Evidence for an Involvement of Supraspinal - and Spinal - Opioid Receptors in the Antihyperalgesic Effect of Chronically Administered Clomipramine in Mononeuropathic Rats

The mechanisms of involvement of the opioidergic system in the antinociceptive effect of antidepressants remain to be elucidated. The present study was designed to determine what type of opioid receptors may be involved at the spinal and supraspinal levels in the antihyperalgesic effect of clomipramine, a tricyclic antidepressant commonly prescribed in the treatment of neuropathic pain. Its antihyperalgesic effect on mechanical hyperalgesia (paw pressure test) in rats induced by chronic constriction injury of the sciatic nerve was assessed after repeated administrations (five injections every half-life, a regimen close to clinical use). Naloxone administered at a dose of 1 mg/kg i.v., which blocks all opioid receptors, or at a low dose of 1 g/kg i.v., which selectively blocks the -opioid receptor, inhibited the antihyperalgesic effect of clomipramine and hence indicated that -opioid receptor is involved. Depending on whether they are administered by the intracerebroventricular or intrathecal route, specific antagonists of the various opioid receptor subtypes [D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2 (CTOP), ; naltrindole (NTI), ; and nor-binaltorphimine (nor-BNI), ] differently modify the antihyperalgesic effect of chronically injected clomipramine. The effect was inhibited by intrathecal administration of CTOP and intracerebroventricular administration of naltrindole, whereas nor-BNI was ineffective whatever the route of injection. These results demonstrate a differential involvement of opioid receptors according to the level of the central nervous system: -receptors at the supraspinal level and -receptors at the spinal level. Clomipramine could act via a neuronal pathway in which these two receptors are needed. Antidepressants (ADs) are effective in neuropathic pain treatment (Onghena and Van Houdenove, 1992; Sindrup and Jensen, 1999). Their analgesic effect seems to be independent of their thymo-analeptic action and is greater with tricyclic drugs (TCAs; nonspecific monoamine reuptake inhibitors) than specific reuptake inhibitors (Onghena and Van Houdenove, 1992). Although ADs have long been used, the mechanism of their analgesic action remains unknown. It probably involves a complex interaction between several neurotransmitter systems. The psychotropic action of ADs, the ineffectiveness of peripheral analgesics in neuropathic pain, and various clinical and experimental results (for review, see Eschalier et al., 1999) suggest a predominant central effect even though some studies have also suggested a peripheral site of action (Sawynok et al., 1999). The most usual hypothesis of mechanism of action is an involvement of the central monoaminergic systems. Their blocking of monoamine reuptake seems to play a major role by activating descending inhibitory pathways. Thus, the antinociceptive effect of various ADs is inhibited by parachlorophenylalanine (an inhibitor of serotonin synthesis), -methyl-p-tyrosine (an inhibitor of noradrenaline synthesis), and serotonin and noradrenergic receptor antagonists (Valverde et al., 1994; Yokogawa et al., 2002). Likewise, Ardid et al. (1995) reported that the antinociceptive effect of clomipramine was inhibited by lesions of the dorsolateralis funiculus, which conveys monoaminergic bulbo-spinal neurons. However, other explanations have been suggested such as an interaction with N-methyl-D-aspartate receptors (Kiefer et al., 1999), with tachykinin receptors (Iwashita and Shimizu, 1992), or with different ion channels (Antkiewicz Michaluk et al., 1991). One other possible mechanism of action for the analgesic effects of TCAs involves interaction with the opioid system. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.103.052613. ABBREVIATIONS: AD, antidepressant; TCA, tricyclic antidepressant; CMI, clomipramine; CCI, chronic constriction injury; DAMGO, [D-Ala,NMe-Phe,Gly-ol]-enkephalin; BUBUC, lsqb]D]-Enkephalin-Thr(OtBU); CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2; NTI, naltrindole; norBNI, nor-binaltorphimine. 0022-3565/03/3071-268–274$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 307, No. 1 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 52613/1093364 JPET 307:268–274, 2003 Printed in U.S.A. 268 at A PE T Jornals on Sptem er 3, 2017 jpet.asjournals.org D ow nladed from ADs are able to displace radiolabeled opioid receptor ligands from their binding sites and, after repeated administration, to modify the density of opioid receptors (Isenberg and Cicero, 1984; Hamon et al., 1987). Several studies have evidenced the inhibition of the antinociceptive effect of ADs by naloxone (Ardid and Guilbaud, 1992; Valverde et al., 1994; Gray et al., 1998; Schreiber et al., 2000), an opioid receptor antagonist, and its enhancement by enkephalinase inhibitor (Gray et al., 1998). However, few studies have been conducted to determine the involvement of the different opioid receptor subtypes in the analgesic effect of ADs. Schreiber et al. (2000) and Gray et al. (1998) demonstrated that the antinociceptive effect of different ADs was mainly influenced by different opioid receptor antagonists. However, these studies failed to determine the involvement of a specific opioid subtype receptor according to the ADs used. The precise point of the neuroaxis at which the opioid receptor is involved was not evaluated, and the studies were performed with acute injections and in acute pain conditions, which does not reflect the clinical use of ADs. Eschalier et al. (1988) and Ardid and Guilbaud (1992) showed that repeated injection (every halflife) induced higher antinociceptive effect than acute administration in acute or chronic pain models, respectively. The aim of the present study was to identify subtypes of opioid receptors involved in the antihyperalgesic effect of repeated administration of clomipramine (CMI) and the site, spinal and/or supraspinal, of their involvement in chronic constriction injury, a mononeuropathic pain model (Bennett and Xie, 1988). Materials and Methods