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Mechanisms of Nociception Evoked by Intrathecal High-dose Morphine
NeuroToxicology 26 (2005) 801–809
Review
Mechanisms of Nociception Evoked by Intrathecal High-dose Morphine Tsukasa Sakurada 1,*, Takaaki Komatsu 1, Shinobu Sakurada 2 1
Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan 2 Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan Received 6 December 2004; accepted 20 December 2004 Available online 4 June 2005
Abstract Morphine is recommended by WHO as the analgesic of choice for effective treatment of moderate to severe cancer pain [World Health Organisation. Cancer pain relief, 2nd ed. Geneva: WHO; 1996]. Indeed spinally administered morphine at small doses injected intrathecally (i.t.) or intracerebroventricularly into animals produces a profound antinociception at both spinal and supraspinal sites. Conversely, high doses of spinally administered morphine elicit a series of scratching, biting and licking in mice, and vocalization and agitation in rats, indicative of a spontaneous nociceptive behavioural response. Hyperalgesia and allodynia are also induced by such morphine treatment in humans as well as animals. These behaviours are not an opioid receptor-mediated event. This article will review the potential mechanisms of spinally mediated nociceptive behaviour evoked by i.t. morphine at high concentrations. We will discuss a possible presynaptic release of nociceptive neurotransmitters/neuromodulators (e.g., substance P, glutamate and dynorphin) in the primary afferent fibers following i.t. high-dose morphine. There must be an intimate interaction of i.t. high-dose morphine with tachykinin neurokinin 1 (NK1) receptors and multiple sites on the N-methyl-D-aspartate (NMDA) receptor complex in the dorsal spinal cord. Since the effect of NMDA receptor activation and the associated Ca2+ influx results in production of nitric oxide (NO) by activation of NO synthase, it seems that spinal NO also plays an important role in nociception evoked by i.t. high-dose morphine. Morphine-3-glucuronide, one of the major metabolites of morphine, has been found to evoke nociceptive behaviour similar to that of i.t. high-dose morphine. It is plausible that morphine-3-glucuronide may be responsible for nociception seen after i.t. high-dose morphine treatment. The demonstration of neural mechanism underlying morphine-induced nociception provides a pharmacological basis for improved pain management with morphine at high doses.
# 2005 Elsevier Inc. All rights reserved. Keywords: Morphine; Intrathecal injection; Spinal cord; Nociceptive behaviour; Substance P; Glutamate; NK1 receptor; NMDA receptor; Nitric oxide
Contents INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MORPHINE-INDUCED NOCICEPTIVE BEHAVIOUR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL SUBSTANCE P AND GLUTAMATE . MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL NITRIC OXIDE. . . . . . . . . . . . . . . . MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL METABOLITES OF MORPHINE . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Corresponding author. Tel.: +81 92 541 0161x416; fax: +81 92 553 5698. E-mail address: [email protected] (T. Sakurada). 0161-813X/$ – see front matter # 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuro.2004.12.011
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INTRODUCTION Morphine with a potent analgesic property has been widely used for the treatment of various kinds of acute pain and for long-term treatment of severe chronic pain. With the advance of pain pharmacology the dorsal horn of the spinal cord is believed to be an important site for the mediation of the antinociceptive effect of morphine and opioids (Yaksh, 1981; Akil et al., 1984; Basbaum and Fields, 1984). There are at least three types of opioid receptors, referred to as m, d and k, in the adult mammalian spinal cord (Mack et al., 1984; Traynor and Rance, 1984). Small doses of spinally administered morphine, when injected epidurally and intrathecally (i.t.), produce reliable analgesia. Animal studies have documented that in the formalininduced flinching test i.t. administration of morphine into rats over a dose range of 1–20 nmol produces a reliable antinociceptive effect by interacting with opioid receptors in the dorsal spinal cord (Watanabe et al., 2003a). As shown in Table 1, some studies have demonstrated that morphine at doses far higher than those required for antinociception, injected i.t. into the spinal subarachnoid space, produces a spontaneous vocalization/squeaking and agitation as well as hyperalgesia and allodynia as opposed to the antinociception at small doses (Tang and Schoenfeld, 1978; Woolf, 1981; Yaksh et al., 1986; Alvarez-Vega et al., 1998). Furthermore, i.t. administration of high-dose morphine into mice was found to induce scratching, biting and licking resembling that of substance P or N-methyl-Daspartate (NMDA) injected i.t. The characteristic behavioural responses are antagonized by co-administration of tachykinin neurokinin 1 (NK1) receptor antagonists, and various types of NMDA receptor antagonists (Sakurada et al., 1996c, 2002). Morphine, injected i.t. into mice, induces a hyperalgesic response to
noxious stimuli and an allodynic response to innocuous tactile stimuli in mice (Hara et al., 1997). A hyperalgesic action has also been known to develop after chronically administered morphine in rats (Kayan and Mitchell, 1968; Mule et al., 1968). In addition, a similar phenomenon has been recognized in humans who developed hyperalgesia, allodynia and myoclonus following i.t. and systemical administrations of morphine at high concentrations (Wert and MacDonald, 1982; Krames et al., 1985; Ali, 1986; Penn and Paice, 1987; Arner et al., 1988; Glavina and Robertshaw, 1988; Potter et al., 1989; Parkinson et al., 1990; Sjogren et al., 1993; De Conno et al., 1991). Previous studies have demonstrated that pain-related behaviours (e.g., hyperalgesia, allodynia, and scratching, biting and licking) and myoclonus evoked by i.t. high-dose morphine are not an opioid receptor-mediated event, since these behaviours evoked by i.t. high-dose morphine are not reversed by pretreatment with naloxone, an opioid receptor antagonist (Yaksh et al., 1986; Yaksh and Harty, 1988; Lutfy et al., 1994; Sakurada et al., 2002; Watanabe et al., 2003b). The mechanism of action underlying i.t. high-dose morphine-associated nociception is still unclear but a critical role has been attributed to an endogenous pain facilitatory system involving NK1 and NMDA receptors in the spinal cord. NMDA receptor activation leads to an increase of NO production, apparently via increased intracellular Ca2+. There is evidence to suggest that NO plays a significant role in spinal nociceptive processing (Meller and Gebhart, 1993). It is also of importance to assess if the phenomena of spontaneous nociception evoked by acutely administered high-dose morphine through i.t. route are due to morphine itself and/or its glucuronide metabolites. To explore possible mechanisms of high-dose morphine-induced nociception may be clinically useful for
Table 1 Comparison of antinociceptive and nociceptive dose of morphine injected intrathecally into animals Response observed
Species
Antinociceptive dose (ED50) or nociceptive dose
References
Antinociception
Mouse
0.15 nmol (early phase formalin test) 0.06 nmol (late phase formalin test)
Sakurada et al. (1995) Sakurada et al. (1995)
Rat
24.5 nmol (early phase formalin test) 16.0 nmol (late phase formalin test)
Watanabe et al. (2003a, 2003b) Watanabe et al. (2003a, 2003b)
Mouse
60–90 nmol (SBL) 30–90 nmol (scratching)
Sakurada et al. (1996c) Sakurada et al. (1996c)
Rat
150 mg (6400 nmol) (agitation) 520 nmol (vocalization, agitation and SBL) 125–500 nmol (agitation) 500 nmol (vocalization)
Yaksh and Harty (1988) Alvarez-Vega et al. (1998) Watanabe et al. (2003a, 2003b) Watanabe et al. (2003a, 2003b)
Nociception
SBL; scratching, biting and licking.
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improved pain management with morphine and opioid analgesics.
MORPHINE-INDUCED NOCICEPTIVE BEHAVIOUR Though morphine and related opioids are widely used to alleviate in the clinical management of pain, its use is often accompanied by tolerance and dependence (Collin and Cesselin, 1991; Trujillo and Akil, 1991; Pasternak, 1993). This has led to increases in opioid dosing requirements during pain, and elicits nonanalgesic side effects such as nausea, respiratory depression and urinary retention. It has also been known that a single spinal administration of morphine into rats at high doses results in hyperalgesia (an increased sensitivity to a stimulus), allodynia (a nociceptive response to an innocuous stimulation), and spontaneous vigorous agitation or vocalization (Woolf, 1981; Yaksh and Harty, 1988; Watanabe et al., 2003b). Mice also exhibited a characteristic nociceptive response after i.t. administration of high-dose morphine (Sakurada et al., 1996c). However, there is a qualitative difference of nociceptive behavioural response to i.t. high-dose morphine in mice when compared with rats; in mice administration of morphine at a high dose of 60 nmol into the spinal lumbar i.t. space elicits a nociceptive behavioural syndrome characterized by severe reciprocal hindlimb scratching followed by biting and licking toward the caudal part of the body without squeaking in mice (Sakurada et al., 1996c; Watanabe et al., 2003b). Behavioural evidence indicates that the latency of morphine-induced scratching is much later than that of substance P- and NMDAinduced response, which occurred within 10 s following i.t. administration in mice. Similarly the vocalization response to i.t. administration of morphine (500 nmol) is late in onset (over 60 s). It is readily speculated that morphine at a high-concentration promotes the presynaptic release of one or more nociceptive neurotransmitters/neuromodulators such as substance P, glutamate or calcitonin-gene related peptide (CGRP) in the dorsal horn of the spinal cord. In rats, high-doses of morphine, injected into the spinal lumbar i.t. space, have been shown to produce a spontaneous nociceptive syndrome mainly consisting of agitation and vocalization (Watanabe et al., 2003b). The behavioural activation evoked by i.t. high-dose morphine are irreversible by the opioid receptor antagonist, naloxone or naltrexone, suggesting a non-opioid receptor mechanism (Woolf, 1981; Yaksh
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et al., 1986; Yaksh and Harty, 1988; Sakurada et al., 2002; Watanabe et al., 2003b). The inability of naloxone to reverse morphine-induced nociceptive response is consistent with the reports that allodynia and clonic seizure-like motor effect produced by i.t. high-dose morphine could not block by opioid receptor antagonists (Yaksh and Harty, 1988; Lutfy et al., 1994). Highdoses of spinally administered morphine have also been reported to produce hyperalgesia in response to noxious stimuli in rats (Woolf, 1981). The morphineinduced hyperalgesia is of clinical interest since hyperalgesic and allodynic states have been reported to occur in humans following administration of high-dose subarachnoid morphine or systemic administration of opioid (Seymour et al., 1982; Wert and MacDonald, 1982; Krames et al., 1985; Ali, 1986; Penn and Paice, 1987; Arner et al., 1988; Glavina and Robertshaw, 1988; Potter et al., 1989; Parkinson et al., 1990; De Conno et al., 1991; Sjogren et al., 1993).
MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL SUBSTANCE P AND GLUTAMATE Substance P is a well-established neurotransmitter/ neuromodulator of nociception in the spinal cord (Basbaum, 1999; Saria, 1999). Administration of morphine and opioid peptides inhibits specifically the release of substance P (Jessell and Iversen, 1977; Yaksh et al., 1980), whereas substance P release is increased by hyperalgesic conditions associated with inflammation (Garry and Hargreaves, 1992; Meller and Gebhart, 1994). The hyperalgesic response can be evoked by i.t. administered substance P (Yashpal et al., 1982; Matsumura et al., 1985). Substance P induces spontaneous nociceptive response consisting of scratching, biting and licking when administered i.t. into mice and rats (Hylden and Wilcox, 1981; Seybold et al., 1982; Takahashi et al., 1987; Bossut et al., 1988). Tachykinin NK1 receptor antagonists produce antinociceptive response in well-established models of pain (Sakurada et al., 1993, 1994b, 1995), as well as blocking scratching, biting and licking responses to i.t. substance P (Sakurada et al., 1989, 1991, 1992, 1994a). The nociceptive response to i.t. high-dose morphine is qualitatively similar to that induced by i.t. injection of substance P. Spinally-mediated behavioural responses evoked by i.t. high-dose morphine are inhibited by i.t. co-administration of the NK1 receptor antagonists, sendide and CP-96,345 in mice (Sakurada et al., 1996c). Pretreatment with i.t. anti-
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Fig. 1. Schematic representation of spinal mechanism in nociception evoked by intrathecal administration of morphine at high doses. Glu: glutamate; SP: substance P; NMDA: N-methyl-D-aspartate; NK1: neurokinin 1; NO: nitric oxide; NOS: nitric oxide synthase; L-Arg: L-arginine; L-Cit: L-citrulline; GC-S: soluble guanylyl cyclase; GTP: guanylyl triphosphate; cGMP: cyclic guanylyl monophosphate.
serum against substance P and i.t. capsaicin, a nonselective substance P depletor, caused a significant reduction of the behavioural response to high-dose morphine. Therefore, morphine-induced behavioural response is considered to be mediated via the release of substance P from the primary afferents in the spinal cord (Fig. 1). This concept is suppotted by in vivo experiments that morphine at high concentrations facilitates substnce P release from guinea-pig brain slices (Chahl, 1990) and from afferent terminals in the trigeminal nucleus (Suarez-Roca et al., 1992). In addition to substance P, the importance of the activation of the NMDA receptor by glutamate is suggested in the mediation of central sensitization. Neurochemical studies show the presence of glutamate in small-diameter dorsal root ganglion neurons (Battaglia and Rustioni, 1988) and in terminals in the superficial dorsal horn of the spinal cord (De Biasi and Rustioni, 1988; Miller et al., 1988). Peripheral stimulation of nociceptive afferents leads to a significant release of glutamate in the spinal cord in vitro (Kangrga and Randic, 1991; Skilling et al., 1988; Malmberg and Yaksh, 1995; Okuda et al., 2001). The NMDA receptor is a ligand-gated ion channel
complex that has multiple regulatory sites sensitive to open channel blockers, glycine and polyamine (Cunningham et al., 1994). Functionally, the NMDA receptor has been suggested to be involved in nociceptive transmission and processing within the spinal cord (Cahusac et al., 1984; Aanonsen and Wilcox, 1987). For instance, i.t. administration of NMDA elicits a series of scratching, biting and licking indicative of nociceptive response in mice (Aanonsen and Wilcox, 1987; Sakurada et al., 1990). Polyamine recognition site in NMDA receptor complex is also important to elicit the characteristic behavioural response to i.t. high-dose morphine, which is reduced by ifenprodil, an antagonist at the NMDA receptorcoupled polyamine site (Sakurada et al., 2002). In fact, spermine, an endogenous polyamine, at extremely low doses (fmol orders), is able to induce similar behavioural response which is ifenprodil-reversible (TanNo et al., 2000). We have demonstrated the potential interactive effects of NMDA receptor antagonists on the bahavioural episode seen after i.t. injection of highdose morphine in mice (Sakurada et al., 2002). The competitive NMDA receptor antagonists, D-APV and CPP, are the most potent in reducing the behavioural
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response of i.t administered high-dose morphine. MK801, a non-competitive NMDA receptor antagonist, blocks the behavioural response to i.t. high-dose morphine, though MK-801 is less potent than the competitive antagonists, D-APV and CPP. This is in line with our previous data that the rank order potency for inhibition of nociceptive response is CPP > DAPV > MK-801 as assayed by the capsaicin test (Sakurada et al., 1998). Capsaicin, injected i.t. into mice, evokes a pain-related behaviour such as scratching, biting and licking similar to that seen after i.t. highdose morphine (Sakurada et al., 1998). In rats, the induced behavioural response (vocalization and agitation) evoked by i.t. administration of high-dose morphine is inhibited by pretreatment with CPP, a competitive antagonist of NMDA receptor and MK801, a non-competitive NMDA receptor antagonist (Watanabe et al., 2003b). These behavioural data in mice and rats suggest that nociceptive responses induced by i.t. high-dose morphine may be mediated through an increased release of glutamate from the primary afferent terminals in the dorsal horn of the spinal cord, and subsequent activation of NMDA receptors (Fig. 1). A extensive line of investigation suggests that dynorphin, a proposed endogenous ligand for the k opioid receptor, located in the spinal cord, plays an important role in sensitization of nociceptive neurons. High-doses of dynorphin produce hyperalgesia, in contrast to analgesia produced by low doses of dynorphin (Vanderah et al., 1996; Laughlin et al., 1997). The hyperalgesic effect is considered to be independent of activation of opioid receptors. The i.t. administration of dynorphin A evokes long-lasting allodynia through NMDA receptors rather than non-opioid mechanisms (Vanderah et al., 1996; Laughlin et al., 1997). Big dynorphin, a prodynorphin-derived peptide, in low fmol amounts, as well as dynorphin A also induces scratching, biting and licking after i.t. injection into the mouse spinal cord (Tan-No et al., 2002). The nociceptive response is naloxone-irreversible. Interestingly, recent studies show that N-ethylmaleimide, a cysteine protease inhibitor, is able to induce similar nociceptive signs by blocking the degradation of prodynorphin-derived peptides (Tan-No et al., 2005). These behavioural findings suggest that spinal dynorphin may also be an importance mediator of morphine-induced nociception (Malan et al., 2000; Wang et al., 2001). Indeed, continuous spinal infusion of morphine produces enhanced sensitivity to normally innocuous mechanical stimuli and thermal hyperalgesia (Vanderah et al., 2000). This spinal treatment elevates dynorphin content in the spinal cord.
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Therefore, it cannot be denied that i.t. high-dose morphine may facilitate dynorphin release from primary afferent neurons, which may be related to induction of nociceptive response to i.t. high-dose morphine.
MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL NITRIC OXIDE There is much evidence to suggest that nitric oxide (NO), an endogenous short-living free radical gas, is involved in the transmission of nociceptive information in the spinal cord (Meller and Gebhart, 1993). NO production is intimately linked to NMDA receptor activation via increased intracellular Ca2+. NO is synthetized from L-arginine through the action of catalytic enzyme, of which there are three types: two of those are constitutive forms, endothelial NOS (eNOS) and neuronal NOS (nNOS) that are calcium/calmodulin-dependent while the third is inducible NOS (iNOS) that is calcium/calmodulin-independent (Nathan and Xie, 1994). Behavioural studies to elucidate the functional role of NO have used inhibitors of NO synthase (NOS) such as L-NG-nitro arginine methyl ester (L-NAME) and G L-N -monomethyl arginine (Moncada et al., 1991). Several studies have demonstrated that spinal NO is involved in nociceptive responses induced by subcutaneous injection of formalin and capsaicin into the hindpaw (Moore et al., 1991; Haley et al., 1992; Malmberg and Yaksh, 1993; Yamamoto et al., 1993; Sakurada et al., 1996a, 1996b, 2001; Watanabe et al., 2003a). NO has also been implicated in spinal cord mechanisms of hyperalgesia induced by peripheral nerve injury (Meller et al., 1992b) and i.t. administration of NMDA (Kitto et al., 1992). Therefore, it is obvious that NO plays a significant role in nociception and hyperalgesia in the spinal cord (Fig. 1). The i.t. administration of high-dose morphine evokes a significant of nitrite/nitrate and glutamate release in the dorsal spinal cord extracellular fluid in rats (Watanabe et al., 2003b). Similar to behavioural results, the increased concentration of nitrite/nitrate and glutamate to i.t. high-dose-morphine is not reversed by peripheral and i.t. naloxone. It therefore reinforces the concept that the effects of i.t. high-dose morphine are brought about by mechanisms that are not dependent of opioid receptor activity in the spinal cord. Pretreatment with the NO synthase inhibitor LNAME causes a significant inhibition of the agitation and vocalization response to i.t. high-dose morphine, whereas D-NAME, an inactive isomer of L-NAME, is ineffective. The behavioural data are in accordance
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with the results that L-NAME prevents a significant increase of nitrite/nitrate release. Considering that NO functions as an intermediary of NMDA receptors in the spinal cord, it seems that i.t. high-dose morphine can act as a nociceptive input through activation of NMDA receptors and NO production. NMDA receptormediated central sensitization and hyperalgesia involves subsequent production of NO (Meller et al., 1992a) and augumented release of glutamate induced by NMDA receptor activation occurs secondary to NO production (Sorkin, 1993). This assumption is supported by the microdyalysis data that morphine-evoked releases of nitrite/nitrate and glutamate are inhibited by pretreatment with the competitive and non-competitive NMDA receptor antagonists, CPP and MK-801 (Watanabe et al., 2003b). More recently, we have demonstrated that i.t. administration of morphine in a high concentration also increases spinal nNOS expression in mice (Komatsu et al., 2004). The induced nociceptive behaviour by i.t. high-dose morphine is inhibited by 7-nitroindazole, a selective nNOS inhibitor rather than 1400 W, a selective iNOS inhibitor. It is therefore evident that nNOS-NO pathway in the spinal cord is involved in elicitation of the nociceptive behaviour after i.t. high-dose morphine.
MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL METABOLITES OF MORPHINE Much attention has to be paid that the effects of synthetic or endogenous compounds may be attributed to the action of their metabolites rather than a direct action of the compound. Morphine is metabolized by conjugation with glucuronide to two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide (Boerner et al., 1975). The antinociceptive potency of morphine-6-glucuronide after intracerebroventricular (i.c.v.) or i.t. administration in rats is greater than that of morphine (Shimomura et al., 1971; Christensen and Jorgensen, 1987; Pasternak et al., 1987). Morphine-6 glucuronide as well as morphine is more selective for m-opioid receptors than for d- and kreceptors (Paul et al., 1989). Morphine-3-glucuronide has been found to detect more than half of morphine administered systemically to rats and humans (Smith, 2000). This metabolite has no binding activity with opioid receptors (Shimomura et al., 1971; Smith, 2000), which is devoid of antinociceptive activity in the behavioural and electrophysiological tests (Shimomura et al., 1971; Sullivan et al., 1989). However, in
spite of this apparent lack of activity, i.t. and i.c.v. administrations of morphine-3-glucuronide have been reported to evoke a range of excitatory behaviours including hyperalgesia, allodynia, myoclonus and seizures in rats, which are independent of non-opioid mechanisms (Woolf, 1981; Yaksh et al., 1986; Yaksh and Harty, 1988; Smith, 2000). Morphine-3-glucuronide is much more potent in evoking hyperalgesia and allodynia than morphine in rats (Woolf, 1981; Yaksh and Harty, 1988). Morphine-3-glucuronide has also shown to act as a functional antagonist of the antinociceptive activities of morphine and morphine-6glucuronide (Smith et al., 1990; Gardmark et al., 1998; Kuo et al., 1991; Gong et al., 1992). Thus, morphine metabolites, morphine-6-glucuronide and morphine-3-glucuronide, completely differ in their pharmacological effects. Both high-dose morphine (150 mg) and morphone-3-glucuronide (3 mg) elicit hyperesthesia and allodynia when administered to rats by the i.t. route (Yaksh et al., 1986). It is therefore plausible that allodynia and hyperalgesia evoked by spinal morphine at a high concentration may result from an increasing accumulation of morphine-3-glucuronide in the spinal cord. This view is supported by our recent behavioural study that i.t. administration of morphine-3-glucuronide at 1/20 the concentration of morphine could induce a nociceptive syndrome of scratching, biting and licking in mice that is indistinguishable from that caused by i.t. morphine at a high concentration (Kohno et al., 2003). These observations lead us to speculate that morphine-3-glucuronide may be responsible for nociceptive behaviour of scratching, biting and licking in mice or vocalization response in rats seen after i.t. high-dose morphine treatment. In conclusion, it is obvious that morphine has both an antinociceptive activity through opioid receptors, and a nociceptive effect through non-opioid mechanism. Hyperalgesia and allodynia are observed both in human and experimental models after i.t. administration of high-dose morphine. This review has explored several different possible mechanisms of spontaneous nociceptive response to i.t. high-dose morphine in animals. The i.t. administration of morphine in a high concentration results in an increased release of substance P and glutamate from the primary afferents in the dorsal horn of the spinal cord. The increased levels of substance P and glutamate induced by high-dose morphine could activate NK1 and NMDA receptors in the post-synaptic neurons. Many distinct pharmacological agents attenuate or block the morphine-induced behaviour: NK1 receptor antagonists, capsaicin, substance P antiserum, NMDA receptor antagonists or
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NOS inhibitors. In addition, it is also of importance to note, however, that subsequent intracellular cascades as well as NO production may result in nociceptive consequences. Diverse targets except these components may be involved in elicitation of nociceptive response evoked by i.t. high-dose morphine. Whatever mechanism is involved, therapeutic strategies to diminish the release of nociceptive neurotransmitters/neuromodulators in the spinal cord and to inhibit the activation of receptors related to nociceptive processing could reduce pain-related behaviour to i.t. highdose morphine. Further study is needed to elucidate this important issue that has enormous implications in the clinical management of pain.
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Review
Mechanisms of Nociception Evoked by Intrathecal High-dose Morphine Tsukasa Sakurada 1,*, Takaaki Komatsu 1, Shinobu Sakurada 2 1
Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan 2 Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan Received 6 December 2004; accepted 20 December 2004 Available online 4 June 2005
Abstract Morphine is recommended by WHO as the analgesic of choice for effective treatment of moderate to severe cancer pain [World Health Organisation. Cancer pain relief, 2nd ed. Geneva: WHO; 1996]. Indeed spinally administered morphine at small doses injected intrathecally (i.t.) or intracerebroventricularly into animals produces a profound antinociception at both spinal and supraspinal sites. Conversely, high doses of spinally administered morphine elicit a series of scratching, biting and licking in mice, and vocalization and agitation in rats, indicative of a spontaneous nociceptive behavioural response. Hyperalgesia and allodynia are also induced by such morphine treatment in humans as well as animals. These behaviours are not an opioid receptor-mediated event. This article will review the potential mechanisms of spinally mediated nociceptive behaviour evoked by i.t. morphine at high concentrations. We will discuss a possible presynaptic release of nociceptive neurotransmitters/neuromodulators (e.g., substance P, glutamate and dynorphin) in the primary afferent fibers following i.t. high-dose morphine. There must be an intimate interaction of i.t. high-dose morphine with tachykinin neurokinin 1 (NK1) receptors and multiple sites on the N-methyl-D-aspartate (NMDA) receptor complex in the dorsal spinal cord. Since the effect of NMDA receptor activation and the associated Ca2+ influx results in production of nitric oxide (NO) by activation of NO synthase, it seems that spinal NO also plays an important role in nociception evoked by i.t. high-dose morphine. Morphine-3-glucuronide, one of the major metabolites of morphine, has been found to evoke nociceptive behaviour similar to that of i.t. high-dose morphine. It is plausible that morphine-3-glucuronide may be responsible for nociception seen after i.t. high-dose morphine treatment. The demonstration of neural mechanism underlying morphine-induced nociception provides a pharmacological basis for improved pain management with morphine at high doses.
# 2005 Elsevier Inc. All rights reserved. Keywords: Morphine; Intrathecal injection; Spinal cord; Nociceptive behaviour; Substance P; Glutamate; NK1 receptor; NMDA receptor; Nitric oxide
Contents INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MORPHINE-INDUCED NOCICEPTIVE BEHAVIOUR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL SUBSTANCE P AND GLUTAMATE . MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL NITRIC OXIDE. . . . . . . . . . . . . . . . MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL METABOLITES OF MORPHINE . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Corresponding author. Tel.: +81 92 541 0161x416; fax: +81 92 553 5698. E-mail address: [email protected] (T. Sakurada). 0161-813X/$ – see front matter # 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuro.2004.12.011
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INTRODUCTION Morphine with a potent analgesic property has been widely used for the treatment of various kinds of acute pain and for long-term treatment of severe chronic pain. With the advance of pain pharmacology the dorsal horn of the spinal cord is believed to be an important site for the mediation of the antinociceptive effect of morphine and opioids (Yaksh, 1981; Akil et al., 1984; Basbaum and Fields, 1984). There are at least three types of opioid receptors, referred to as m, d and k, in the adult mammalian spinal cord (Mack et al., 1984; Traynor and Rance, 1984). Small doses of spinally administered morphine, when injected epidurally and intrathecally (i.t.), produce reliable analgesia. Animal studies have documented that in the formalininduced flinching test i.t. administration of morphine into rats over a dose range of 1–20 nmol produces a reliable antinociceptive effect by interacting with opioid receptors in the dorsal spinal cord (Watanabe et al., 2003a). As shown in Table 1, some studies have demonstrated that morphine at doses far higher than those required for antinociception, injected i.t. into the spinal subarachnoid space, produces a spontaneous vocalization/squeaking and agitation as well as hyperalgesia and allodynia as opposed to the antinociception at small doses (Tang and Schoenfeld, 1978; Woolf, 1981; Yaksh et al., 1986; Alvarez-Vega et al., 1998). Furthermore, i.t. administration of high-dose morphine into mice was found to induce scratching, biting and licking resembling that of substance P or N-methyl-Daspartate (NMDA) injected i.t. The characteristic behavioural responses are antagonized by co-administration of tachykinin neurokinin 1 (NK1) receptor antagonists, and various types of NMDA receptor antagonists (Sakurada et al., 1996c, 2002). Morphine, injected i.t. into mice, induces a hyperalgesic response to
noxious stimuli and an allodynic response to innocuous tactile stimuli in mice (Hara et al., 1997). A hyperalgesic action has also been known to develop after chronically administered morphine in rats (Kayan and Mitchell, 1968; Mule et al., 1968). In addition, a similar phenomenon has been recognized in humans who developed hyperalgesia, allodynia and myoclonus following i.t. and systemical administrations of morphine at high concentrations (Wert and MacDonald, 1982; Krames et al., 1985; Ali, 1986; Penn and Paice, 1987; Arner et al., 1988; Glavina and Robertshaw, 1988; Potter et al., 1989; Parkinson et al., 1990; Sjogren et al., 1993; De Conno et al., 1991). Previous studies have demonstrated that pain-related behaviours (e.g., hyperalgesia, allodynia, and scratching, biting and licking) and myoclonus evoked by i.t. high-dose morphine are not an opioid receptor-mediated event, since these behaviours evoked by i.t. high-dose morphine are not reversed by pretreatment with naloxone, an opioid receptor antagonist (Yaksh et al., 1986; Yaksh and Harty, 1988; Lutfy et al., 1994; Sakurada et al., 2002; Watanabe et al., 2003b). The mechanism of action underlying i.t. high-dose morphine-associated nociception is still unclear but a critical role has been attributed to an endogenous pain facilitatory system involving NK1 and NMDA receptors in the spinal cord. NMDA receptor activation leads to an increase of NO production, apparently via increased intracellular Ca2+. There is evidence to suggest that NO plays a significant role in spinal nociceptive processing (Meller and Gebhart, 1993). It is also of importance to assess if the phenomena of spontaneous nociception evoked by acutely administered high-dose morphine through i.t. route are due to morphine itself and/or its glucuronide metabolites. To explore possible mechanisms of high-dose morphine-induced nociception may be clinically useful for
Table 1 Comparison of antinociceptive and nociceptive dose of morphine injected intrathecally into animals Response observed
Species
Antinociceptive dose (ED50) or nociceptive dose
References
Antinociception
Mouse
0.15 nmol (early phase formalin test) 0.06 nmol (late phase formalin test)
Sakurada et al. (1995) Sakurada et al. (1995)
Rat
24.5 nmol (early phase formalin test) 16.0 nmol (late phase formalin test)
Watanabe et al. (2003a, 2003b) Watanabe et al. (2003a, 2003b)
Mouse
60–90 nmol (SBL) 30–90 nmol (scratching)
Sakurada et al. (1996c) Sakurada et al. (1996c)
Rat
150 mg (6400 nmol) (agitation) 520 nmol (vocalization, agitation and SBL) 125–500 nmol (agitation) 500 nmol (vocalization)
Yaksh and Harty (1988) Alvarez-Vega et al. (1998) Watanabe et al. (2003a, 2003b) Watanabe et al. (2003a, 2003b)
Nociception
SBL; scratching, biting and licking.
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improved pain management with morphine and opioid analgesics.
MORPHINE-INDUCED NOCICEPTIVE BEHAVIOUR Though morphine and related opioids are widely used to alleviate in the clinical management of pain, its use is often accompanied by tolerance and dependence (Collin and Cesselin, 1991; Trujillo and Akil, 1991; Pasternak, 1993). This has led to increases in opioid dosing requirements during pain, and elicits nonanalgesic side effects such as nausea, respiratory depression and urinary retention. It has also been known that a single spinal administration of morphine into rats at high doses results in hyperalgesia (an increased sensitivity to a stimulus), allodynia (a nociceptive response to an innocuous stimulation), and spontaneous vigorous agitation or vocalization (Woolf, 1981; Yaksh and Harty, 1988; Watanabe et al., 2003b). Mice also exhibited a characteristic nociceptive response after i.t. administration of high-dose morphine (Sakurada et al., 1996c). However, there is a qualitative difference of nociceptive behavioural response to i.t. high-dose morphine in mice when compared with rats; in mice administration of morphine at a high dose of 60 nmol into the spinal lumbar i.t. space elicits a nociceptive behavioural syndrome characterized by severe reciprocal hindlimb scratching followed by biting and licking toward the caudal part of the body without squeaking in mice (Sakurada et al., 1996c; Watanabe et al., 2003b). Behavioural evidence indicates that the latency of morphine-induced scratching is much later than that of substance P- and NMDAinduced response, which occurred within 10 s following i.t. administration in mice. Similarly the vocalization response to i.t. administration of morphine (500 nmol) is late in onset (over 60 s). It is readily speculated that morphine at a high-concentration promotes the presynaptic release of one or more nociceptive neurotransmitters/neuromodulators such as substance P, glutamate or calcitonin-gene related peptide (CGRP) in the dorsal horn of the spinal cord. In rats, high-doses of morphine, injected into the spinal lumbar i.t. space, have been shown to produce a spontaneous nociceptive syndrome mainly consisting of agitation and vocalization (Watanabe et al., 2003b). The behavioural activation evoked by i.t. high-dose morphine are irreversible by the opioid receptor antagonist, naloxone or naltrexone, suggesting a non-opioid receptor mechanism (Woolf, 1981; Yaksh
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et al., 1986; Yaksh and Harty, 1988; Sakurada et al., 2002; Watanabe et al., 2003b). The inability of naloxone to reverse morphine-induced nociceptive response is consistent with the reports that allodynia and clonic seizure-like motor effect produced by i.t. high-dose morphine could not block by opioid receptor antagonists (Yaksh and Harty, 1988; Lutfy et al., 1994). Highdoses of spinally administered morphine have also been reported to produce hyperalgesia in response to noxious stimuli in rats (Woolf, 1981). The morphineinduced hyperalgesia is of clinical interest since hyperalgesic and allodynic states have been reported to occur in humans following administration of high-dose subarachnoid morphine or systemic administration of opioid (Seymour et al., 1982; Wert and MacDonald, 1982; Krames et al., 1985; Ali, 1986; Penn and Paice, 1987; Arner et al., 1988; Glavina and Robertshaw, 1988; Potter et al., 1989; Parkinson et al., 1990; De Conno et al., 1991; Sjogren et al., 1993).
MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL SUBSTANCE P AND GLUTAMATE Substance P is a well-established neurotransmitter/ neuromodulator of nociception in the spinal cord (Basbaum, 1999; Saria, 1999). Administration of morphine and opioid peptides inhibits specifically the release of substance P (Jessell and Iversen, 1977; Yaksh et al., 1980), whereas substance P release is increased by hyperalgesic conditions associated with inflammation (Garry and Hargreaves, 1992; Meller and Gebhart, 1994). The hyperalgesic response can be evoked by i.t. administered substance P (Yashpal et al., 1982; Matsumura et al., 1985). Substance P induces spontaneous nociceptive response consisting of scratching, biting and licking when administered i.t. into mice and rats (Hylden and Wilcox, 1981; Seybold et al., 1982; Takahashi et al., 1987; Bossut et al., 1988). Tachykinin NK1 receptor antagonists produce antinociceptive response in well-established models of pain (Sakurada et al., 1993, 1994b, 1995), as well as blocking scratching, biting and licking responses to i.t. substance P (Sakurada et al., 1989, 1991, 1992, 1994a). The nociceptive response to i.t. high-dose morphine is qualitatively similar to that induced by i.t. injection of substance P. Spinally-mediated behavioural responses evoked by i.t. high-dose morphine are inhibited by i.t. co-administration of the NK1 receptor antagonists, sendide and CP-96,345 in mice (Sakurada et al., 1996c). Pretreatment with i.t. anti-
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Fig. 1. Schematic representation of spinal mechanism in nociception evoked by intrathecal administration of morphine at high doses. Glu: glutamate; SP: substance P; NMDA: N-methyl-D-aspartate; NK1: neurokinin 1; NO: nitric oxide; NOS: nitric oxide synthase; L-Arg: L-arginine; L-Cit: L-citrulline; GC-S: soluble guanylyl cyclase; GTP: guanylyl triphosphate; cGMP: cyclic guanylyl monophosphate.
serum against substance P and i.t. capsaicin, a nonselective substance P depletor, caused a significant reduction of the behavioural response to high-dose morphine. Therefore, morphine-induced behavioural response is considered to be mediated via the release of substance P from the primary afferents in the spinal cord (Fig. 1). This concept is suppotted by in vivo experiments that morphine at high concentrations facilitates substnce P release from guinea-pig brain slices (Chahl, 1990) and from afferent terminals in the trigeminal nucleus (Suarez-Roca et al., 1992). In addition to substance P, the importance of the activation of the NMDA receptor by glutamate is suggested in the mediation of central sensitization. Neurochemical studies show the presence of glutamate in small-diameter dorsal root ganglion neurons (Battaglia and Rustioni, 1988) and in terminals in the superficial dorsal horn of the spinal cord (De Biasi and Rustioni, 1988; Miller et al., 1988). Peripheral stimulation of nociceptive afferents leads to a significant release of glutamate in the spinal cord in vitro (Kangrga and Randic, 1991; Skilling et al., 1988; Malmberg and Yaksh, 1995; Okuda et al., 2001). The NMDA receptor is a ligand-gated ion channel
complex that has multiple regulatory sites sensitive to open channel blockers, glycine and polyamine (Cunningham et al., 1994). Functionally, the NMDA receptor has been suggested to be involved in nociceptive transmission and processing within the spinal cord (Cahusac et al., 1984; Aanonsen and Wilcox, 1987). For instance, i.t. administration of NMDA elicits a series of scratching, biting and licking indicative of nociceptive response in mice (Aanonsen and Wilcox, 1987; Sakurada et al., 1990). Polyamine recognition site in NMDA receptor complex is also important to elicit the characteristic behavioural response to i.t. high-dose morphine, which is reduced by ifenprodil, an antagonist at the NMDA receptorcoupled polyamine site (Sakurada et al., 2002). In fact, spermine, an endogenous polyamine, at extremely low doses (fmol orders), is able to induce similar behavioural response which is ifenprodil-reversible (TanNo et al., 2000). We have demonstrated the potential interactive effects of NMDA receptor antagonists on the bahavioural episode seen after i.t. injection of highdose morphine in mice (Sakurada et al., 2002). The competitive NMDA receptor antagonists, D-APV and CPP, are the most potent in reducing the behavioural
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response of i.t administered high-dose morphine. MK801, a non-competitive NMDA receptor antagonist, blocks the behavioural response to i.t. high-dose morphine, though MK-801 is less potent than the competitive antagonists, D-APV and CPP. This is in line with our previous data that the rank order potency for inhibition of nociceptive response is CPP > DAPV > MK-801 as assayed by the capsaicin test (Sakurada et al., 1998). Capsaicin, injected i.t. into mice, evokes a pain-related behaviour such as scratching, biting and licking similar to that seen after i.t. highdose morphine (Sakurada et al., 1998). In rats, the induced behavioural response (vocalization and agitation) evoked by i.t. administration of high-dose morphine is inhibited by pretreatment with CPP, a competitive antagonist of NMDA receptor and MK801, a non-competitive NMDA receptor antagonist (Watanabe et al., 2003b). These behavioural data in mice and rats suggest that nociceptive responses induced by i.t. high-dose morphine may be mediated through an increased release of glutamate from the primary afferent terminals in the dorsal horn of the spinal cord, and subsequent activation of NMDA receptors (Fig. 1). A extensive line of investigation suggests that dynorphin, a proposed endogenous ligand for the k opioid receptor, located in the spinal cord, plays an important role in sensitization of nociceptive neurons. High-doses of dynorphin produce hyperalgesia, in contrast to analgesia produced by low doses of dynorphin (Vanderah et al., 1996; Laughlin et al., 1997). The hyperalgesic effect is considered to be independent of activation of opioid receptors. The i.t. administration of dynorphin A evokes long-lasting allodynia through NMDA receptors rather than non-opioid mechanisms (Vanderah et al., 1996; Laughlin et al., 1997). Big dynorphin, a prodynorphin-derived peptide, in low fmol amounts, as well as dynorphin A also induces scratching, biting and licking after i.t. injection into the mouse spinal cord (Tan-No et al., 2002). The nociceptive response is naloxone-irreversible. Interestingly, recent studies show that N-ethylmaleimide, a cysteine protease inhibitor, is able to induce similar nociceptive signs by blocking the degradation of prodynorphin-derived peptides (Tan-No et al., 2005). These behavioural findings suggest that spinal dynorphin may also be an importance mediator of morphine-induced nociception (Malan et al., 2000; Wang et al., 2001). Indeed, continuous spinal infusion of morphine produces enhanced sensitivity to normally innocuous mechanical stimuli and thermal hyperalgesia (Vanderah et al., 2000). This spinal treatment elevates dynorphin content in the spinal cord.
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Therefore, it cannot be denied that i.t. high-dose morphine may facilitate dynorphin release from primary afferent neurons, which may be related to induction of nociceptive response to i.t. high-dose morphine.
MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL NITRIC OXIDE There is much evidence to suggest that nitric oxide (NO), an endogenous short-living free radical gas, is involved in the transmission of nociceptive information in the spinal cord (Meller and Gebhart, 1993). NO production is intimately linked to NMDA receptor activation via increased intracellular Ca2+. NO is synthetized from L-arginine through the action of catalytic enzyme, of which there are three types: two of those are constitutive forms, endothelial NOS (eNOS) and neuronal NOS (nNOS) that are calcium/calmodulin-dependent while the third is inducible NOS (iNOS) that is calcium/calmodulin-independent (Nathan and Xie, 1994). Behavioural studies to elucidate the functional role of NO have used inhibitors of NO synthase (NOS) such as L-NG-nitro arginine methyl ester (L-NAME) and G L-N -monomethyl arginine (Moncada et al., 1991). Several studies have demonstrated that spinal NO is involved in nociceptive responses induced by subcutaneous injection of formalin and capsaicin into the hindpaw (Moore et al., 1991; Haley et al., 1992; Malmberg and Yaksh, 1993; Yamamoto et al., 1993; Sakurada et al., 1996a, 1996b, 2001; Watanabe et al., 2003a). NO has also been implicated in spinal cord mechanisms of hyperalgesia induced by peripheral nerve injury (Meller et al., 1992b) and i.t. administration of NMDA (Kitto et al., 1992). Therefore, it is obvious that NO plays a significant role in nociception and hyperalgesia in the spinal cord (Fig. 1). The i.t. administration of high-dose morphine evokes a significant of nitrite/nitrate and glutamate release in the dorsal spinal cord extracellular fluid in rats (Watanabe et al., 2003b). Similar to behavioural results, the increased concentration of nitrite/nitrate and glutamate to i.t. high-dose-morphine is not reversed by peripheral and i.t. naloxone. It therefore reinforces the concept that the effects of i.t. high-dose morphine are brought about by mechanisms that are not dependent of opioid receptor activity in the spinal cord. Pretreatment with the NO synthase inhibitor LNAME causes a significant inhibition of the agitation and vocalization response to i.t. high-dose morphine, whereas D-NAME, an inactive isomer of L-NAME, is ineffective. The behavioural data are in accordance
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with the results that L-NAME prevents a significant increase of nitrite/nitrate release. Considering that NO functions as an intermediary of NMDA receptors in the spinal cord, it seems that i.t. high-dose morphine can act as a nociceptive input through activation of NMDA receptors and NO production. NMDA receptormediated central sensitization and hyperalgesia involves subsequent production of NO (Meller et al., 1992a) and augumented release of glutamate induced by NMDA receptor activation occurs secondary to NO production (Sorkin, 1993). This assumption is supported by the microdyalysis data that morphine-evoked releases of nitrite/nitrate and glutamate are inhibited by pretreatment with the competitive and non-competitive NMDA receptor antagonists, CPP and MK-801 (Watanabe et al., 2003b). More recently, we have demonstrated that i.t. administration of morphine in a high concentration also increases spinal nNOS expression in mice (Komatsu et al., 2004). The induced nociceptive behaviour by i.t. high-dose morphine is inhibited by 7-nitroindazole, a selective nNOS inhibitor rather than 1400 W, a selective iNOS inhibitor. It is therefore evident that nNOS-NO pathway in the spinal cord is involved in elicitation of the nociceptive behaviour after i.t. high-dose morphine.
MECHANISMS OF MORPHINE-INDUCED NOCICEPTION: SPINAL METABOLITES OF MORPHINE Much attention has to be paid that the effects of synthetic or endogenous compounds may be attributed to the action of their metabolites rather than a direct action of the compound. Morphine is metabolized by conjugation with glucuronide to two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide (Boerner et al., 1975). The antinociceptive potency of morphine-6-glucuronide after intracerebroventricular (i.c.v.) or i.t. administration in rats is greater than that of morphine (Shimomura et al., 1971; Christensen and Jorgensen, 1987; Pasternak et al., 1987). Morphine-6 glucuronide as well as morphine is more selective for m-opioid receptors than for d- and kreceptors (Paul et al., 1989). Morphine-3-glucuronide has been found to detect more than half of morphine administered systemically to rats and humans (Smith, 2000). This metabolite has no binding activity with opioid receptors (Shimomura et al., 1971; Smith, 2000), which is devoid of antinociceptive activity in the behavioural and electrophysiological tests (Shimomura et al., 1971; Sullivan et al., 1989). However, in
spite of this apparent lack of activity, i.t. and i.c.v. administrations of morphine-3-glucuronide have been reported to evoke a range of excitatory behaviours including hyperalgesia, allodynia, myoclonus and seizures in rats, which are independent of non-opioid mechanisms (Woolf, 1981; Yaksh et al., 1986; Yaksh and Harty, 1988; Smith, 2000). Morphine-3-glucuronide is much more potent in evoking hyperalgesia and allodynia than morphine in rats (Woolf, 1981; Yaksh and Harty, 1988). Morphine-3-glucuronide has also shown to act as a functional antagonist of the antinociceptive activities of morphine and morphine-6glucuronide (Smith et al., 1990; Gardmark et al., 1998; Kuo et al., 1991; Gong et al., 1992). Thus, morphine metabolites, morphine-6-glucuronide and morphine-3-glucuronide, completely differ in their pharmacological effects. Both high-dose morphine (150 mg) and morphone-3-glucuronide (3 mg) elicit hyperesthesia and allodynia when administered to rats by the i.t. route (Yaksh et al., 1986). It is therefore plausible that allodynia and hyperalgesia evoked by spinal morphine at a high concentration may result from an increasing accumulation of morphine-3-glucuronide in the spinal cord. This view is supported by our recent behavioural study that i.t. administration of morphine-3-glucuronide at 1/20 the concentration of morphine could induce a nociceptive syndrome of scratching, biting and licking in mice that is indistinguishable from that caused by i.t. morphine at a high concentration (Kohno et al., 2003). These observations lead us to speculate that morphine-3-glucuronide may be responsible for nociceptive behaviour of scratching, biting and licking in mice or vocalization response in rats seen after i.t. high-dose morphine treatment. In conclusion, it is obvious that morphine has both an antinociceptive activity through opioid receptors, and a nociceptive effect through non-opioid mechanism. Hyperalgesia and allodynia are observed both in human and experimental models after i.t. administration of high-dose morphine. This review has explored several different possible mechanisms of spontaneous nociceptive response to i.t. high-dose morphine in animals. The i.t. administration of morphine in a high concentration results in an increased release of substance P and glutamate from the primary afferents in the dorsal horn of the spinal cord. The increased levels of substance P and glutamate induced by high-dose morphine could activate NK1 and NMDA receptors in the post-synaptic neurons. Many distinct pharmacological agents attenuate or block the morphine-induced behaviour: NK1 receptor antagonists, capsaicin, substance P antiserum, NMDA receptor antagonists or
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NOS inhibitors. In addition, it is also of importance to note, however, that subsequent intracellular cascades as well as NO production may result in nociceptive consequences. Diverse targets except these components may be involved in elicitation of nociceptive response evoked by i.t. high-dose morphine. Whatever mechanism is involved, therapeutic strategies to diminish the release of nociceptive neurotransmitters/neuromodulators in the spinal cord and to inhibit the activation of receptors related to nociceptive processing could reduce pain-related behaviour to i.t. highdose morphine. Further study is needed to elucidate this important issue that has enormous implications in the clinical management of pain.
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