuropathy caused by unilateral ligation of two spinal nerves (Kim and Chung, 1992). This model produces a robust, long-lasting and highly reproducible allodynia and hyperalgesia to mechanical and cooling stimulation (Kim and Chung, 1992; Rijyttg et al., 1999) without causing distress or measurable anxiety to the animals (Kontinen et al., 1999). Also, heat hyperalgesia has been described following spinal nerve ligation in many laboratories (Kim and Chung, 1992). However, in contrast to hypersensitivity to mechanical and cooling stimulation, heat hyperalgesia in this model has been more variable and it has not been observed in all experimental conditions (Bian et al.,
*Corresponding author: A. Pertovaara, Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. Tel.: +358 (40) 760-7123; Fax: +358 (2) 250-2610; E-mail: [email protected]
of Turku,
Kiinamyllynkatu
IO, FIN-20520
Turku,
Finland
1998; Riiyttg et al., 1999). Concomitant with an increased sensitivity to stimuli activating predominantly thick myelinated fibers, spinal nerve ligation causes a marked reduction in the number of myelinated axons innervating the allodynic skin (R6yttti et al., 1999). This paradoxical finding suggests that spinal nerve ligation induces a central amplification, disinhibition of tactile signals, or both. To determine whether findings with the spinal nerve ligation-induced model of neuropathy can be generalized to other pathophysiological conditions, a parallel series of studies on plasticity of central pain transmission and modulation was performed using an acute model of hyperalgesia and allodynia induced by neurogenic inflammation. Role of supraspinal controls It is well-established that brainstem spinal pathways have an important role in the control of spinal nociceptive responses (Fields and Basbaum, 1999). In general, the influence of the brainstem on spinal nociception has been considered to be predominantly inhibitory. However, there is accumulating evidence indicating that brainstem-spinal pathways may not only attenuate pain, but descending controls may also contribute to facilitation or disinhibition of nociceptive signals at the spinal cord level depending on the submodality of test stimulation, pathophysiological condition and the neural pathway (for reviews, see Maier et al., 1992; Lima et al., 1998; Urban and Gebhart, 1999). Studies addressing the role of supraspinal control in the spinal nerve ligation-induced model of neuropathy have shown that a reversible block of the rostroventromedial medulla
232
INTRACEREBRAL
INJECTION
SYSTEMIC
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Fig. 1. Selective attenuation of tactile allodynia following lidocaine-induced block of the RVM or PAG in rats with a spinal nerve ligation-induced neuropathy. (A) Following lidocaine (20 kg) administration in the RVM the hindlimb withdrawal threshold to monofilament stimulation was elevated in the neuropathic side (oper paw), but not in the contralateral side (ctrl paw). Saline (SAL) administration in the RVM had no influence on tactile allodynia. (B) The selective attenuation of tactile allodynia following supraspinal administration of lidocaine was not due to a systemic effect, since systemic administration of lidocaine at the dose of 40 ug had no influence on tactile ahodynia. (C) The antiallodynic effect of lidocaine in the RVM was dose-related. Lidocaine at the dose of 20 ug produced an equipotent antiallodynia following administration in the RVM and the PAG. (D) An antiallodynic dose of lidocaine in the RVM or PAG did not produce any change in the latency of the radiant heat-induced tail-flick in neuropathic animals. The error bars represent S.E.M. (n = 4-7). *P < 0.05 (reference: in A and B, the corresponding pre-injection threshold; in C and D, the saline group). Adapted from Pertovaara et al. (1996).
(RVM) or periaqueductal gray (PAG) by lidocaine selectively attenuate tactile allodynia (Fig. 1; Pertovaara et al., 1996). In line with this, midthoracic spinalization also selectively attenuated tactile allodynia in neuropathic animals (Fig. 2; Bian et al., 1998; Kauppila et al., 1998). These findings, together with similar findings in other models of hypersensitivity (Herrero and Cervero, 1996; Urban et al.,
1996; Kauppila, 1997; Mans&a and Pertovaara, 1997; Pertovaara, 1998; Sung et al., 1998), suggest that a positive feedback loop involving structures rostra1 to the injured segment contributes to mechanical hypersensitivity at the spinal cord level. However, because mechanical hypersensitivity induced by neurogenic inflammation is not completely abolished by spinalization (Pertovaara, 1998), at least
233
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Fig. 2. Effect of spinalization on hindlimb withdrawal reflex response elicited by mechanical stimulation with monofilaments (A) versus radiant heat (B) in rats with no other pathophysiology (CM) and in rats with a spinal nerve ligation-induced neuropathy (Np). Np-ip, neuropathic side; Np-ct, side contralateral to neuropathy; Pre, prior to spinal transection; Post, 10 h after midthoracic transection of the spinal cord. Note a marked elevation of threshold to mechanical stimulation (antiallodynic effect) that is accompanied by a decrease in radiant heat-induced withdrawal latency (hyperalgesic effect) in the neuropathic limb following spinal transection. *P < 0.05 (reference: the corresponding value prior to spinalization; n = 64, #P c 0.05 (reference: the corresponding value in the Ctrl-group). Adapted from Kauppila et al. (1998).
part of the mechanical hypersensitivity observed in spinal dorsal horn neurons is due to spinal segmental mechanisms, which is in line with earlier studies demonstrating central hypersensitivity in spinal preparations (Coderre et al., 1993). In contrast to mechanically evoked responses, heat-evoked responses were enhanced following spinalization (Kauppila et al., 1998), indicating that heat-evoked responses are predominantly under tonic inhibitory controls. The tonic descending inhibition of heat-evoked responses varied depending on the segmental level, being stronger on tail- than limb-evoked responses (Bian et al., 1998; Kauppila et al., 1998), and more distinct in neuropathic than control animals (Fig. 2B; Kauppila et al., 1998). The influence of supraspinal controls on spinal nociception may also vary depending on whether the nociceptive signals originate from the area of primary hyperalgesia (the injured site in which hypersensitivity is predominantly due to peripheral sensitization of nociceptors) or from the area of secondary hyperalgesia (adjacent to the injured site, in which hypersensitivity is mainly due to central mechanisms). That is, brainstem-spinal pathways predominantly facilitate secondary hyperalgesia, but not primary hyperalgesia (Urban et al., 1996, 1999b; Pertovaara, 1998). The complexity of descending modulatory systems is illustrated by the previous findings that at least in some non-neurogenie inflammatory conditions, the descending inhibitory control of ascending nociceptive signals from the inflamed region is enhanced (Schaible et
al., 1991; Ren and Dubner, 1996; Tsuruoka and Willis, 1996). These findings add to the accumulating evidence indicating that various pathophysiological conditions, including experimental neuropathy, may significantly change the brainstem-spinal control of nociceptive signals and that the direction of change may depend on various experimental factors. Dependence of hypersensitivity on maintained injury discharge versus afferent barrage at the time of injury Previous studies indicate that the afferent barrage induced by experimental nerve injury may trigger enhanced pain sensitivity, revealed by the preemptive effect of local lidocaine treatment in some models of neuropathy (e.g. Kauppila and Pertovaara, 1991; Luukko et al., 1994; for a review see Jensen and Nikolajsen, 2000, this volume). The injury discharge may trigger the enhanced responsiveness due to a number of neurochemical changes in the central nervous system and particularly in the spinal dorsal horn; these plastic changes presumably involve an important contribution of N-methyl-D-aspartate (NMDA) receptors (Coderre et al., 1993; see Moore et al., 2000, this volume; Sandktihler et al., 2000, this volume). This is supported in two different spinal nerve ligation-induced models of neuropathy by the finding that a single administration of an NMDA receptor antagonist systemically prior to, but not after, the nerve injury dose-dependently attenuated the
234
(A)
Mechanical
hyperalgesia
Tactile
allodynia
iceiflt---~+~.<~.~.o f ~~~~ dl
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d3
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Fig. 3. An NMDA receptor antagonist, MK-801 (1 kg), in the RVM attenuated development of mechanical hyperalgesia (A) and tactile allodynia (B) for weeks when administered 15 min before (MK-801 pre) but not 25 min after (MK-801 post) ligation of spinal nerves. In A, the y-axis indicates the difference between hindlimb withdrawal thresholds to noxious mechanical stimulation (threshold difference ~0 g indicates hyperalgesia of the operated side). In B, the y-axis indicates the hindlimb withdrawal threshold to monofilament stimulation of the operated side. The error bars represent S.E.M. (n = 8 in each group). dl-3, postoperative days 1-3; w2, postoperative days 12-14. *P < 0.05, ** P < 0.01 vs. corresponding value in the saline group. Adapted from Wei and Pertovaara (199913).
development of neuropathic symptoms for several days (Kim et al., 1997; Wei and Pertovaara, 1999a). Microinjection of a single dose of an NMDA receptor antagonist in the rostroventral medulla (RVM) prior to, but not after, the nerve injury also significantly suppressed the development of neuropathic symptoms for 2 weeks (Fig. 3; Wei and Pertovaara, 1999b), indicating that the preemptive effect induced by systemic NMDA receptor antagonists may in part be due to a supraspinal action. In line with this finding, supraspinal administration of NMDA receptor antagonists as well as a nitric oxide synthase inhibitor attenuated hypersensitivity in other pathophysiological models (Coutinho et al., 1999; Urban et al., 1999a,b). It should be noted that this finding does not exclude a contribution of spinal NMDA receptors in the development and maintenance of hypersensitivity. Antihyperalgesic effects by intrathecal NMDA receptor antagonists demonstrated in various pathophysiological models (Coderre et al., 1993), including the spinal nerve ligation-induced model of neuropathy (Leem et al., 1996), indicate that spinal NMDA receptors also play an important role in the maintenance of hypersensitivity. Moreover, these findings do not exclude a contribution of ectopic discharge originating from peripheral nerves (Lee et al., 1999) as an important factor for the maintenance of neuropathic symptoms. Indeed, the attenuation of neuropathic symptoms by dorsal rhizotomy supports the hypothesis that on-going discharge from peripheral nerves is of importance for the maintenance of
neuropathic symptoms induced by spinal nerve ligation (Yoon et al., 1996). The importance of on-going afferent barrage for maintenance of fully developed central hyperalgesia has also been demonstrated in other experimental models of hypersensitivity. For example, the secondary hyperalgesia induced by neurogenic inflammation is distinctly dependent on on-going activity in peripheral nerve fibers as shown by immediate and reversible abolishment of central hyperalgesia by cold block of the injury discharge (e.g. Gronroos and Pertovaara, 1993). Together, these findings suggest that an afferent barrage at the time of spinal nerve ligation may trigger sensitization of a positive feedback loop involving NMDA receptors in the spinal cord and the brainstem. However, this pronociceptive central circuitry may not alone explain the neuropathic symptoms, and an ongoing ectopic discharge from the injured (and possibly neighboring) peripheral nerves is probably also needed to maintain hyperresponsiveness at the spinal cord level. Behavioral effectiveness of centrally acting analgesic compounds in neuropathy, with particular emphasis on drugs influencing descending controls Spinal nerve ligation produces changes in the potency of several analgesic drugs, including those presumably acting on descending controls. Morphine is known to modulate nociception at different levels
235
of the neuraxis, from the periphery to a number of supraspinal sites, and this includes action on various descending pain modulatory pathways (Fields and Basbaum, 1999; see also Ingram, 2000, this volume). Several behavioral studies indicate that the antinociceptive potency of intrathecal morphine in spinal nerve ligation-induced model of neuropathy is considerably reduced (Bian et al., 1995; Lee et al., 1995), and this may be due to upregulation of cholecystokinin (Xu et al., 1993; Nichols et al., 1995). However, supraspinal and systemic morphine seem to have a strong antinociceptive potency following spinal nerve ligation (Bian et al., 1995; Lee et al., 1995; Wei et al., 1998). Following spinal nerve ligation, naloxone, an opioid receptor antagonist, does not modulate skin sensitivity either in rats with tactile allodynia (Wei et al., 1998) or in asymptomatic animals (Xu et al., 1999). This finding indicates that spinal nerve ligation does not activate tonic (descending or spinal segmental) opioidergic controls that would mask neuropathic symptoms. It is well-established that descending noradrenergic pain modulatory systems attenuate pain due to action on spinal clz-adrenoceptors (for a review, see Pertovaara, 1993). The pain-attenuating effect of systemic cl*-adrenoceptor agonists is markedly enhanced in spinal nerve ligation-induced neuropathy (Wei and Pertovaara, 1997), other models of neuropathy (Kayser et al., 1995) and neurogenic inflammation (Mansikka and Pertovaara, 1995). The enhanced effectiveness of q-adrenergic compounds in various pathophysiological conditions can, at least in part, be explained by mechanisms at the spinal cord level (Stanfa and Dickenson, 1994; Mansikka et al., 1996; Wei and Pertovaara, 1997), whereas supraspinally c12-adrenergic compounds may have, if anything, pronociceptive effects in hyperalgesic animals (Fig. 4A,B; Mansikka et al., 1996). This, however, does not exclude the possibility that peripheral az-adrenoceptors might play a role in some pathophysiological conditions. Paradoxically, an a*-adrenoceptor administered in the lateral reticular nucleus of the caudal ventrolateral medulla, but not in the RVM or spinal cord, produced, in animals with a secondary hyperalgesia, a selective antihyperalgesic effect, suggesting that the facilitatory spinal-brainstem-spinal circuitry may involve clz-adrenoceptors at the medullary level (Fig. 4;
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40
(mid
Fig. 4. Plasticity in the supraspinal az-adrenergic modulation of secondary hyperalgesia/allodynia following mustard oil-induced neurogenic inflammation in the rat. Medetomi dine (MED; an az-adrenoceptor agonist), atipamezole (ATI; an az-adrenoceptor antagonist) or saline (SAL) were microinjetted into the medullary lateral reticular nucleus (LRN) or raphe magnus nucleus (RMG) at time point -12 min. To produce neurogenic inflammation, the ankle of one hindpaw was treated with mustard oil at time point 0 and the hindlimb withdrawal threshold was determined by applying monofilaments to the paw at a site 2 cm outside the border of neurogenic inflammation (a site with secondary hyperalgesia; open symbols) or to the contralateral paw (control; filled symbols). (A) Mustard oil induced, within a few minutes, a marked threshold decrease for about 30-40 min in the treated side and this effect was not influenced by saline in the LRN. (Bi A low dose of medetomidine (1 ug) in the LRN tended to enhance secondary hyperalgesia without influencing thresholds in the control limb. In contrast, following intrathecal administration, this low dose of medetomidine completely reversed the hyperalgesia without influencing nociception in non-inflamed tissue (shown in the original article). (C) Atipamezole (2.5 ug) in the LRN produced a paradoxical antihyperalgesic effect. (D) The effect of atipamezole (2.5 pg) in the RMG on hyperalgesia was not significant. Neither did intrathecal atipamezole (2.5 p.g) influence hyperalgesia (shown in the original article). The error bars represent S.E.M. (n = 4-7 in each group). Adapted from Mans&a et al. (1996).
Mansikka et al., 1996). Interestingly, it was recently shown that an wz-adrenoceptor antagonist alone administered intrathecally could unmask al-
236 lodynia in asymptomatic animals with a spinal nerve ligation, whereas existing allodynia was not modified by an cl*-adrenoceptor antagonist (Xu et al., 1999). This finding suggests that in some conditions, nerve injury may promote the potency of endogenous oz-adrenergic action, possibly including activation of descending noradrenergic pathways, which contributes to attenuation of neuropathic symptoms due to action on spinal c12-adrenoceptors. Neuropeptide FF in the PAG produced a selective attenuation of tactile allodynia in rats with a spinal nerve ligation-induced neuropathy (Wei et al., 1998). Following intrathecal administration neuropeptide FF attenuates pain responses in neuropathic animals as well in non-neuropathic ones (Panula et al., 1999). Thus, neuropeptide FF has a dual action by selectively attenuating descending facilitatory or disinhibitory influence at the brainstem level and by an accompanying more general attenuation of pain responses at the spinal cord level. Moreover, spinal administration of neuropeptide FF has enhanced the potency of descending inhibitory controls following inflammation (Pertovaara et al., 1998) and neuropathy (Wei and Pertovaara, unpublished). These findings suggest that neuropeptide FF may provide possibilities for selective treatment of neuropathic symptoms due to enhancement of descending inhibitory controls at the spinal cord level and due to an accompanying attenuation of descending facilitation or disinhibition at the brainstem level.
Spontaneous IO.01
Response properties and brainstem-spinal control of nociceptive spinal dorsal horn neurons in neuropathic animals Neurophysiological studies in rats with a spinal nerve ligation-induced neuropathy indicate that a characteristic change in the response properties of spinal dorsal horn wide-dynamic range (WDR) neurons, which are considered to have an important role for pain, is their increased spontaneous activity (Fig. 5A; Pertovaara et al., 1997; Chapman et al., 1998). This may reflect injury-induced ectopic discharge in primary afferent neurons (Lee et al., 1999). Also, an increase in responsivity of spinal dorsal horn WDR neurons to mechanical stimulation has been observed in some (Leem et al., 1995, 1996; Pertovaara et al., 1997) but not all (Chapman et al., 1998) investigations. The responses of spinal WDR neurons to noxious heat have been almost identical with those in non-neuropathic animals (Pertovaara et al., 1997; Chapman et al., 1998). In line with behavioral findings, spinalization or reversible block of the RVM by lidocaine selectively attenuated the enhanced mechanically evoked responses to spinal dorsal horn WDR neurons in animals with neurogenic inflammation (Fig. 6; Pertovaara, 1998), indicating that descending brainstem-spinal pathways contribute to mechanical hyperresponsiveness. The noxious heat-evoked responses to spinal dorsal horn WDR neurons from non-neuropathic skin were markedly attenuated by electrical stimulation of the PAG, whereas the inhibitory effect of PAG-stimulation on heat-evoked responses from the neuropathic
Attenuation of heatevoked responses by PAG stimulation
activity *
1501
Fig. 5. Response characteristics of spinal dorsal horn WDR neurons following spinal nerve ligation-induced neuropathy in the rat. (A) Spontaneous activity ipsilateral to the spinal nerve ligation (Np-ip), contralateral to the spinal nerve ligation (Np-ct) and in unoperated control animals (Ctrl). (B) Effect of electrical stimulation of the PAG on noxious heat-evoked responses from the hindpaw ipsilateral (Np-ip) or contralateral (Np-ct) to the spinal nerve ligation. 100% = the response prior to PAG stimulation. *P < 0.05, **P i 0.01 (reference: Ctrl group in A, the corresponding response without PAG stimulation in B). Adapted from Pertovaara et al. (1997).
237
(4
Heat Mech. Adjacent
SPINAL
Mech. Remote
50 ‘a WDR
46g WDR
4.5 LTM
TRANSECTION
300 -**7 250 t
1
M.O.
+LIDO-RVM
M.O.
+LIDO-RVM
Fig. 6. Response characteristics and supraspinal modulation of spinal dorsal horn neuron responses following mustard oil-induced neurogenic inflammation in rats. (A) Mustard oil (M.O.) applied adjacent to the receptive fields of WDR neurons did not enhance their responses to noxious heat, whereas responses to noxious mechanical stimuli were significantly enhanced. Mustard oil in a remote site (forepaw) did not enhance mechanically evoked responses. (B) Mustard oil adjacent to the receptive field of spinal pain (WDR) neurons produced an equal enhancement of mechanically evoked responses both to low (4 g) and high (46 g) intensity stimuli, whereas responses to spinal dorsal horn mechanoreceptive (LTM) neurons were not influenced. (C) Following spinal transection, mustard oil applied adjacent to the receptive field produced a significant hyperexcitability to mechanical stimuli in WDR neurons that was significantly weaker than that in rats with an intact spinal cord (compare with graph A) and not attenuated by lidocaine (40 ug) in the RVM, rostra1 to the spinal transection. (D) Lidocaine (LIDO; 40 pg) in the RVM significantly attenuated mustard oil-induced hyperexcitability in rats with an intact spinal cord. 100% = the response prior to application of mustard oil. *P < 0.05, **P < 0.01, ***P < 0.005, (reference: the corresponding response prior to mustard oil.) Ns, non-significant. Adapted from Pertovaara (1998).
skin was reduced (Fig. 5B; Pertovaara et al., 1997). This finding resembles the reduction of descending inhibition from the PAG described in animals with neurogenic inflammation (Lin et al., 1997) and it indicates that neuropathy and neurogenic inflammation may significantly attenuate phasic inhibitory controls originating in the midbrain. Response properties of nociceptive medullary neurons presumably involved in descending controls in neuropathic animals At the brainstem level, the RVM is a site that has an important role in modulation of spinal nocicep-
tive signals (Fields and Basbaum, 1999). The RVM neurons can be classified into three main groups: (1) On-cells that fire prior to a nocifensive reflex; (2) Off-cells that pause prior to a nocifensive reflex; and (3) neutral cells that have no nociception-related response (Fields and Basbaum, 1999). According to our recent results, On- or Off-type RVM neurons did not express any marked submodality dependence in their responsivity to noxious heat versus noxious mechanical stimulation in inflammatory or neuropathic conditions (Keski-Vakkuri and Pertovaara, 1999). It was expected that the selective attenuation of mechanical hypersensitivity observed in behavioral studies following spinal transection or lidocaine
238
block of the RVM (Pertovaara et al., 1996; Kauppila et al., 1998) was due to submodality-dependent response properties of RVM neurons. Moreover, following spinal nerve ligation-induced neuropathy, spontaneous activity or evoked responses to noxious mechanical and heat stimulation in nociceptive On-type neurons of the RVM were not significantly changed (Pertovaara and Wei, 2000). This finding suggests that the response properties of nociceptive On-type neurons in the RVM may not explain the hypersensitivity induced by spinal nerve ligation. This result is in line with that observed in another model of neuropathy, the chronic constriction injury of the sciatic nerve (Luukko and Pertovaara, 1993). In contrast, a sciatic transection caused an enhancement of excitatory responses to nociceptive RVM neurons from the hypersensitive skin area adjacent to the denervated area (Pertovaara and Kauppila, 1989). Moreover, the hyperalgesia induced by opioid-abstinence has been correlated with enhanced responsivity of On-type neurons of the RVM (Fields and Basbaum, 1999). Thus, a change in response properties of nociceptive On-neurons in the RVM may contribute to facilitation of spinal reflexes in models of central hyperalgesia induced by opioid-abstinence or transection of the sciatic nerve, but their role in the spinal nerve ligation-induced model of neuropathy is less evident. Since the response properties of On-type RVM neurons (and possibly also Off-type neurons) do not correspond with behavioral changes induced by spinal nerve ligation, the contribution of the RVM to behavioral hypersensitivity in this neuropathy model could be due to a change in discharge properties of other types of RVM neurons (neutral neurons), due to a change in synchronization of descending signals between RVM neurons, or due to a change in synaptic efficacy of spinal terminals of the RVM neurons. The reduced inhibitory effect of PAG stimulation at the spinal cord level under neuropathic conditions (Pertovaara et al., 1997) is in line with the latter hypothesis, since the RVM is an important relay between the PAG and the spinal dorsal horn (Fields and Basbaum, 1999). The response properties of RVM neurons in neuropathic animals have been characterized only after the development of neuropathic symptoms. However, the role of RVM neurons during development and maintenance of neuropathic symptoms may dif-
fer. Evidence for this possibility is the finding that a single administration of an NMDA receptor antagonist in the RVM prior to nerve injury, but not after the injury, attenuated development of neuropathic symptoms for several days (Fig. 3; Wei and Pertovaara, 1999b). This result raises the possibility that the afferent barrage at the time of nerve injury, via activation of a pronociceptive circuitry involving the RVM, causes long-lasting changes in the synaptic efficacy of the spinal terminals of RVM neurons. According to this proposal, a discharge rate of RVM neurons, that is within the same range as in control conditions, could be enough to produce enhanced spinal (facilitatory) actions following development of neuropathy. This hypothesis is compatible with the two seemingly paradoxical findings observed in fully developed neuropathy: lack of marked changes in response properties of nociceptive RVM neurons (Keski-Vakkuri and Pertovaara, 1999; Pertovaara and Wei, 2000) and the attenuation of hyperresponsiveness at the spinal cord level following lidocaine block of the RVM or spinal transection (e.g. Pertovaara et al., 1996; Kauppila et al., 1998). Furthermore, neurophysiological studies are performed under general anesthesia, whereas behavioral studies are performed in awake animals, and this may provide a confounding factor when comparing behavioral findings with electrophysiological results. This caveat applies especially to recordings of supraspinal neuron responses that are known to be sensitive to anesthetic agents (Oliveras et al., 199 1). Possible spinal actions of descending influence Brainstem-spinal pathways may modulate spinal sensory responses due to an action that is pre- or postsynaptic to the spinal dorsal horn neuron, or both, and these influences may involve a number of spinal segmental interneurons. There is previous evidence indicating that following spinalization presynaptic inhibition of A-fiber input to the spinal dorsal horn is enhanced (Quevedo et al., 1993) whereas presynaptic inhibition of C-fiber input is attenuated (Calvillo et al., 1982). Since mechanically evoked responses are predominantly, although not exclusively, mediated by A-fibers and heat-evoked responses by C-fibers, this dissociative effect of supraspinal controls on presynaptic inputs into the spinal cord might
239
provide a mechanism contributing to submodalitydependent descending control of nociceptive input to the spinal cord. This hypothesis is further supported by the finding that spinalization and lidocaine block of the RVM selectively attenuated mechanically evoked responses of spinal dorsal WDR neurons, whereas heat-evoked responses of the same neurons were not attenuated in animals with a mechanical hyperresponsiveness induced by neurogenic inflammation (Fig. 6; Pertovaara, 1998). This electrophysiological finding is in line with the hypothesis that the supraspinal facilitatory influence was due to a selective action presynaptic to the spinal dorsal horn WDR neuron. In addition to excitatory amino acids and in particular their action on NMDA receptors, there are many other neurochemical mediators potentially contributing to descending facilitatory or disinhibitory effects at the spinal cord level. For example, there is evidence indicating that serotonin released from descending axons may lead to unmasking of silent synapses (Zhuo, 2000, this volume). Also, protein kinase C in postsynaptic spinal dorsal horn neurons has an important role in spinal hypersensitivity and attenuation of descending inhibitory effects (Lin et al., 1997; Malmberg, 2000, this volume). The differential descending control of physiological and pathophysiological sensory input to the spinal cord is likely to reflect corresponding differences in neurochemistry. A better understanding of these complex pronociceptive changes may provide possibilities to develop more selective treatments of pathophysiological pain.
injured and possibly neighboring peripheral nerves may be required for the maintenance of hyperalgesia and pain. The analgesic efficacy of various drugs, including those acting on descending controls, is also changed by this model of neuropathy. Neurophysiological studies have revealed increased spontaneous activity and enhanced mechanical responsiveness in the presumed spinal pain-relay neurons. Importantly, spinal nerve ligation may induce significant changes in descending control of spinal nociception as indicated by selective attenuation of mechanical hypersensitivity by blockade of brainstem-spinal pathways. Moreover, phasic descending inhibition of heat-evoked responses is reduced in neuropathic animals. These findings in neuropathic animals, and similar observations in animals with neurogenic inflammation, indicate that nerve injury or neurogenic inflammation may produce selective plastic changes in the brainstem-spinal control of pain. These central changes in endogenous pain control mechanisms may explain, although not fully, some of the neuropathic symptoms. The selectivity of this pathophysiological plasticity in descending controls and its underlying neurochemisty may provide possibilities to develop treatments that attenuate neuropathic symptoms without influencing physiological pain responses. The selective antiallodynia by supraspinally administered neuropeptide FF and enhancement of descending inhibitory controls by spinally administered neuropeptide FF provides just one example demonstrating that this therapeutic approach is, at least experimentally, applicable and deserves to be studied further.
Conclusions
Abbreviations
The spinal nerve ligation-induced model of neuropathy (Kim and Chung, 1992) has proved a highly useful model for investigation of mechanisms underlying neuropathic pain. The nerve ligation produces a number of changes in pain transmission and modulation pathways that may contribute to neuropathic symptoms. The injury discharge at the time of surgery appears to trigger central mechanisms involving glutamatergic NMDA receptors in the brainstem as well as in the spinal cord that contribute to the development and maintenance of hyperalgesia. Additionally, an on-going ectopic discharge from the
NMDA receptor PAG RVM WDR neuron
N-methyl-D-aspartate receptor periaqueductal gray rostroventromedial medulla wide-dynamic range neuron
Acknowledgements The author wishes to thank Drs. H. Wei, T. Kauppila, M.M. H;im&iinen, H. Mansikka, U. Keski-Vakkuri, M. Luukko, P Panula, V.K. Kontinen and E. Mecke for their contributions to the series of studies described. The author’s work was supported by the
240 Academy of Finland, TEKES, and Sigrid JusClius Foundation, Helsinki, Finland. References Bian, D., Nichols, M., Ossipov, M.H., Lai, J. and Porreca, F. (1995) Characterization of the antiallodynic efficacy of morphine in a model of neuropathic pain in rats. NeuroReporr, 6: 1981-1984. Bian, D., Ossipov, M.H., Malan Jr., T.P. and Porreca, F. (1998) Tactile allodynia, but not thermal hyperalgesia, of the hindlimbs is blocked by spinal transection in rats with nerve injury. Neurosci. Let?., 241: 19-82. Calvillo, O., Madrid, J. and Rudomin, P. (1982) Presynaptic depolarization of unmyelinated primary afferent fibers in the spinal cord of the cat. Neuroscience, 7: 1389-1409. Chapman, V.C., Suzuki, R. and Dickenson, A.H. (1998) Electrophysiological characterization of spinal neuronal response properties in anesthetized rats after ligation of spinal nerves L5-L6. J. Physiol., 507(3): 881-894. Coderre, T.J., Katz, J., Vaccarino, A.L. and Melzack, R. (1993) Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain, 53: 1-27. Coutinho, S.V., Urban, M.O. and Gebhart. G.F. (1999) Role of glutamate receptors and nitric oxide in the rostra1 ventromedial medulla in visceral hyperalgesia. Pain, 78: 59-69. Fields, H.L. and Basbaum, A.I. (1999) Central nervous system mechanisms of pain modulation, In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain, 4th Ed. Churchill Livingstone, Hong Kong, pp. 309-329. Griinroos, M. and Pertovaara, A. (1993) Capsaicin-induced central facilitation of a nociceptive flexion reflex in humans. Neurosci. Left., 159: 215-218. Herrero, J.F. and Cervero, F. (1996) Supraspinal influence on the facilitation of rat nociceptive reflexes induced by carrageenan monoarthritis. Neurosci. L&t., 209: 21-24. Ingram, S.L. (2000) Cellular and molecular mechanisms of opioid action. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain, Progress in Brain Research, Vol. 129. Elsevier Science, Amsterdam, pp. 483-492. Jensen, T.S. and Nikolajsen, L. (2000) Pre-emptive analgesiain postamputation pain: an update. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), In: Nervous Sysrem Plasticity and Chronic Pain, Progress in Brain Research, Vol. 129. Elsevier Science, Amsterdam, pp. 493-503. Kauppila, T. (1997) Spinahzation increases the mechanical stimulation-induced withdrawal reflex threshold after a sciatic cut in the rat. Brain Res., 770: 310-312. Kauppila, T. and Pertovaara, A. (1991) Effects of different sensory and behavioral manipulations on autotomy caused by a sciatic lesion in rats. Enp. Neural., 111: 128- 130. Kauppila, T., Kontinen, V.K. and Pertovaara, A. (1998) Influence of spinalization on spinal withdrawal reflex responses varies depending on the submodality of the test stimulus and the experimental pathophysiological condition in the rat. Brain Res., 797: 234-242.
Kayser, V., Desmeules, J. and Guilbaud, G. (1995) Systemic clonidine differentially modulates the abnormal reactions to mechanical and thermal stimuli in rats with peripheral mononeuropathy. Pain, 60: 275-285. Keski-Vakkuri, U. and Pertovaara, A. (1999) Dependence of onand off-responses to nociceptive neurons of the rostroventromedial medulla. Acfa Physiol. Stand., 165: A32-33. Kim, S.H. and Chung, J.M. (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain, 50: 355-363. Kim, Y.I., Na, H.S., Yoon, Y.W., Han, H.C., Ko, K.H. and Hong, S.K. (1997) NMDA receptors are important for both mechanical and thermal allodynia from peripheral nerve injury in rats. NeuroReport, 8: 2149-2153. Kontinen, V.K., Kauppila, T., Paananen, S., Pertovaara, A. and Kalso, E. (1999) Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy. Pain, 80: 341-346. Lee, Y.W., Chaplan, S.R. and Yaksh, T.L. (1995) Systemic and supraspinal, but not spinal, opiates suppress allodynia in a rat neuropathic pain model. Neurosci. Lett., 199: 11 I- 114. Lee, D.H., Kim, H.T., Chung, K. and Chung, J.M. (1999) Receptor subtype mediating the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats. .I. Neurophysiol., 81: 2226-2233. Leem, J.W., Park, ES. and Paik, K.S. (1995) Electrophysiological evidence for the antinociceptive effect of transcutaneous electrical stimulation on mechanically evoked responsiveness of dorsal horn neurons in neuropathic rats. Neurosci. Lett., 192: 197-200. Leem, J.W., Choi, E.J., Park, E.S. and Paik, KS. (1996) N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists differentially suppress dorsal horn neuron responses to mechanical stimuli in rats with peripheral nerve injury. Neurosci. Lett., 211: 37-40. Lima, D., Almeida, A. and Tavares, I. (1998) The endogenous pain control system: facilitating and inhibitory pathways. In S.N. Ayrapetyan and A.V. Apkarian (Eds.), Pain Mechanisms and Management. 10s Press, Amsterdam, pp. 198-211. Lin, Q., Peng, Y.B. and Willis, W.D. (1997) Possible role of protein kinase C in the sensitization of primate spinothalamic tract neurons. J. Neurosci., 16: 3026-3034. Luukko, M. and Pertovaara, A. (1993) Influence of an experimental peripheral mononeuropathy on the responses of medial bulboreticular neurons to noxious skin stimulation and the modulation of the responses by an alpha-2-adrenoceptor agonist in the rat. Exp. Neural., 124: 390-394. Luukko, M., Konttinen, Y., Kemppinen, P. and Pertovaara, A. (1994) Influence of various experimental parameters on the incidence of thermal and mechanical hyperalgesia induced by a constriction mononeuropathy of the sciatic nerve in lightly anesthetized rats. Exp. Neural., 128: 143-154. Maier, S.F., Wiertelak, E.P. and Watkins, L.R. (1992) Endogenous pain facilitatory systems. Am. Pain Sot. J., 1: 191-198. Malmberg, A. (2000) Protein kinase subtypes involved in injury-induced nociception. In J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plastic@ and Chronic
241
Pain, Progress in Brain Research, Vol. 129. Elsevier Science, Amsterdam, pp. 51-59. Mansikka, H. and Pertovaara, A. (1995) Influence of selective alpha-2-adrenergic agents on mustard oil-induced hyperalgesia in rats. Eur J. Pharmacol., 281: 43-48. Mansikka, H. and Pertovaara, A. (1997) Supraspinal influence on hindlimb withdrawal thresholds and mustard oil-induced secondary allodynia in rats. Brain Res. Bull., 42: 359-365. Mansikka, H., Id&rpl&He&kill, J.J. and Pertovaara, A. (1996) Different roles of alpha-2-adrenoceptors of the medulla versus the spinal cord in modulation of mustard oil- induced hyperalgesia in rats. Eur J. Pharmacol., 291: 19-26. Moore, K.A., Baba. H. and Woolf, C.J. (2000) Synaptic transmission and plasticity in the superficial dorsal horn. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain, Progress in Brain Research, Vol. 129. Elsevier Science, Amsterdam, pp. 63-80. Nichols, M.L., Bian, D., Ossipov, M.H., Lai, J. and Porreca, F. (1995) Regulation of antiallodynic efficacy by CCK in a model of neuropathic pain in rats. J. Pharmacol. Exp. Ther, 275: 1339-1345. Oliveras, J.L., Montagne-Clavel, J. and Martin, G. (1991) Drastic changes of ventromedial medulla neuronal properties induced by barbiturate anesthesia. I. Comparison of the single-unit types in the same awake and pentobarbital-treated rats. Brain Res., 563: 241-250. Panula, P., Kalso, E., Nieminen, M.L., Kontinen, V.K., Brandt, A. and Pertovaara, A. (1999) Neuropeptide FF and modulation of pain, Brain Res. Interact., 848: 191-196. Pertovaara, A. (1993) Antinociception induced by alpha-2adrenoceptor agonists, with special emphasis on medetomidine studies. Prog. Neurobiol., 40: 691-709. Pertovaara, A. (1998) A neuronal correlate of secondary hyperalgesia in the rat spinal dorsal horn is submodality selective and facilitated by supraspinal influence. Exp. Neurol., 149: 193-202. Pertovaara, A. and Kauppila, T. (1989) Effect of chronic sciatic nerve cut on saphenous nerve input to midline bulboreticular formation in the rat. Neurosci. Lett., 105: 68-72. Pertovaara, A. and Wei, H. (2000) Attenuation of ascending nociceptive signals to the rostroventromedial medulla induced by a novel alpha-2-adrenoceptor agonist, MPV-2426, following intrathecal application in neuropathic rats. Anesthesiology, 92: 1082-1092. Pertovaara, A., Wei, H. and HPmll&ren, M.M. (1996) Lidocaine in the rostroventromedial medulla and the periaqueductal gray attenuates allodynia in neuropathic rats. Neurosci. Lett., 218: 127-130. Pertovaara, A., Kontinen, V.K. and Kalso, E.A. (1997) Chronic spinal nerve ligation induces changes in response characteristics of nociceptive spinal dorsal horn neurons and in their descending control originating in the periaqueductal gray in the rat. Exp. Neural., 147: 428-436. Pertovaara, A., Hlmalillinen, M.M., Kauppila, T. and Panula, P. (1998) Carrageenan-induced changes in spinal nociception and its modulation by the brainstem. NemoReport, 9: 351-355. Quevedo, J., Eguibar, J.R., Schmidt, R.F. and Rudomin, P (1993)
Primary afferent depolarization of muscle afferents elicited by stimulation of joint afferents in cats with intact neuraxis and during reversible spinalization. J. Neurophysiol., 70: 18991910. Ren, K. and Dubner, R. (1996) Enhanced descending modulation of nociception in rats with persistent hindpaw inflammation. J Neurophysiol., 16: 3025-3037. Riiyttl, M., Wei, H. and Pertovaara, A. (1999) Spinal nerve ligation-induced neuropathy in the rat: sensory disorders and correlation between histology of the peripheral nerves. Pain, 80: 161-170. Sandktihler, J., Benrath, J., Brechtel, C., Ruscheweyh, R. and Heinke, B. (2000) Synaptic mechanisms of hyperalgesia. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain, Progress in Brain Research, Vol. 129. Elsevier Science, Amsterdam, pp. 8 l- 100. Schaible, H.-G., Neugebauer, V., Cervero, F. and Schmidt, R.F. (1991) Changes in tonic descending inhibition of spinal neurons with articular input during the development of acute arthritis in the cat. J. Neurophysiol., 66: 1021-1032. Stanfa, L.C. and Dickenson, A.H. (1994) Enhanced alpha-2 adrenergic controls and spinal morphine potency in inflammation. NemoReport, 5: 469-472. Sung, B., Na, H.S., Kim, Y.I., Yoon, Y.W., Han, H.C., Nam, S.H. and Hong, S.K. (1998) Supraspinal involvement in the production of mechanical allodynia by spinal nerve injury in rats. Neurosci. Lett., 246: 117-119. Tsuruoka, M. and Willis, W.D. (1996) Descending modulation from the region of the locus coeruleus on nociceptive sensitivity in a rat model of inflammatory hyperalgesia. Brain Res., 743: 86-92. Urban, M.O. and Gebhart, G.F. (1999) Supraspinal contribution to hyperalgesia. Proc. Natl. Acad. Sci. U.S.A., 96: 7687-7692. Urban, M.O., Coutinho, S.V. and Gebhart, G.F. (1999a) Involvement of excitatory amino acid receptors and nitric oxide in the rostra1 ventromedial medulla in modulating secondary hyperalgesia produced by mustard oil. Pain, 81: 45-55. Urban, M.O., Jiang, M.C. and Gebhart, G.F. (1996) Participation of central descending nociceptive facilitatory systems in secondary hyperalgesia. Brain Res., 737: 83-91. Urban, M.O., Zahn, PK. and Gebhart, G.F. (1999b) Descending facilitatory influences from the rostra1 medial medulla mediate secondary, but not primary hyperalgesia in the rat. Neuroscience, 90: 349-352. Wei, H. and Pertovaara, A. (1997) Peripherally administered alpha-2-adrenoceptor agonist in the modulation of chronic allodynia induced by spinal nerve ligation in the rat. Anesth. Analg., 85: 1122-I 127. Wei, H. and Pertovaara, A. (1999a) Influence of preemptive treatment with MK-801, an N-methyl-D-aspartate receptor antagonist, on development of neuropathic symptoms induced by spinal nerve ligation in the rat. Anesthesiology, 91: 3 13-3 16. Wei, H. and Pertovaara, A. (1999b) MK-801, an NMDA receptor antagonist, in the rostroventromedial medulla attenuates development of neuropathic symptoms in the rat. NemoReport, 10: 2933-2937. Wei, H., Panula, P and Pertovaara, A. (1998) A differential
242 modulation of allodynia, hyperalgesia and nociception by neuropeptide FF in the periaqueductal gray of neuropathic rats. Neuroscience, 86: 31 l-319. Xu, M., Kontinen, V.K. and Kalso, E. (1999) Endogenous noradrenergic tone controls symptoms of allodynia in the spinal nerve ligation model of neuropathic pain. Eu,: J. Phannacol., 366: 41-45. Xu, X.J., Puke, M.J.C., Verge, V.M.K., Wiesenfeld-Hallin, Z., Hughes, J. and Hokfelt, T. (1993) Up-regulation of cholecystokinin in primary sensory neurons is associated with mor-
phine insensitivity in experimental neuropathic pain in the rat. Lett., 152: 129-132. Yoon, Y.W., Na, H.S. and Chung, J.M. (1996) Contributions of injured and intact afferents to neuropathic pain in an experimental rat model. Pain, 64: 27-36. Zhuo, M. (2000) Silent glutamatergic synapses and long-term facilitation in spinal dorsal horn neurons. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticiry and Chronic Pain, Progress in Bruin Research, Vol. 129. Elsevier Science, Amsterdam, pp. 101-I 13. Neurosci.