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Evidence for ε-opioid receptor-mediated β-endorphin-induced analgesia
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Evidence for ε-opioid receptormediated β-endorphin-induced analgesia Leon F. Tseng Among the opioid receptors, which have been pharmacologically classified as µ, δ, κ and ε, the existence of the ε receptor has been controversial, and this receptor is generally not recognized as a member of the opioid peptide receptor family because it has not been precisely characterized. However, results from pharmacological, physiological and opioid receptor binding studies clearly indicate the presence of ε-opioid receptors, which are distinct from µ-, δ- or κ-opioid receptors. This putative ε-opioid receptor is stimulated supraspinally by the endogenous opioid peptide β-endorphin, which induces the release of Met-enkephalin, which, in turn, acts on spinal δ2-opioid receptors to produce antinociception. In this article, this β-endorphin-sensitive ε-opioid receptormediated descending pain control system, which is distinct from that activated by the µ-opioid receptor agonist morphine, is described and the physiological role of the β-endorphin-mediated system in pain control activated by coldwater swimming and intraplantar injection of formalin is discussed.
The multiplicity of opioid receptors, µ, δ, κ and ε, is mirrored physiologically by a multiplicity of endogenous opioid ligands: endomorphin-1 and endomorphin-2 act on µ-opioid receptors, enkephalins act on δ-opioid receptors, dynorphin-A1–17 acts on κ-opioid receptors, and β-endorphin acts on ε-opioid receptors1–3. The classical opiate morphine, which is isolated from the capsule of the poppy plant Papaver somniferum, shows a preference for µ-opioid receptors, but also binds with low affinity to δ- and κ-opioid receptors. Synthetic opioid agonists and antagonists for µ-, δ- and κ-opioid receptors with considerable selectivity are now available (Table 1). However, selective agonists and antagonists with specificity for ε-opioid receptors have not been developed. Role of ε-opioid receptors in antinociception induced by β-endorphin given supraspinally, but not spinally
Leon F. Tseng Dept of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. e-mail: [email protected]
β-Endorphin is an endogenous opioid peptide in the brain, which produces antinociception when injected into the brain in humans and a variety of species of animals2. β-Endorphin has been reported in both in vitro and in vivo studies to be a nonselective opioid receptor agonist, and binds to or stimulates ε-, µ-, δand κ-opioid receptors with different potencies and affinities1–4. Although β-endorphin is expected to stimulate any of these opioid receptors nonselectively, producing a variety of opioid pharmacological responses, a degree of selectivity for opioid receptor activities has been identified, depending on the pharmacological responses observed and the sites of injection of β-endorphin. For example, the http://tips.trends.com
bulbospinal pain control system activated by β-endorphin administered supraspinally to produce antinociception is mediated solely by the stimulation of the putative ε-opioid receptors2,3. This view is supported by results obtained using the tail-flick test; antinociception induced by β-endorphin given intracerebroventricularly (i.c.v.) in mice was not blocked by pretreatment with the µ-opioid receptor antagonists CTOP (D-Phe-Cys-Tyr-D-Try-Orn-ThrPen-Thr-NH2) or β-funaltrexamine (β-FNA), the δ-opioid receptor antagonists naltrindole or ICI174864 or the κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI). The same treatments with these µ-, δ- and κ-opioid receptor antagonists effectively block antinociception induced by the µ-opioid agonists morphine or DAMGO (D-Ala2,NMePhe4,Gly-ol5), the δ-opioid agonist deltorphin II and the κ-opioid agonist U50488H, respectively2. Furthermore, pretreatment with a ventricular combination of the µ-, δ- and κ-opioid antagonists β-FNA, naltrindole and nor-BNI still fails to block the antinociception induced by i.c.v.-administered β-endorphin (L.F. Tseng, unpublished). By contrast, β-endorphin-induced antinociception is blocked by pretreatment with i.c.v.administered β-endorphin1–27, which in this case is defined as a putative ε-opioid receptor antagonist because this same treatment with β-endorphin1–27 does not block antinociception induced by µ-, δ- or κ-opioid receptor agonists2,3. It is therefore concluded that the supraspinal antinociception induced by β-endorphin is mediated by the stimulation of putative ε-opioid receptors, but not µ-, δ- or κ-opioid receptors. β-Endorphin given intrathecally also produces antinociception in different species of animals5,6. However, antinociception induced by β-endorphin given spinally is mediated by the stimulation of κ- and µ-opioid receptors and not ε- or δ-opioid receptors, because such antinociception is blocked by pretreatment with the κ-opioid receptor antagonists nor-BNI or WIN44441 or the µ-opioid receptor antagonist CTOP, but not by either the ε-opioid antagonist β-endorphin1–27 or the δ-opioid receptor antagonists naltrindole or ICI174864 (Ref. 5). In studies using a place-preference paradigm, Bals-Kubik et al.7 reported that the reinforcing effects of β-endorphin are blocked by β-endorphin1–27, CTOP
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Table 1. Opioid receptors and their endogenous ligands, exogenous opioid agonists and exogenous opioid antagonistsa Opioid receptors Endogenous ligands Epsilon (ε) Mu (µ)
β-Endorphin, β-endorphin1–27 Endomorphin-1, endomorphin-2
Delta (δ)
Met-enkephalin
Kappa (κ)
Dynorphin A1–17
Opioid agonists
Opioid antagonists
Etorphine, bremazocine Morphine, etorphine, DAMGO, pentazocine (D-Ala2)deltorphin II (δ2), DPDPE (δ1), (–) TAN67 (δ1) U50488H (κ1), naloxone benzoyl hydrazone(κ3), bremazocine, pentazocine
β-Endorphin1–27 β-FNA, CTOP Naltrindole (δ1, δ2), naltriben (δ2), BNTX (δ1), TIPP4 (δ1) Nor-BNI
aAbbreviations: BNTX, 7-benzylidene naltrexamine; CTOP, D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH ; DAMGO, [D-Ala2, NMePhe4, Gly-ol5] 2 enkephalin; DPDPE, (D-Pen2,5) enkephalin; β-FNA, β-funaltrexamine; Nor-BNI, nor-binaltorphimine; TIPP4, H-Tyr-Tic-Phe-Phe-OH.
and ICI171864, indicating that these effects involve the activation of ε-, µ- and δ-opioid receptors. Furthermore, feeding elicited by ventricular β-endorphin is preferentially reduced by either selective µ-opioid receptor antagonists or antisense oligodenoxynucleotides (ODNs) directed against the Oprm clone8. In this review, this distinctive ε-opioid receptor-mediated pain control system that is pharmacologically activated by β-endorphin from supraspinal sites to produce antinociception is described and compared with that activated by the µ-opioid receptor agonist morphine. In addition, the physiological roles of the β-endorphin-mediated system in pain control activated by cold-water swimming and intraplantar injection of formalin are also described. Localization of ε-opioid receptors
Herz et al.9 were the first to report the unique ε-opioid receptor activity elicited by β-endorphin in the rat vas deferens. Subsequently, others have reported the characterization of the ε-opioid receptor in the brain and other tissues1–3. Indeed, receptor binding studies employing [3H]β-endorphin and [3H]ethylketocyclazocine provide biochemical evidence supporting the presence of ε-opioid receptors in the brain1. Using autoradiography of [3H]β-endorphin binding in the rat brain, Goodman et al.10 concluded that the pattern of [3H]β-endorphin labeling appears unique, consistent with the proposal of central ε-opioid receptors. However, unlike µ-, δand κ-opioid receptors, which have been much more precisely characterized and cloned and expressed11, the ε-opioid receptor has not been well characterized and has not been cloned. Two main factors have hindered the progress of the characterization of ε-opioid receptors: (1) selective ε-opioid receptor agonists and antagonists have not been developed; and (2) unlike other opioid receptors, a specific role for this receptor in functions other than analgesia has not been identified. Comparison of β-endorphin- and morphine-induced antinociception Absence of cross-tolerance
Supraspinal β-endorphin and morphine in mice fail to develop antinociceptive cross-tolerance. Thus, acute http://tips.trends.com
pretreatment of mice with ventricular morphine for three hours attenuates the antinociception induced by morphine, but not by β-endorphin. Similarly, pretreatment of mice with β-endorphin for two hours, which attenuates the antinociception induced by β-endorphin, does not affect the antinociception induced by morphine12. Furthermore, mice rendered tolerant to morphine by subcutaneous implantation with a morphine pellet for three days do not exhibit significant cross-tolerance to β-endorphin13. Differing brain sites at which β-endorphin and morphine produce antinociception
Using the intracerebral microinjection technique, the rat brain sites that are sensitive to β-endorphin and morphine for producing antinociception have been shown to be essentially different, although some overlap can be found. In brainstem regions, the sites most sensitive to β-endorphin for producing antinociception with the tail-flick test are located in the caudal medial medulla, such as the raphe obscurus, the raphe pallidus and the adjacent midline reticular formation3,14. By contrast, the medullary sites most sensitive to morphine for producing antinociception are located in areas of the rostral ventromedial medulla (RVM), such as the raphe magnus nucleus, gigantocellular nucleus and gigantocellular reticular nucleus α (Ref. 14). The locus coeruleus is a pontine site sensitive to both β-endorphin and morphine for producing antinociception14. In midbrain regions, microinjection of either β-endorphin or morphine into the ventrolateral periaqueductal gray (vlPAG) inhibits the tail-flick response. In forebrain regions, the sites most sensitive to β-endorphin for producing antinociception are located in ventromedial regions, such as the medial posterior nucleus accumbens, medial preoptic area and arcuate hypothalamic nucleus15 and ventrolateral regions such as the amygdala16. The sites sensitive to morphine for producing antinociception are located in regions of the medial preoptic nucleus, amygdala and arcuate hypothalamic nucleus, but not the nucleus accumbens3,15–17. The differential distributions of brain sites sensitive to β-endorphin and morphine for producing antinociception provide strong evidence to
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support the hypothesis that the antinociceptive effects induced by β-endorphin and morphine are mediated by different neural mechanisms. The opioid receptor antagonist naloxone, administered into the PAG, is much more effective in antagonizing the antinociception induced by morphine than β-endorphin injected into the PAG. By contrast, β-endorphin1–27 administered into the PAG effectively attenuates the antinociception induced by β-endorphin, but not morphine, injected into the PAG (Refs 2,3). Smith et al.18 demonstrated that multiple receptors are involved in the antinociceptive response to either β-endorphin or morphine microinjected into the PAG. The multiple receptors for β-endorphin present in the PAG are discriminated by virtue of the shallow, multiphasic dose–inhibition curves generated with the opioid receptor antagonist CTP (D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2). Some of the PAG receptors involved in antinociception are specific for β-endorphin because doses of CTP that block ~80% of the effect of the peptide do not affect the antinociception produced by an equi-effective dose of morphine. Moreover, in contrast to its ability to antagonize morphine, naltrexone fails to inhibit the entire response to β-endorphin. Both acetylcholine receptor antagonists and NMDA receptor antagonists administered into the RVM block morphine-induced antinociception elicited from the vlPAG, but fail to alter β-endorphin-induced antinociception elicited from the vlPAG (Refs 17,19). Both morphine and β-endorphin given into either the basolateral or central nuclei of the amygdala also produce antinociception in the tail-flick test. Pretreatment with naltrexone in the vlPAG reduces the antinociception induced by morphine and β-endorphin injected into the amygdala, which indicates that an opioid synapse in the PAG is essential for producing the antinociception elicited from the amygdala. However, pretreatment with the µ-opioid receptor antagonist β-FNA or the δ2-opioid receptor antagonist naltrindole isothiocyanate in the PAG significantly attenuates the antinociception induced by morphine, but not that induced by β-endorphin injected into the amygdala16,17. The synergistic antinociceptive interactions observed between the amygdala and vlPAG for subthreshold doses of morphine or β-endorphin applied to both sites fail to occur when morphine is applied to the amygdala, and β-endorphin is applied to the vlPAG, presumably because β-endorphin is activating a different neurochemical circuit within the vlPAG than does morphine16,17. Different bulbospinal pain control systems
The bulbospinal pain control model for morphineinduced antinociception, originally proposed by Basbaum and Fields, includes the midbrain PAG, brainstem RVM (particularly the nucleus raphe magnus and adjacent reticular nuclei) and the spinal http://tips.trends.com
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dorsal horn20. The antinociception induced by morphine microinjected into the PAG results from the activation of the excitatory connection between the PAG and the medullary raphe nuclei. The raphe neurons, in turn, project via a pathway in the dorsal part of the lateral funiculus of the spinal cord to the region of termination of the nociceptive primary afferent fibers in the spinal dorsal horn20. In addition, the dorsolateral pontomesencephalic tegmentum (DLPT) also plays a crucial role in the pain-modulating actions of the PAG and RVM. The DLPT includes all of the noradrenaline-containing neurons that project to the RVM and spinal cord. Proudfit and co-workers21 have clearly demonstrated that the descending noradrenaline-mediated systems are engaged from the PAG and RVM through the locus coeruleus, the A5 noradrenaline-containing group and, to a lesser degree, the A7 noradrenaline-containing groups in mediating morphine-induced antinociception. However, the exact neuronal circuitry of the bulbospinal pain control system for β-endorphin-induced antinociception is not completely clear at this time. The bulbospinal pain control systems activated by supraspinal β-endorphin and morphine involve different descending neural pathways, which use a variety of neurotransmitters and receptors in the spinal cord. Supraspinal β-endorphin-induced antinociception is mediated by the neuronal release of Met-enkephalin, which acts on δ2-opioid receptors in the spinal cord2,3. β-Endorphin, but not morphine, given supraspinally selectively releases Met-enkephalin, but not dynorphin, from the spinal cord22. Inhibition of the degradation of Met-enkephalin with bestatin and thiorphan increases the release of Met-enkephalin and potentiates the antinociception induced by supraspinally administered β-endorphin23,24. Furthermore, pretreatment with a rabbit antiserum against Met-enkephalin, which binds extracellular Met-enkephalin, attenuates β-endorphin-induced antinociception2. The opioid receptor in the spinal cord that is stimulated by the released Met-enkephalin has been identified as δ2-, and not δ1- or µ-, opioid receptors2,3,25. Intrathecal pretreatment with an antisense ODN against mRNA for the δ-opioid receptor to reduce the number of δ-opioid receptors in the spinal cord attenuates the antinociception induced by supraspinally administered β-endorphin26. These findings support the view that Met-enkephalin release and δ2-opioid receptors in the spinal cord are involved in supraspinal β-endorphin-induced antinociception. By contrast, the antinociception produced by supraspinal morphine is mediated by spinopetal 5-HTand noradrenaline-mediated systems, which stimulate 5-HT-receptors and α2-adrenoceptors, respectively, in the spinal cord2,3. Morphine given intraventricularly induces the release of noradrenaline in addition to 5-HT, but not Met-enkephalin, from the spinal cord2,3. The antinociception induced by supraspinal morphine
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is enhanced by desipramine and fluoxetine administered spinally, which inhibit the reuptake of noradrenaline and 5-HT, respectively24, and is attenuated by pretreatment with DSP4 or 6-hydroxydopamine and 5,7-dihydroxytryptamine spinally, which cause the degeneration of the noradrenaline- and 5-HT-containing fibers, respectively2. Intrathecal treatment with the selective α2-adrenoceptor antagonist yohimbine and the 5-HT receptor antagonist methysergide, but not naloxone, blocks the antinociception induced by morphine given supraspinally, which indicates that α2-adrenoceptors and 5-HT-receptors, but not opioid receptors, in the spinal cord are involved in morphine-induced antinociception2,3. Differential modulation of supraspinal β-endorphin- and morphine-induced antinociception Sulfated cholecystokinin octapeptide (CCK-8s)
The endogenous cholecystokinin neuropeptide CCK-8s functions as a selective antagonist of opioid-induced antinociception, at both spinal and supraspinal levels27. Briefly, CCK-8s administered spinally potently antagonizes antinociception induced by spinal administration of morphine in the tail-flick test, whereas acute administration of the CCK1 receptor antagonists proglumide and lorglumide enhance spinal morphine-induced antinociception27,28, an effect that is blocked or reversed by chronic treatment with CCK receptor antagonists28. The inhibition of the thermal hyperalgesia induced by intrathecal morphine in the paw withdrawal test is enhanced by intrathecal pretreatment with the CCK2 receptor antagonist PD135158 in sciatic nerve injured rats29. Similarly, intrathecal pretreatment with proglumide or the selective CCK2 receptor antagonist L365260 enhances intrathecally administered morphine-induced antinociception in a model of visceral pain in the rat30. These observations, together with the coincident distribution of CCK with enkephalins and endomorphins in the dorsal horn of the spinal cord, suggest the possibility of a modulatory interaction between opioid-induced antinociception and CCK activity. It has been postulated that morphine modulates its own antinociceptive activity by increasing CCK release in the spinal cord, and indeed Zou et al.31 have demonstrated that morphine administration increases the release of CCK in the spinal cord. CCK in the spinal cord also appears to be involved in modulating the descending pain control system activated by β-endorphin administered supraspinally. Intrathecal administration of CCK-8s in mice selectively antagonizes the antinociception induced by supraspinally administered β-endorphin, but not that induced by supraspinally administered morphine or DAMGO (Ref. 32). The attenuating effect of CCK-8s on supraspinal β-endorphin-induced antinociception is mediated by the stimulation of CCK receptors in the spinal cord because spinal http://tips.trends.com
pretreatment with the CCK1 receptor antagonist L364718 or the CCK2 receptor antagonist L365260 reverses the effect caused by CCK-8s. By contrast, blockade of CCK receptors in the spinal cord by intrathecal injection of the CCK1 receptor antagonists proglumide or L364718 enhances the antinociception induced by supraspinally administered β-endorphin32. Hawranko et al.33 reported that rats exposed to repeated hot-plate stress exhibit stressinduced analgesia, but reduced antinociception in response to the administration of β-endorphin into the PAG. These alterations are prevented by the intrathecal treatment with the CCK2 receptor antagonist L365260. Thus, CCK might modulate opioid-mediated effects through a feedback mechanism, so that the presence of an opioid such as Met-enkephalin triggers the release of endogenous CCK, thereby returning the animal to a state of baseline sensitivity. Intraventricular injection of β-endorphin releases Met-enkephalin and also CCK from the spinal cord34. The released CCK might in turn antagonize the β-endorphin-induced antinociception either by antagonizing the δ-opioid receptor activity, which is stimulated by the released Met-enkephalin, or by inhibiting the release of Met-enkephalin from the spinal cord35. Rady et al.36 reported that CCK given intrathecally antagonizes the antinociception induced by the δ2-opioid agonist DSLET {[D-Ser2]Leu-enkephalin-Thr6}, but not that induced by the δ1-opioid agonist DPDPE [(D-Pen2,5)enkephalin]. Furthermore, Suh et al.35 demonstrated that CCK-8s added to spinal perfusates attenuates the spinal release of Met-enkephalin induced by supraspinally administered β-endorphin. Thus, CCK-8s and its receptors in the spinal cord play a negative feedback role in modulating the antinociception induced by β-endorphin injected supraspinally and the antinociception induced by morphine given spinally, but not supraspinally. GABA
Because the primary actions of opioids are inhibitory, it has been proposed that opioids can activate the descending pain control system by disinhibiting inhibitory GABA-containing neurons, which, in turn, results in the activation of excitatory neurons. The pharmacological actions of pentobarbital are mediated by potentiation or mimicry of the effects of GABA (Ref. 37). Pentobarbital anesthesia attenuates the antinociception induced by morphine, but not by β-endorphin, given supraspinally in the rat and mouse38,39. Indeed, Smith et al.40 reported that pentobarbital anesthesia in rats caused a marked increase in the antinociceptive potency of β-endorphin microinjected into the PAG of the rat, whereas the antinociceptive response to microinjection of morphine into the PAG was markedly attenuated during pentobarbital anesthesia. Stimulation of GABAB receptors at supraspinal sites by baclofen attenuates supraspinally
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administered β-endorphin-, but not morphine-, induced antinociception. However, activation of GABAA receptors by muscimol given supraspinally attenuates both supraspinally administered β-endorphin- and morphine-induced antinociception41. The blockade of GABAA receptors in the spinal cord by intrathecal injection of SR95531, a selective GABAA receptor antagonist, attenuates the antinociception induced by morphine, but not by β-endorphin, given supraspinally. By contrast, blockade of GABAB receptors in the spinal cord by 5-aminovaleric acid given spinally attenuates the analgesia induced by β-endorphin, but not by morphine, given supraspinally42. These results indicate that spinal GABAA and supraspinal GABAB receptors differentially modulate antinociception induced by supraspinally administered morphine and β-endorphin, and provides additional evidence that morphine and β-endorphin antinociception are mediated by the activation of different pain control systems.
NO–cGMP in the spinal cord also differentially modulates antinociception induced by supraspinally administered morphine and β-endorphin. The antinociception induced by morphine given supraspinally is potentiated by spinal administration of the NO synthase inhibitor Nω-nitro-L-arginine, hemoglobin (which binds NO) or the cGMP inhibitor methylene blue, but is attenuated by spinal administration of L-arginine or 3-morpholinosydnonimine. By contrast, antinociception induced by β-endorphin given supraspinally is attenuated by spinally administered Nω-nitro-L-arginine, hemoglobin or methylene blue. However, pretreatment with L-arginine spinally does not affect supraspinal β-endorphin-induced antinociception. Thus, inhibition of the spinal cord NO–cGMP system potentiates the antinociceptive effect of morphine but attenuates β-endorphin-induced antinociception. Conversely, activation of the spinal cord NO–cGMP system attenuates morphine-, but not β-endorphin-, induced antinociception47.
Glutamate
β-Endorphin-mediated system is involved in analgesia induced by cold-water swimming
Recent studies have demonstrated that NMDA and non-NMDA glutamate receptors are involved in the production of antinociception, and indeed microinjection of NMDA or glutamate into the nucleus raphe magnus or PAG produces antinociception in rats43. NMDA and non-NMDA receptors at supraspinal sites play different roles in β-endorphin- and morphine-induced antinociception in mice. Blockade of NMDA or non-NMDA receptors by i.c.v. administration of MK801, a non-competitive NMDA antagonist, or CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), a competitive non-NMDA receptor antagonist, attenuates the antinociception induced by morphine, but not by β-endorphin, given supraspinally. The blockade of NMDA receptors by either competitive or non-competitive NMDA receptor antagonists administered into the RVM blocks morphine-, but not β-endorphin-, induced antinociception following injection into the vlPAG (Ref. 44). Nitric-oxide–cGMP
Nitric oxide (NO) has been proposed to act as a biological messenger in the CNS. NO, derived from L-arginine by the action of NO synthase, binds and activates soluble guanylyl cyclase, producing an increase in the concentration of cGMP, which can then act through protein kinases, phosphodiesterases or directly on ion channels45. Activation of the NO–cGMP system at supraspinal sites differentially modulates β-endorphin- and morphine-induced antinociception in mice. Increased production of NO from L-arginine or increased release of NO by the NO donors 3-morpholino-sydnonimine or sodium nitroprusside given supraspinally potentiate β-endorphin-, but not morphine-, induced antinociception46. http://tips.trends.com
There is a striking similarity between β-endorphininduced analgesia and the analgesia induced by continuous cold-water swimming (CWS) in a 2°C ice-water bath. Early studies by Bodnar et al.48 demonstrated that CWS produces analgesia that is neither cross-tolerant with morphine nor reversed by naloxone. Like β-endorphin-induced analgesia, the analgesia induced by CWS shows many dissociations from that of morphine-induced analgesia so that a model of collateral inhibition has been proposed between these two forms of analgesia (i.e. blockade of one system would potentiate the other system)49. The CWS-induced analgesia presented simultaneously with morphine-induced analgesia results in a diminished combined analgesic response, which is time-, dose- and temperature-dependent. This CWSinduced analgesia has been proposed to be mediated by the activation of endogenous opioid systems selectively at δ2-opioid receptors at supraspinal sites50 and by multiple spinal opioid receptors51. The β-endorphin-mediated system has been suggested to be involved in the analgesia induced by CWS. Such a system involves the release of β-endorphin acting on putative ε-opioid receptors at supraspinal sites and the release of Met-enkephalin acting on δ2-opioid receptors at the spinal sites to produce analgesia. This view is supported by the finding that CWS-induced analgesia is blocked selectively by supraspinal pretreatment with an antiserum against β-endorphin and by spinal pretreatment with an antiserum against Met-enkephalin3. CWS-induced analgesia is blocked by the δ2-receptor antagonists naltrindole or naltriben, but not by the δ1-opioid receptor antagonist BNTX, the µ-opioid receptor antagonist CTOP or the κ-opioid receptor antagonist nor-BNI given spinally3,52.
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Furthermore, intrathecal pretreatment with an antisense ODN against the mRNA for the δ-opioid receptor to reduce the number of δ-opioid receptors in the spinal cord attenuates CWS-induced analgesia53. These findings support the view that CWS releases β-endorphin at supraspinal sites and subsequently releases Met-enkephalin, which acts on δ2-opioid receptors in the spinal cord to produce analgesia. Activation of the β-endorphin-mediated system modulates formalin-induced nociception
Acknowledgements I thank James M. Fujimoto for the reading and suggestions of this manuscript. This work is supported by NIH Grant DA03811and NIH Grant DA12588.
Intraplantar injection of a diluted solution of formalin causes nociceptive licking in the mouse and flinching in the rat, which closely resembles human clinical pain. These nociceptive responses to formalin appear in two phases: an initial period of acute nociceptive behavior lasting from the time of injection for 10 min and a second tonic phase occurring 15 min after injection and lasting 50–60 min (Ref. 54). The initial acute phase might represent the direct stimulation of nociceptors, whereas the second phase might represent an enhanced response of the sensitized central neurons resulting from low-level neuronal input following a peripheral inflammatory insult54. This peripheral inflammatory process elicits marked increases in β-endorphin-like immunoreactivity in the ventral PAG and other brain regions that are important in pain control55, and also increases the release of β-endorphin in the arcuate nucleus56. Furthermore, pretreatment with an antiserum against β-endorphin or with the ε-receptor antagonist β-endorphin1–27 markedly enhances the antinociceptive response to formalin57. Hamba58 reported that rats display increased behavioral responses to formalin injection after lesions of the arcuate nucleus of the hypothalamus, the main site of β-endorphin-producing cells in the CNS. These findings strongly indicate that formalin-induced stimulation activates the central β-endorphinmediated system and induces the release of β-endorphin, which, in turn, inhibits the nociceptive response. Because the first phase of the nociceptive response to formalin stimulation is not affected by pretreatment with the β-endorphin antiserum, the central β-endorphin-mediated system is probably not tonically active under normal circumstances, but is stimulated initially by formalin during the first phase of the nociceptive response. Pertussis-toxin-resistant β-endorphin-mediated antinociception
Pretreatment of mice or rats with pertussis toxin (PTX), a protein isolated from the culture medium of
References 1 Nock, B. (1995) κ and ε Opioid receptor binding. In The Pharmacology of Opioid Peptides (Tseng, L.F., ed.), pp. 29–56, Harwood Academic Publishers GMBH 2 Tseng, L.F. (1995) Mechanisms of β-endorphininduced antinociception. In The Pharmacology of Opioid Peptides (Tseng, L.F., ed.), pp. 249–269, Harwood Academic Publishers GMBH http://tips.trends.com
Bordetella pertussis, either supraspinally or spinally, attenuates antinociceptive and other effects induced by morphine and other µ-opioid receptor agonists3. Similarly, antinociception induced by the selective δ-opioid agonist deltorphin II or by the κ-opioid agonist U50488H is attenuated by pretreatment with PTX (Ref. 3) because these opioid receptors are Gi–Go-coupled receptors, which are inhibited by treatment with PTX. However, the antinociception induced by β-endorphin given supraspinally in mice is not affected by pretreatment with PTX supraspinally, but is effectively attenuated by pretreatment with PTX spinally59. This observation is consistent with the notion that β-endorphin-induced antinociception is mediated by the stimulation of non-µ-, non-δ-, non-κ-opioid receptors at supraspinal sites and by δ-opioid receptors at spinal sites. Interestingly, the CWS-induced analgesia is also not affected by pretreatment with PTX supraspinally, but is markedly attenuated by pretreatment with PTX spinally60. These findings provide additional evidence that putative ε-opioid receptors, which are distinct from µ, δ and κ receptors, mediate β-endorphin-mediated analgesia. Concluding remarks
Evidence obtained from studies of β-endorphininduced antinociception clearly supports the notion that there is a putative ε-opioid receptor that is distinct from µ-, δ and κ-opioid receptors. These putative ε-opioid receptors stimulated by β-endorphin are not Gi–Go-protein-coupled receptors because the supraspinal β-endorphin-induced antinociception is resistant to pretreatment with PTX supraspinally. β-Endorphin administered supraspinally activates these putative ε-opioid receptors at supraspinal sites and subsequently induces the release of Met-enkephalin that acts on δ2-opioid receptors in the spinal cord to produce antinociception. CCK, GABA, glutamate and NO–cGMP in the spinal cord differentially modulate β-endorphin- and morphineinduced antinociception. Environmentally induced stress, such as CWS or formalin injection, also activates the β-endorphin-mediated system and presumably uses the same or a similar descending pain control pathway for producing analgesia. The core issues for the progress of ε-opioid receptor research in the future depend on: (1) the successful development of selective ε-opioid receptor agonists and antagonists that can be used to characterize ε-opioid receptors; and (2) the successful cloning and expression of these ε-opioid receptors.
3 Narita, M. and Tseng, L.F. (1998) Evidence for the existence of the β-endorphin-sensitive ‘ε-opioid receptor’ in the brain: the mechanisms of ε-mediated antinociception. Jpn. J. Pharmacol. 76, 233–253 4 Shook, J.E. et al. (1988) Opioid receptor selectivity of β-endorphin in vitro and in vivo: µ, δ, and ε receptors. J. Pharmacol. Exp. Ther. 246, 1018–1025
5 Tseng, L.F. and Collins, K.A. (1992) The inhibition of the tail-flick response induced by β-endorphin administered intrathecally is mediated by the activation of κ- and µ-opioid receptors in the mouse. Eur. J. Pharmacol. 214, 59–65 6 Yaksh, T.L. and Henry, J.L. (1978) Antinociceptive effects of intrathecally administered human β-endorphin in the rat and cat. Can. J. Physiol. Pharmacol. 56, 754–759
Review
7 Herz, A. and Spanagel, R. (1995) Endogenous opioids and addiction. In The Pharmacology of Opioid Peptides (Tseng, L.F., ed.), pp. 445–462, Harwood Academic Publishers GMBH 8 Silva, R.M. et al. (2001) β-Endorphin-induced feeding: pharmacological characterization using selective opioid antagonists and antisense probes in rats. J. Pharmacol. Exp. Ther. 297, 590–596 9 Schulz, R. et al. (1981) pharmacological characterization of the ε-opiate receptor. J. Pharmacol. Exp. Ther. 216, 604–606 10 Goodman, R.R. et al. (1983) Autoradiography of [3H]β-endorphin binding in brain. Brain Res. 288, 334–337 11 Miotto, K. et al. (1995) Molecular characterization of opioid receptors. In The Pharmacology of Opioid Peptides (Tseng, L.F., ed.), pp. 57–71, Harwood Academic Publishers GMBH 12 Suh, H.H. and Tseng, L.F. (1990) Lack of antinociceptive cross-tolerance between intracerebroventricularly administered β-endorphin and morphine or DPDPE in mice. Life Sci. 46, 759–765 13 Tseng, L.F. et al. (1993) Partial antinociceptive cross-tolerance to intracerebroventricular β-endorphin in mice tolerant to systemic morphine. Eur. J. Pharmacol. 241, 63–70 14 Tseng, L.F. et al. (1990) Brainstem sites differentially sensitive to β-endorphin and morphine for analgesia and the release of Met-enkephalin in anesthetized rats J. Pharmacol. Exp. Ther. 253, 930–937 15 Tseng, L.F. and Wang, Q. (1992) Forebrain sites differentially sensitive to β-endorphin and morphine for analgesia and release of Metenkephalin in the pentobarbital-anesthetized rat. J. Pharmacol. Exp. Ther. 261, 1028–1036 16 Pavlovic, Z.W. and Bodnar, R.J. (1998) Opioid supraspinal analgesic synergy between the amygdala and periaqueductal gray in rats. Brain Res. 779, 158–169 17 Bodnar, R.J. (2000) Supraspinal circuitry mediating opioid antinociception: antagonist and synergy in multiple sites. J. Biomed. Sci. 7, 177–180 18 Monroe, P.J. et al. (1996) Biochemical and pharmacological characterization of multiple β-endorphinergic antinociceptive systems in the rat periaqueductal gray. J. Pharmacol. Exp. Ther. 276, 65–73 19 Spinella, M. et al. (1999) Actions of NMDA and cholinergic receptor antagonists in the rostral ventromedial medulla upon β-endorphin analgesia elicited from the ventrolateral periaqueductal gray. Brain Res. 829, 151–159 20 Basbaum, A.I. and Fields, H.L. (1984) Endogenous pain control systems: brainstem spinal pathways and endogenous circuitry. Annu. Rev. Neurosci. 7, 309–338 21 Proudfit, H.K. (1988) Pharmacologic evidence for the modulation of noradrenergic neurons. In Progress in Brain Research (Vol. 77) (Fields, H.L. and Besson, J.M., eds), pp. 357–370, Elsevier Science 22 Tseng, L.F. et al. (1985) Release of immunoreactive Met-enkephalin from the spinal cord by intraventricular β-endorphin but not morphine in anesthetized rats. Brain Res. 343, 60–69 23 Suh, H.H. and Tseng, L.F. (1990) Intrathecal administration of thiorphan and bestatin enhances the antinociception and release of Met-enkephalin induced by β-endorphin injected http://tips.trends.com
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intraventricularly in anesthetized rats. Neuropeptides 16, 91–96 Suh, H.H. and Tseng, L.F. (1990) Intrathecal thiorphan, bestatin, desipramine and fluoxetine differentially potentiate the antinociceptive effects induced by β-endorphin and morphine administered intracerebroventricularly. Neuropharmacology 29, 207–214 Tseng, L.F. et al. (1993) Spinal δ2 but not δ1 opioid receptors are involved in intracerebroventricular β-endorphin-induced antinociception in the mouse. Life Sci. 52, L211–L215 Tseng, L.F. and Collins, K.A. (1994) Antisense oligodeoxynucleotide to a δ-opioid receptor given intrathecally blocks i.c.v. administered β-endorphin-induced antinociception in the mouse. Life Sci. 55, PL127–PL131 Faris, P.L. et al. (1983) Evidence for neuropeptide cholecystokinin as an antagonist of opiate analgesia. Science 219, 310–312 Kellstein, D.E. and Mayer, D.J. (1990) Chronic administration of cholecystokinin antagonists reverses the enhancement of spinal morphine analgesia induced by acute pretreatment. Brain Res. 516, 263–270 Yamamoto, T. and Sakashita, Y. (1999) Differential effects of intrathecally administered morphine and its interaction with cholecystokinin-B antagonist on thermal hyperalgesia following two models of experimental mononeuropathy in the rat. Anesthesiology 90, 1382–1391 Friedrich, A.F. and Gebhart, G.F. (2000) Effects of spinal cholecystokinin receptor antagonists on morphine antinociception in a model of visceral pain in the rat. J. Pharmacol. Exp. Ther. 292, 538–544 Zhou, Y. et al. (1994) Increased release of immunoreactive cholecystokinin octapeptide by morphine and potentiation of µ-opioid analgesia by CCKB receptor antagonist L-365,260 in the rat spinal cord. Eur. J. Pharmacol. 234, 147–154 Tseng, L.F. and Collins, K.A. (1992) Cholecystokinin administered intrathecally selectively antagonizes intracerebroventricular β-endorphin-induced antinociception in mice. J. Pharmacol. Exp. Ther. 260, 1086–1092 Hawranko, A.A. (1999) Anti-analgesia and reduced antinociception from supraspinally administered β-endorphin in stressed rats: dependence on spinal cholecystokinin via cholecystokinin B receptors. Neurosci. Lett. 267, 101–104 Tseng, L.F. and Huang, F.Y. (1992) β-Endorphin administered intraventricularly releases immunoreactive cholecystokinin and Met-enkephalin from the spinal cord in the pentobarbital anesthetized rat. Eur. J. Pharmacol. 215, 309–312 Suh, H.H. et al. (1992) Intrathecal cholecystokinin octapeptide attenuates the antinociception and release of immunoreactive Met-enkephalin induced by intraventricular β-endorphin in the rat. Neuropeptides. 21, 131–137 Rady, J.J. et al. (1998) Antianalgesic action of dynorphin A mediated by spinal cholecystokinin. Soc. Exp. Biol. Med. 220, 178–183 Macdonald, R.L. and McLean, M.J. (1987) Mechanisms of anticonvulsant drug action. Electroencephalogr. Clin. Neurophysiol. (Suppl.) 39, 200–208 Ossipov, M.H. and Gebhart, G.F. (1984) Light pentobarbital anesthesia diminishes the
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antinociceptive potency of morphine administered intracranially but not intrathecally in the rat. Eur. J. Pharmacol. 97, 137–140 Tseng, L.F. and Tang, R. (1992) Pentobarbital anesthesia attenuates inhibition of the tail-flick response induced by morphine but not β-endorphin administered intracerebroventricularly in the mouse. Eur. J. Pharmacol. 214, 175–180 Smith, D.J. et al. (1992) Antinociception from the administration of β-endorphin into the periaqueductal gray of rat is enhanced while that of morphine is inhibited by barbiturate anesthesia. Neurosci. Lett. 146, 143–146 Suh, H.W. et al. (1995) Differential modulation by muscimol and baclofen on antinociception induced by morphine, β-endorphin, D-Pen2,5enkephalin and U50,488H administered intracerebroventricularly in the mouse. NaunynSchmiedeberg’s Arch. Pharmacol. 352, 614–619 Suh, H.W. et al. (1996) Effects of GABA receptor antagonists injected spinally on antinociception induced by opioids administered supraspinally in mice. Eur. J. Pharmacol. 307, 141–147 Jensen, T.S. and Yaksh, T.L. (1992) The antinociceptive activity of excitatory amino acids in the rat brainstem: an anatomical and pharmacological analysis. Brain Res. 569, 255–267 Suh, H.W. et al. (1995) Non-NMDA receptor antagonist attenuates antinociception induced by morphine but not β-endorphin, D-Pen2-D-Pen5enkephalin, and U50,488H administered intracerebroventricularly in mice. Neuropeptides 28, 125–129 Moncada, S. et al. (1991) Nitric oxide: physiology, physiopathology, and pharmacology. Pharmacol. Rev. 43, 109–142 Xu, J.Y. and Tseng, L.F. (1993) Increase of nitric oxide by L-arginine potentiates β-endorphin- but not µ-, δ-, or κ-opioid agonist-induced antinociception in the mouse. Eur. J. Pharmacol. 236, 137–142 Xu, J.Y. and Tseng, L.F. (1995) Nitric oxide/cyclic guanosine monophosphate system in the spinal cord differentially modulates intracerebroventricularly administered morphine- and β-endorphin-induced antinociception in the mouse. J. Pharmacol. Exp. Ther. 274, 8–16 Bodnar, R.J. (1990) Effects of opioid peptides on peripheral stimulation and ‘stress’-induced analgesia in animals. Crit. Rev. Neurobiol. 6, 39–48 Kirchgressner, A.L. et al. (1982) Naloxazone and pain-inhibitory systems: evidence for a collateral inhibition model. Pharmacol. Biochem. Behav. 17, 1175–1179 Vanderah, T.W. et al. (1992) Mediation of swimstress antinociception by the opioid delta2 receptor in the mouse. J. Pharmacol. Exp. Ther. 262, 190–197 Watkins, L.R. et al. (1992) Parallel activation of multiple spinal opiate systems appears to mediate ‘non-opiate’ stress-induced analgesia. Brain Res. 594, 99–108 Mizoguchi, H. et al. (1997) [Met5]enkephalin and δ2-opioid receptors in the spinal cord is involved in the cold water swimming-induced antinociception in the mouse. Life Sci. 61, PL81–PL86 Mizoguchi, H. et al. (1995) Antisense oligodeoxynucleotide to a δ-opioid receptor blocks
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the antinociception induced by cold water swimming. Regul. Pept. 59, 255–259 Dubner, R. and Ren, K. (1999) Assessing transient and persistent pain in animals. In Textbook of Pain (Wall, P.D. and Melzack, R., eds), pp. 359–369, Churchill Livingstone Porro, C.A. et al. (1991) Central β-endorphin system involvement in the reaction to acute tonic pain. Exp. Brain Res. 83, 549–554 Zangen, A. et al. (1998) Nociceptive stimulus induces release of endogenous β-endorphin in the rat brain. Neuroscience 85, 659–662 Wu, H. et al. (2001) Antisera against endogenous opioids increase the nocifensive response to formalin:demonstration of inhibitory β-endorphinergic control. Eur. J. Pharmacol. 421, 39–43 Hamba, M. (1988) Effects of lesion and stimulation of rats hypothalamic arcuate nucleus on the pain system. Brain Res. Bull. 21, 757–763
59 Tseng, L.F. and Collins, K.A. (1996) Pretreatment with pertussis toxin differentially modulates morphine- and β-endorphin-induced antinociception in the mouse. J. Pharmacol. Exp. Ther. 279, 39–46
60 Mizoguchi, H. et al. (1996) Pretreatment with pertussis toxin spinally but not supraspinally attenuates cold water swimming-induced antinociception in the mouse. Eur. J. Pharmacol. 309, 37–40
Chemical names DSP4: N-(2-chloroethyl)-N-ethyl2-bromobenzylamine hydrochloride ICI171864: N,N-diallyl-Tyr-Aib-Aib-Phe-Leu L364718 (devazepide): 1-methyl-3-(2-indoloyl)amino5-phenyl-3H-1,4-benzodiazepine-2-one L365260: 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5phenyl-1H-1,4-benzodiazepin-3-yl)-N ′-(3-methylphenyl)urea PD135158: 4-{[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2[[[1.7.7-trimethyl-bicylclo[2.2.2]hept-2-yloxy]carbonyl] amino]propyl]amino]-1 phenylethyl]amino-4-oxo[1S-1α.2β[S*(S*)]4α]}-butanoate N-methyl-D-glucamine
SR95531: 2-(3-carboxypropy)-3-amino-6(4-methoxyphenyl)pyridazinium bromide (-)TAN67: 2-methyl-4aα-(3-hydroxyphenyl)1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,3g]isoquinoline U50488H: trans(±)-3,4-dichloro-N-methyl-N-[2-(1pyrrolidinyl)cyclohexyl]benzene-acetamide methane sulfonate WIN44441: (−)-1-cyclopentyl-5-(1,2,3,4,5,6hexahydro-8-hydroxy-3,6,11-trimethyl-2,6,methano3-benzazocine-11-yl)-3-pentanone methanesulfonoate
Cerebrovascular structure and dementia: new drug targets Jeffrey Atkinson Effective pharmacological treatment of cognitive disorders in dementia is lacking despite extensive efforts to produce active therapy aimed at neuronal and vascular targets. In this review, the evidence for the involvement of vascular mechanisms in the pathology and evolution of dementia will be examined and the potential importance of age-related changes in cerebrovascular structure and cerebral blood flow (CBF) autoregulation will be discussed. With a description of recent clinical results (on statins, angiotensinconverting enzyme inhibitors and Ca2++ channel blockers) and experimental results (on β-amyloid), the impact of drugs on cerebrovascular targets is examined. The working hypothesis that targeting vascular mechanisms in dementia is an option for future therapy is proposed.
Jeffrey Atkinson Cardiovascular Research Group Nancy (EA 3116), Pharmacy Faculty, Henri Poincaré University, 54000 Nancy, France. e-mail: atkinson@ pharma.u-nancy.fr
Recent reviews have discussed, in detail, the involvement of the vasculature in the pathology and evolution of dementia1–4. Briefly, the classification of dementia into primary, non-vascular [e.g. dementia associated with Alzheimer’s disease (AD)], and secondary, vascular (i.e. a wide range of dementias that have a primary vascular origin, such as cognitive decline associated with stroke, multi-infarct or cerebrovascular dementia, and white matter complications such as leukoaraiosis (neuroimaging abnormalities of the white matter encompassing a variety of pathological phenomena with different risk factors and forms of cognitive disturbance)] is changing. Indeed, evidence from experiments in humans and animal models suggests that the distinction between the two types of dementia might not be so clear-cut. For example, AD was found more often and was more severe in nuns who exhibited http://tips.trends.com
evidence of brain infarcts following cerebrovascular disease (CVD)5 than those nuns with no brain infarcts, which suggests that CVD precipitates AD at a stage when it would not be detected clinically. Leukoaraiosis is associated with a deficit in cognition6 whereas stroke survivors have a higher risk or intensity of dementia than stroke-free subjects7, and there is debate on the importance of silent strokes in dementia8. Silent strokes are a form of focal brain injury following blockage or rupture of a blood vessel that occurs without acute symptoms but that might be associated with mood disorder, memory loss and difficulty in walking. Events that are not primarily cerebrovascular in origin are also involved in the development of dementia. For example, coronary artery bypass surgery can produce long-term cognitive decline in ~50% of patients9, although the mechanism involved and the type of neuroprotective agent required to prevent such dementia are still under discussion. In old rats, chronic brain hypoperfusion produces deficits in visuo-spatial learning10, and the concept is emerging that the link between CVD and dementia reflects an amplification of progressive, age-related alterations in the regulation of cerebral blood flow (CBF)11. Cognitive function declines with age12 and mild cognitive impairment in an elderly individual might well represent early-stage AD with steady progression to greater stages of dementia severity13.
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Evidence for ε-opioid receptormediated β-endorphin-induced analgesia Leon F. Tseng Among the opioid receptors, which have been pharmacologically classified as µ, δ, κ and ε, the existence of the ε receptor has been controversial, and this receptor is generally not recognized as a member of the opioid peptide receptor family because it has not been precisely characterized. However, results from pharmacological, physiological and opioid receptor binding studies clearly indicate the presence of ε-opioid receptors, which are distinct from µ-, δ- or κ-opioid receptors. This putative ε-opioid receptor is stimulated supraspinally by the endogenous opioid peptide β-endorphin, which induces the release of Met-enkephalin, which, in turn, acts on spinal δ2-opioid receptors to produce antinociception. In this article, this β-endorphin-sensitive ε-opioid receptormediated descending pain control system, which is distinct from that activated by the µ-opioid receptor agonist morphine, is described and the physiological role of the β-endorphin-mediated system in pain control activated by coldwater swimming and intraplantar injection of formalin is discussed.
The multiplicity of opioid receptors, µ, δ, κ and ε, is mirrored physiologically by a multiplicity of endogenous opioid ligands: endomorphin-1 and endomorphin-2 act on µ-opioid receptors, enkephalins act on δ-opioid receptors, dynorphin-A1–17 acts on κ-opioid receptors, and β-endorphin acts on ε-opioid receptors1–3. The classical opiate morphine, which is isolated from the capsule of the poppy plant Papaver somniferum, shows a preference for µ-opioid receptors, but also binds with low affinity to δ- and κ-opioid receptors. Synthetic opioid agonists and antagonists for µ-, δ- and κ-opioid receptors with considerable selectivity are now available (Table 1). However, selective agonists and antagonists with specificity for ε-opioid receptors have not been developed. Role of ε-opioid receptors in antinociception induced by β-endorphin given supraspinally, but not spinally
Leon F. Tseng Dept of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. e-mail: [email protected]
β-Endorphin is an endogenous opioid peptide in the brain, which produces antinociception when injected into the brain in humans and a variety of species of animals2. β-Endorphin has been reported in both in vitro and in vivo studies to be a nonselective opioid receptor agonist, and binds to or stimulates ε-, µ-, δand κ-opioid receptors with different potencies and affinities1–4. Although β-endorphin is expected to stimulate any of these opioid receptors nonselectively, producing a variety of opioid pharmacological responses, a degree of selectivity for opioid receptor activities has been identified, depending on the pharmacological responses observed and the sites of injection of β-endorphin. For example, the http://tips.trends.com
bulbospinal pain control system activated by β-endorphin administered supraspinally to produce antinociception is mediated solely by the stimulation of the putative ε-opioid receptors2,3. This view is supported by results obtained using the tail-flick test; antinociception induced by β-endorphin given intracerebroventricularly (i.c.v.) in mice was not blocked by pretreatment with the µ-opioid receptor antagonists CTOP (D-Phe-Cys-Tyr-D-Try-Orn-ThrPen-Thr-NH2) or β-funaltrexamine (β-FNA), the δ-opioid receptor antagonists naltrindole or ICI174864 or the κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI). The same treatments with these µ-, δ- and κ-opioid receptor antagonists effectively block antinociception induced by the µ-opioid agonists morphine or DAMGO (D-Ala2,NMePhe4,Gly-ol5), the δ-opioid agonist deltorphin II and the κ-opioid agonist U50488H, respectively2. Furthermore, pretreatment with a ventricular combination of the µ-, δ- and κ-opioid antagonists β-FNA, naltrindole and nor-BNI still fails to block the antinociception induced by i.c.v.-administered β-endorphin (L.F. Tseng, unpublished). By contrast, β-endorphin-induced antinociception is blocked by pretreatment with i.c.v.administered β-endorphin1–27, which in this case is defined as a putative ε-opioid receptor antagonist because this same treatment with β-endorphin1–27 does not block antinociception induced by µ-, δ- or κ-opioid receptor agonists2,3. It is therefore concluded that the supraspinal antinociception induced by β-endorphin is mediated by the stimulation of putative ε-opioid receptors, but not µ-, δ- or κ-opioid receptors. β-Endorphin given intrathecally also produces antinociception in different species of animals5,6. However, antinociception induced by β-endorphin given spinally is mediated by the stimulation of κ- and µ-opioid receptors and not ε- or δ-opioid receptors, because such antinociception is blocked by pretreatment with the κ-opioid receptor antagonists nor-BNI or WIN44441 or the µ-opioid receptor antagonist CTOP, but not by either the ε-opioid antagonist β-endorphin1–27 or the δ-opioid receptor antagonists naltrindole or ICI174864 (Ref. 5). In studies using a place-preference paradigm, Bals-Kubik et al.7 reported that the reinforcing effects of β-endorphin are blocked by β-endorphin1–27, CTOP
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Table 1. Opioid receptors and their endogenous ligands, exogenous opioid agonists and exogenous opioid antagonistsa Opioid receptors Endogenous ligands Epsilon (ε) Mu (µ)
β-Endorphin, β-endorphin1–27 Endomorphin-1, endomorphin-2
Delta (δ)
Met-enkephalin
Kappa (κ)
Dynorphin A1–17
Opioid agonists
Opioid antagonists
Etorphine, bremazocine Morphine, etorphine, DAMGO, pentazocine (D-Ala2)deltorphin II (δ2), DPDPE (δ1), (–) TAN67 (δ1) U50488H (κ1), naloxone benzoyl hydrazone(κ3), bremazocine, pentazocine
β-Endorphin1–27 β-FNA, CTOP Naltrindole (δ1, δ2), naltriben (δ2), BNTX (δ1), TIPP4 (δ1) Nor-BNI
aAbbreviations: BNTX, 7-benzylidene naltrexamine; CTOP, D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH ; DAMGO, [D-Ala2, NMePhe4, Gly-ol5] 2 enkephalin; DPDPE, (D-Pen2,5) enkephalin; β-FNA, β-funaltrexamine; Nor-BNI, nor-binaltorphimine; TIPP4, H-Tyr-Tic-Phe-Phe-OH.
and ICI171864, indicating that these effects involve the activation of ε-, µ- and δ-opioid receptors. Furthermore, feeding elicited by ventricular β-endorphin is preferentially reduced by either selective µ-opioid receptor antagonists or antisense oligodenoxynucleotides (ODNs) directed against the Oprm clone8. In this review, this distinctive ε-opioid receptor-mediated pain control system that is pharmacologically activated by β-endorphin from supraspinal sites to produce antinociception is described and compared with that activated by the µ-opioid receptor agonist morphine. In addition, the physiological roles of the β-endorphin-mediated system in pain control activated by cold-water swimming and intraplantar injection of formalin are also described. Localization of ε-opioid receptors
Herz et al.9 were the first to report the unique ε-opioid receptor activity elicited by β-endorphin in the rat vas deferens. Subsequently, others have reported the characterization of the ε-opioid receptor in the brain and other tissues1–3. Indeed, receptor binding studies employing [3H]β-endorphin and [3H]ethylketocyclazocine provide biochemical evidence supporting the presence of ε-opioid receptors in the brain1. Using autoradiography of [3H]β-endorphin binding in the rat brain, Goodman et al.10 concluded that the pattern of [3H]β-endorphin labeling appears unique, consistent with the proposal of central ε-opioid receptors. However, unlike µ-, δand κ-opioid receptors, which have been much more precisely characterized and cloned and expressed11, the ε-opioid receptor has not been well characterized and has not been cloned. Two main factors have hindered the progress of the characterization of ε-opioid receptors: (1) selective ε-opioid receptor agonists and antagonists have not been developed; and (2) unlike other opioid receptors, a specific role for this receptor in functions other than analgesia has not been identified. Comparison of β-endorphin- and morphine-induced antinociception Absence of cross-tolerance
Supraspinal β-endorphin and morphine in mice fail to develop antinociceptive cross-tolerance. Thus, acute http://tips.trends.com
pretreatment of mice with ventricular morphine for three hours attenuates the antinociception induced by morphine, but not by β-endorphin. Similarly, pretreatment of mice with β-endorphin for two hours, which attenuates the antinociception induced by β-endorphin, does not affect the antinociception induced by morphine12. Furthermore, mice rendered tolerant to morphine by subcutaneous implantation with a morphine pellet for three days do not exhibit significant cross-tolerance to β-endorphin13. Differing brain sites at which β-endorphin and morphine produce antinociception
Using the intracerebral microinjection technique, the rat brain sites that are sensitive to β-endorphin and morphine for producing antinociception have been shown to be essentially different, although some overlap can be found. In brainstem regions, the sites most sensitive to β-endorphin for producing antinociception with the tail-flick test are located in the caudal medial medulla, such as the raphe obscurus, the raphe pallidus and the adjacent midline reticular formation3,14. By contrast, the medullary sites most sensitive to morphine for producing antinociception are located in areas of the rostral ventromedial medulla (RVM), such as the raphe magnus nucleus, gigantocellular nucleus and gigantocellular reticular nucleus α (Ref. 14). The locus coeruleus is a pontine site sensitive to both β-endorphin and morphine for producing antinociception14. In midbrain regions, microinjection of either β-endorphin or morphine into the ventrolateral periaqueductal gray (vlPAG) inhibits the tail-flick response. In forebrain regions, the sites most sensitive to β-endorphin for producing antinociception are located in ventromedial regions, such as the medial posterior nucleus accumbens, medial preoptic area and arcuate hypothalamic nucleus15 and ventrolateral regions such as the amygdala16. The sites sensitive to morphine for producing antinociception are located in regions of the medial preoptic nucleus, amygdala and arcuate hypothalamic nucleus, but not the nucleus accumbens3,15–17. The differential distributions of brain sites sensitive to β-endorphin and morphine for producing antinociception provide strong evidence to
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support the hypothesis that the antinociceptive effects induced by β-endorphin and morphine are mediated by different neural mechanisms. The opioid receptor antagonist naloxone, administered into the PAG, is much more effective in antagonizing the antinociception induced by morphine than β-endorphin injected into the PAG. By contrast, β-endorphin1–27 administered into the PAG effectively attenuates the antinociception induced by β-endorphin, but not morphine, injected into the PAG (Refs 2,3). Smith et al.18 demonstrated that multiple receptors are involved in the antinociceptive response to either β-endorphin or morphine microinjected into the PAG. The multiple receptors for β-endorphin present in the PAG are discriminated by virtue of the shallow, multiphasic dose–inhibition curves generated with the opioid receptor antagonist CTP (D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2). Some of the PAG receptors involved in antinociception are specific for β-endorphin because doses of CTP that block ~80% of the effect of the peptide do not affect the antinociception produced by an equi-effective dose of morphine. Moreover, in contrast to its ability to antagonize morphine, naltrexone fails to inhibit the entire response to β-endorphin. Both acetylcholine receptor antagonists and NMDA receptor antagonists administered into the RVM block morphine-induced antinociception elicited from the vlPAG, but fail to alter β-endorphin-induced antinociception elicited from the vlPAG (Refs 17,19). Both morphine and β-endorphin given into either the basolateral or central nuclei of the amygdala also produce antinociception in the tail-flick test. Pretreatment with naltrexone in the vlPAG reduces the antinociception induced by morphine and β-endorphin injected into the amygdala, which indicates that an opioid synapse in the PAG is essential for producing the antinociception elicited from the amygdala. However, pretreatment with the µ-opioid receptor antagonist β-FNA or the δ2-opioid receptor antagonist naltrindole isothiocyanate in the PAG significantly attenuates the antinociception induced by morphine, but not that induced by β-endorphin injected into the amygdala16,17. The synergistic antinociceptive interactions observed between the amygdala and vlPAG for subthreshold doses of morphine or β-endorphin applied to both sites fail to occur when morphine is applied to the amygdala, and β-endorphin is applied to the vlPAG, presumably because β-endorphin is activating a different neurochemical circuit within the vlPAG than does morphine16,17. Different bulbospinal pain control systems
The bulbospinal pain control model for morphineinduced antinociception, originally proposed by Basbaum and Fields, includes the midbrain PAG, brainstem RVM (particularly the nucleus raphe magnus and adjacent reticular nuclei) and the spinal http://tips.trends.com
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dorsal horn20. The antinociception induced by morphine microinjected into the PAG results from the activation of the excitatory connection between the PAG and the medullary raphe nuclei. The raphe neurons, in turn, project via a pathway in the dorsal part of the lateral funiculus of the spinal cord to the region of termination of the nociceptive primary afferent fibers in the spinal dorsal horn20. In addition, the dorsolateral pontomesencephalic tegmentum (DLPT) also plays a crucial role in the pain-modulating actions of the PAG and RVM. The DLPT includes all of the noradrenaline-containing neurons that project to the RVM and spinal cord. Proudfit and co-workers21 have clearly demonstrated that the descending noradrenaline-mediated systems are engaged from the PAG and RVM through the locus coeruleus, the A5 noradrenaline-containing group and, to a lesser degree, the A7 noradrenaline-containing groups in mediating morphine-induced antinociception. However, the exact neuronal circuitry of the bulbospinal pain control system for β-endorphin-induced antinociception is not completely clear at this time. The bulbospinal pain control systems activated by supraspinal β-endorphin and morphine involve different descending neural pathways, which use a variety of neurotransmitters and receptors in the spinal cord. Supraspinal β-endorphin-induced antinociception is mediated by the neuronal release of Met-enkephalin, which acts on δ2-opioid receptors in the spinal cord2,3. β-Endorphin, but not morphine, given supraspinally selectively releases Met-enkephalin, but not dynorphin, from the spinal cord22. Inhibition of the degradation of Met-enkephalin with bestatin and thiorphan increases the release of Met-enkephalin and potentiates the antinociception induced by supraspinally administered β-endorphin23,24. Furthermore, pretreatment with a rabbit antiserum against Met-enkephalin, which binds extracellular Met-enkephalin, attenuates β-endorphin-induced antinociception2. The opioid receptor in the spinal cord that is stimulated by the released Met-enkephalin has been identified as δ2-, and not δ1- or µ-, opioid receptors2,3,25. Intrathecal pretreatment with an antisense ODN against mRNA for the δ-opioid receptor to reduce the number of δ-opioid receptors in the spinal cord attenuates the antinociception induced by supraspinally administered β-endorphin26. These findings support the view that Met-enkephalin release and δ2-opioid receptors in the spinal cord are involved in supraspinal β-endorphin-induced antinociception. By contrast, the antinociception produced by supraspinal morphine is mediated by spinopetal 5-HTand noradrenaline-mediated systems, which stimulate 5-HT-receptors and α2-adrenoceptors, respectively, in the spinal cord2,3. Morphine given intraventricularly induces the release of noradrenaline in addition to 5-HT, but not Met-enkephalin, from the spinal cord2,3. The antinociception induced by supraspinal morphine
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is enhanced by desipramine and fluoxetine administered spinally, which inhibit the reuptake of noradrenaline and 5-HT, respectively24, and is attenuated by pretreatment with DSP4 or 6-hydroxydopamine and 5,7-dihydroxytryptamine spinally, which cause the degeneration of the noradrenaline- and 5-HT-containing fibers, respectively2. Intrathecal treatment with the selective α2-adrenoceptor antagonist yohimbine and the 5-HT receptor antagonist methysergide, but not naloxone, blocks the antinociception induced by morphine given supraspinally, which indicates that α2-adrenoceptors and 5-HT-receptors, but not opioid receptors, in the spinal cord are involved in morphine-induced antinociception2,3. Differential modulation of supraspinal β-endorphin- and morphine-induced antinociception Sulfated cholecystokinin octapeptide (CCK-8s)
The endogenous cholecystokinin neuropeptide CCK-8s functions as a selective antagonist of opioid-induced antinociception, at both spinal and supraspinal levels27. Briefly, CCK-8s administered spinally potently antagonizes antinociception induced by spinal administration of morphine in the tail-flick test, whereas acute administration of the CCK1 receptor antagonists proglumide and lorglumide enhance spinal morphine-induced antinociception27,28, an effect that is blocked or reversed by chronic treatment with CCK receptor antagonists28. The inhibition of the thermal hyperalgesia induced by intrathecal morphine in the paw withdrawal test is enhanced by intrathecal pretreatment with the CCK2 receptor antagonist PD135158 in sciatic nerve injured rats29. Similarly, intrathecal pretreatment with proglumide or the selective CCK2 receptor antagonist L365260 enhances intrathecally administered morphine-induced antinociception in a model of visceral pain in the rat30. These observations, together with the coincident distribution of CCK with enkephalins and endomorphins in the dorsal horn of the spinal cord, suggest the possibility of a modulatory interaction between opioid-induced antinociception and CCK activity. It has been postulated that morphine modulates its own antinociceptive activity by increasing CCK release in the spinal cord, and indeed Zou et al.31 have demonstrated that morphine administration increases the release of CCK in the spinal cord. CCK in the spinal cord also appears to be involved in modulating the descending pain control system activated by β-endorphin administered supraspinally. Intrathecal administration of CCK-8s in mice selectively antagonizes the antinociception induced by supraspinally administered β-endorphin, but not that induced by supraspinally administered morphine or DAMGO (Ref. 32). The attenuating effect of CCK-8s on supraspinal β-endorphin-induced antinociception is mediated by the stimulation of CCK receptors in the spinal cord because spinal http://tips.trends.com
pretreatment with the CCK1 receptor antagonist L364718 or the CCK2 receptor antagonist L365260 reverses the effect caused by CCK-8s. By contrast, blockade of CCK receptors in the spinal cord by intrathecal injection of the CCK1 receptor antagonists proglumide or L364718 enhances the antinociception induced by supraspinally administered β-endorphin32. Hawranko et al.33 reported that rats exposed to repeated hot-plate stress exhibit stressinduced analgesia, but reduced antinociception in response to the administration of β-endorphin into the PAG. These alterations are prevented by the intrathecal treatment with the CCK2 receptor antagonist L365260. Thus, CCK might modulate opioid-mediated effects through a feedback mechanism, so that the presence of an opioid such as Met-enkephalin triggers the release of endogenous CCK, thereby returning the animal to a state of baseline sensitivity. Intraventricular injection of β-endorphin releases Met-enkephalin and also CCK from the spinal cord34. The released CCK might in turn antagonize the β-endorphin-induced antinociception either by antagonizing the δ-opioid receptor activity, which is stimulated by the released Met-enkephalin, or by inhibiting the release of Met-enkephalin from the spinal cord35. Rady et al.36 reported that CCK given intrathecally antagonizes the antinociception induced by the δ2-opioid agonist DSLET {[D-Ser2]Leu-enkephalin-Thr6}, but not that induced by the δ1-opioid agonist DPDPE [(D-Pen2,5)enkephalin]. Furthermore, Suh et al.35 demonstrated that CCK-8s added to spinal perfusates attenuates the spinal release of Met-enkephalin induced by supraspinally administered β-endorphin. Thus, CCK-8s and its receptors in the spinal cord play a negative feedback role in modulating the antinociception induced by β-endorphin injected supraspinally and the antinociception induced by morphine given spinally, but not supraspinally. GABA
Because the primary actions of opioids are inhibitory, it has been proposed that opioids can activate the descending pain control system by disinhibiting inhibitory GABA-containing neurons, which, in turn, results in the activation of excitatory neurons. The pharmacological actions of pentobarbital are mediated by potentiation or mimicry of the effects of GABA (Ref. 37). Pentobarbital anesthesia attenuates the antinociception induced by morphine, but not by β-endorphin, given supraspinally in the rat and mouse38,39. Indeed, Smith et al.40 reported that pentobarbital anesthesia in rats caused a marked increase in the antinociceptive potency of β-endorphin microinjected into the PAG of the rat, whereas the antinociceptive response to microinjection of morphine into the PAG was markedly attenuated during pentobarbital anesthesia. Stimulation of GABAB receptors at supraspinal sites by baclofen attenuates supraspinally
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administered β-endorphin-, but not morphine-, induced antinociception. However, activation of GABAA receptors by muscimol given supraspinally attenuates both supraspinally administered β-endorphin- and morphine-induced antinociception41. The blockade of GABAA receptors in the spinal cord by intrathecal injection of SR95531, a selective GABAA receptor antagonist, attenuates the antinociception induced by morphine, but not by β-endorphin, given supraspinally. By contrast, blockade of GABAB receptors in the spinal cord by 5-aminovaleric acid given spinally attenuates the analgesia induced by β-endorphin, but not by morphine, given supraspinally42. These results indicate that spinal GABAA and supraspinal GABAB receptors differentially modulate antinociception induced by supraspinally administered morphine and β-endorphin, and provides additional evidence that morphine and β-endorphin antinociception are mediated by the activation of different pain control systems.
NO–cGMP in the spinal cord also differentially modulates antinociception induced by supraspinally administered morphine and β-endorphin. The antinociception induced by morphine given supraspinally is potentiated by spinal administration of the NO synthase inhibitor Nω-nitro-L-arginine, hemoglobin (which binds NO) or the cGMP inhibitor methylene blue, but is attenuated by spinal administration of L-arginine or 3-morpholinosydnonimine. By contrast, antinociception induced by β-endorphin given supraspinally is attenuated by spinally administered Nω-nitro-L-arginine, hemoglobin or methylene blue. However, pretreatment with L-arginine spinally does not affect supraspinal β-endorphin-induced antinociception. Thus, inhibition of the spinal cord NO–cGMP system potentiates the antinociceptive effect of morphine but attenuates β-endorphin-induced antinociception. Conversely, activation of the spinal cord NO–cGMP system attenuates morphine-, but not β-endorphin-, induced antinociception47.
Glutamate
β-Endorphin-mediated system is involved in analgesia induced by cold-water swimming
Recent studies have demonstrated that NMDA and non-NMDA glutamate receptors are involved in the production of antinociception, and indeed microinjection of NMDA or glutamate into the nucleus raphe magnus or PAG produces antinociception in rats43. NMDA and non-NMDA receptors at supraspinal sites play different roles in β-endorphin- and morphine-induced antinociception in mice. Blockade of NMDA or non-NMDA receptors by i.c.v. administration of MK801, a non-competitive NMDA antagonist, or CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), a competitive non-NMDA receptor antagonist, attenuates the antinociception induced by morphine, but not by β-endorphin, given supraspinally. The blockade of NMDA receptors by either competitive or non-competitive NMDA receptor antagonists administered into the RVM blocks morphine-, but not β-endorphin-, induced antinociception following injection into the vlPAG (Ref. 44). Nitric-oxide–cGMP
Nitric oxide (NO) has been proposed to act as a biological messenger in the CNS. NO, derived from L-arginine by the action of NO synthase, binds and activates soluble guanylyl cyclase, producing an increase in the concentration of cGMP, which can then act through protein kinases, phosphodiesterases or directly on ion channels45. Activation of the NO–cGMP system at supraspinal sites differentially modulates β-endorphin- and morphine-induced antinociception in mice. Increased production of NO from L-arginine or increased release of NO by the NO donors 3-morpholino-sydnonimine or sodium nitroprusside given supraspinally potentiate β-endorphin-, but not morphine-, induced antinociception46. http://tips.trends.com
There is a striking similarity between β-endorphininduced analgesia and the analgesia induced by continuous cold-water swimming (CWS) in a 2°C ice-water bath. Early studies by Bodnar et al.48 demonstrated that CWS produces analgesia that is neither cross-tolerant with morphine nor reversed by naloxone. Like β-endorphin-induced analgesia, the analgesia induced by CWS shows many dissociations from that of morphine-induced analgesia so that a model of collateral inhibition has been proposed between these two forms of analgesia (i.e. blockade of one system would potentiate the other system)49. The CWS-induced analgesia presented simultaneously with morphine-induced analgesia results in a diminished combined analgesic response, which is time-, dose- and temperature-dependent. This CWSinduced analgesia has been proposed to be mediated by the activation of endogenous opioid systems selectively at δ2-opioid receptors at supraspinal sites50 and by multiple spinal opioid receptors51. The β-endorphin-mediated system has been suggested to be involved in the analgesia induced by CWS. Such a system involves the release of β-endorphin acting on putative ε-opioid receptors at supraspinal sites and the release of Met-enkephalin acting on δ2-opioid receptors at the spinal sites to produce analgesia. This view is supported by the finding that CWS-induced analgesia is blocked selectively by supraspinal pretreatment with an antiserum against β-endorphin and by spinal pretreatment with an antiserum against Met-enkephalin3. CWS-induced analgesia is blocked by the δ2-receptor antagonists naltrindole or naltriben, but not by the δ1-opioid receptor antagonist BNTX, the µ-opioid receptor antagonist CTOP or the κ-opioid receptor antagonist nor-BNI given spinally3,52.
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Furthermore, intrathecal pretreatment with an antisense ODN against the mRNA for the δ-opioid receptor to reduce the number of δ-opioid receptors in the spinal cord attenuates CWS-induced analgesia53. These findings support the view that CWS releases β-endorphin at supraspinal sites and subsequently releases Met-enkephalin, which acts on δ2-opioid receptors in the spinal cord to produce analgesia. Activation of the β-endorphin-mediated system modulates formalin-induced nociception
Acknowledgements I thank James M. Fujimoto for the reading and suggestions of this manuscript. This work is supported by NIH Grant DA03811and NIH Grant DA12588.
Intraplantar injection of a diluted solution of formalin causes nociceptive licking in the mouse and flinching in the rat, which closely resembles human clinical pain. These nociceptive responses to formalin appear in two phases: an initial period of acute nociceptive behavior lasting from the time of injection for 10 min and a second tonic phase occurring 15 min after injection and lasting 50–60 min (Ref. 54). The initial acute phase might represent the direct stimulation of nociceptors, whereas the second phase might represent an enhanced response of the sensitized central neurons resulting from low-level neuronal input following a peripheral inflammatory insult54. This peripheral inflammatory process elicits marked increases in β-endorphin-like immunoreactivity in the ventral PAG and other brain regions that are important in pain control55, and also increases the release of β-endorphin in the arcuate nucleus56. Furthermore, pretreatment with an antiserum against β-endorphin or with the ε-receptor antagonist β-endorphin1–27 markedly enhances the antinociceptive response to formalin57. Hamba58 reported that rats display increased behavioral responses to formalin injection after lesions of the arcuate nucleus of the hypothalamus, the main site of β-endorphin-producing cells in the CNS. These findings strongly indicate that formalin-induced stimulation activates the central β-endorphinmediated system and induces the release of β-endorphin, which, in turn, inhibits the nociceptive response. Because the first phase of the nociceptive response to formalin stimulation is not affected by pretreatment with the β-endorphin antiserum, the central β-endorphin-mediated system is probably not tonically active under normal circumstances, but is stimulated initially by formalin during the first phase of the nociceptive response. Pertussis-toxin-resistant β-endorphin-mediated antinociception
Pretreatment of mice or rats with pertussis toxin (PTX), a protein isolated from the culture medium of
References 1 Nock, B. (1995) κ and ε Opioid receptor binding. In The Pharmacology of Opioid Peptides (Tseng, L.F., ed.), pp. 29–56, Harwood Academic Publishers GMBH 2 Tseng, L.F. (1995) Mechanisms of β-endorphininduced antinociception. In The Pharmacology of Opioid Peptides (Tseng, L.F., ed.), pp. 249–269, Harwood Academic Publishers GMBH http://tips.trends.com
Bordetella pertussis, either supraspinally or spinally, attenuates antinociceptive and other effects induced by morphine and other µ-opioid receptor agonists3. Similarly, antinociception induced by the selective δ-opioid agonist deltorphin II or by the κ-opioid agonist U50488H is attenuated by pretreatment with PTX (Ref. 3) because these opioid receptors are Gi–Go-coupled receptors, which are inhibited by treatment with PTX. However, the antinociception induced by β-endorphin given supraspinally in mice is not affected by pretreatment with PTX supraspinally, but is effectively attenuated by pretreatment with PTX spinally59. This observation is consistent with the notion that β-endorphin-induced antinociception is mediated by the stimulation of non-µ-, non-δ-, non-κ-opioid receptors at supraspinal sites and by δ-opioid receptors at spinal sites. Interestingly, the CWS-induced analgesia is also not affected by pretreatment with PTX supraspinally, but is markedly attenuated by pretreatment with PTX spinally60. These findings provide additional evidence that putative ε-opioid receptors, which are distinct from µ, δ and κ receptors, mediate β-endorphin-mediated analgesia. Concluding remarks
Evidence obtained from studies of β-endorphininduced antinociception clearly supports the notion that there is a putative ε-opioid receptor that is distinct from µ-, δ and κ-opioid receptors. These putative ε-opioid receptors stimulated by β-endorphin are not Gi–Go-protein-coupled receptors because the supraspinal β-endorphin-induced antinociception is resistant to pretreatment with PTX supraspinally. β-Endorphin administered supraspinally activates these putative ε-opioid receptors at supraspinal sites and subsequently induces the release of Met-enkephalin that acts on δ2-opioid receptors in the spinal cord to produce antinociception. CCK, GABA, glutamate and NO–cGMP in the spinal cord differentially modulate β-endorphin- and morphineinduced antinociception. Environmentally induced stress, such as CWS or formalin injection, also activates the β-endorphin-mediated system and presumably uses the same or a similar descending pain control pathway for producing analgesia. The core issues for the progress of ε-opioid receptor research in the future depend on: (1) the successful development of selective ε-opioid receptor agonists and antagonists that can be used to characterize ε-opioid receptors; and (2) the successful cloning and expression of these ε-opioid receptors.
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Chemical names DSP4: N-(2-chloroethyl)-N-ethyl2-bromobenzylamine hydrochloride ICI171864: N,N-diallyl-Tyr-Aib-Aib-Phe-Leu L364718 (devazepide): 1-methyl-3-(2-indoloyl)amino5-phenyl-3H-1,4-benzodiazepine-2-one L365260: 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5phenyl-1H-1,4-benzodiazepin-3-yl)-N ′-(3-methylphenyl)urea PD135158: 4-{[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2[[[1.7.7-trimethyl-bicylclo[2.2.2]hept-2-yloxy]carbonyl] amino]propyl]amino]-1 phenylethyl]amino-4-oxo[1S-1α.2β[S*(S*)]4α]}-butanoate N-methyl-D-glucamine
SR95531: 2-(3-carboxypropy)-3-amino-6(4-methoxyphenyl)pyridazinium bromide (-)TAN67: 2-methyl-4aα-(3-hydroxyphenyl)1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,3g]isoquinoline U50488H: trans(±)-3,4-dichloro-N-methyl-N-[2-(1pyrrolidinyl)cyclohexyl]benzene-acetamide methane sulfonate WIN44441: (−)-1-cyclopentyl-5-(1,2,3,4,5,6hexahydro-8-hydroxy-3,6,11-trimethyl-2,6,methano3-benzazocine-11-yl)-3-pentanone methanesulfonoate
Cerebrovascular structure and dementia: new drug targets Jeffrey Atkinson Effective pharmacological treatment of cognitive disorders in dementia is lacking despite extensive efforts to produce active therapy aimed at neuronal and vascular targets. In this review, the evidence for the involvement of vascular mechanisms in the pathology and evolution of dementia will be examined and the potential importance of age-related changes in cerebrovascular structure and cerebral blood flow (CBF) autoregulation will be discussed. With a description of recent clinical results (on statins, angiotensinconverting enzyme inhibitors and Ca2++ channel blockers) and experimental results (on β-amyloid), the impact of drugs on cerebrovascular targets is examined. The working hypothesis that targeting vascular mechanisms in dementia is an option for future therapy is proposed.
Jeffrey Atkinson Cardiovascular Research Group Nancy (EA 3116), Pharmacy Faculty, Henri Poincaré University, 54000 Nancy, France. e-mail: atkinson@ pharma.u-nancy.fr
Recent reviews have discussed, in detail, the involvement of the vasculature in the pathology and evolution of dementia1–4. Briefly, the classification of dementia into primary, non-vascular [e.g. dementia associated with Alzheimer’s disease (AD)], and secondary, vascular (i.e. a wide range of dementias that have a primary vascular origin, such as cognitive decline associated with stroke, multi-infarct or cerebrovascular dementia, and white matter complications such as leukoaraiosis (neuroimaging abnormalities of the white matter encompassing a variety of pathological phenomena with different risk factors and forms of cognitive disturbance)] is changing. Indeed, evidence from experiments in humans and animal models suggests that the distinction between the two types of dementia might not be so clear-cut. For example, AD was found more often and was more severe in nuns who exhibited http://tips.trends.com
evidence of brain infarcts following cerebrovascular disease (CVD)5 than those nuns with no brain infarcts, which suggests that CVD precipitates AD at a stage when it would not be detected clinically. Leukoaraiosis is associated with a deficit in cognition6 whereas stroke survivors have a higher risk or intensity of dementia than stroke-free subjects7, and there is debate on the importance of silent strokes in dementia8. Silent strokes are a form of focal brain injury following blockage or rupture of a blood vessel that occurs without acute symptoms but that might be associated with mood disorder, memory loss and difficulty in walking. Events that are not primarily cerebrovascular in origin are also involved in the development of dementia. For example, coronary artery bypass surgery can produce long-term cognitive decline in ~50% of patients9, although the mechanism involved and the type of neuroprotective agent required to prevent such dementia are still under discussion. In old rats, chronic brain hypoperfusion produces deficits in visuo-spatial learning10, and the concept is emerging that the link between CVD and dementia reflects an amplification of progressive, age-related alterations in the regulation of cerebral blood flow (CBF)11. Cognitive function declines with age12 and mild cognitive impairment in an elderly individual might well represent early-stage AD with steady progression to greater stages of dementia severity13.
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