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A Calcitonin Gene-Related Peptide Receptor Antagonist Prevents the Development of Tolerance to Spinal Morphine Analgesia

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A Calcitonin Gene-Related Peptide Receptor Antagonist Prevents the Development of Tolerance to Spinal Morphine Analgesia The Journal of Neuroscience, April 1, 1996, 16(7):2342-2351 A Calcitonin Gene-Related Peptide Receptor Antagonist Prevents the Development of Tolerance to Spinal Morphine Analgesia Daniel P. M6nard,l Denise van Rossurn,’ S. Kar,l S. St. Pierre,2 M. Sutak,3 K. Jhamandas,3 and R6mi Quirionl l Douglas Hospital Research Center and Department of Psychiatry and Pharmacology and Therapeutics, McGill University, Verdun, Quebec, Canada, H4H I R3, 21nstitut Nationale de la Recherche Scientifique-Santi: Pointe Claire, Quebec, Canada, H9R 1 G6, and “Department of Pharmacology, Queen’s University, Kingston, Ontario, Canada K7L 3N6 Tolerance to morphine analgesia is believed to result from a deed, cotreatments with hCGRP,,, prevented, in a dose- neuronal adaptation produced by continuous drug administra- dependent manner, the development of tolerance to morphine- tion, although the precise mechanisms involved have yet to be induced analgesia in both the rat tail-flick/tail-immersion and established. Recently, we reported selective alterations in rat paw-pressure tests. Moreover, alterations in spinal CGRP spinal calcitonin gene-related peptide (CGRP) markers in markers seen in morphine-tolerant animals were not observed morphine-tolerant animals. In fact, increases in CGRP-like im- after a coadministration of morphine and hCGRP,-,,. These munostaining and decrements in specific [‘251]hCGRP binding results demonstrate the existence of specific interaction be- in the superficial laminae of the dorsal horn were correlated with tween CGRP and the development of tolerance to the spinal the development of tolerance to the spinal antinociceptive ac- antinociceptive effects of morphine. They also suggest that tion of morphine. Other spinally located peptides such as sub- CGRP receptor antagonists could become useful adjuncts in stance P, galanin, and neuropeptide Y were unaffected. Thus, the treatment of pain and tolerance to the antinociceptive the major goal of the present study was to investigate whether effects of morphine. the development of tolerance to spinally infused morphine could be modulated by the blockade of dorsal horn CGRP Key words: analgesia;autoradiography; immunostaining;spi- receptors using the potent CGRP antagonist hCGRP,-,,. In- nal cord; opioids; tolerance Morphine is used widely in the clinical management of various cholecystokinin (Rezayat et al., 1994), potentiated morphine an- types of pain, including as an adjunct in the treatment of cancer algesia in naive animals (Gouardkres et al., 1993b; Rezayat et al., (Trachtenberg, 1994). Although morphine is very useful as an 1994; Stanfa et al., 1994). Thus, recent interest has focused on the analgesic, its clinical application in chronic pain is limited by rapid possible role of substance P (SP) in the antinociception and development of tolerance to its antinociceptive properties (John- tolerance to the spinal effects of morphine, because this neu- stone and Smith, 1992). The basis of tolerance to the antinocicep- ropeptide is one of the major sensory peptides modulating pain tive actions of morphine and related opioids is only poorly under- transmission (Hem-y, 1976). Consistent alterations in spinal SP stood (Collier and Schneider, 1969; Yaksh and Noueihed, 1985; markers, however, have not been observed in morphine-tolerant Rasmussen et al., 1990; Yamamoto and Meltzer, 1992). For animals (Gouardkres et al., 1993a; MCnard et al., 1995a). example, although a possible role for brain and spinal cord opioid Calcitonin gene-related peptide (CGRP) is known to be colo- receptors in tolerance has been proposed (Holt et al., 1975; Pert calized with SP and glutamate and co-released with SP from and Snyder, 1976; Werling et al., 1989), clear evidence for their primary afferent fibers in the dorsal horn of the spinal cord direct involvement and that of opioid receptor-linked transduc- (Gibson et al., 1984; Woolf and Wiesenfeld-Hallin, 1986). Specific tion mechanisms (De Vries et al., 1991) is still mostly lacking. CGRP receptor binding sites are concentrated in the dorsal horn Recently it was proposed that tolerance to the antinociception of of the spinal cord (Yashpal et al., 1992). Additionally, CGRP morphine could be mediated, at least in part, through the activa- induces algesic effects in certain models of nociception (Cridland tion of physiologically antagonistic systems and/or the inhibition and Henry, 1988) and modulates acute antinociceptive action of of facilitatory ones (Lake et al., 1991; Trujillo and Akil, 1991; opioid agonists (Welch et al., 1989). In fact, CGRP inhibits the Gutstein and Trujillo, 1993; Rezayat ct al., 1994; Stanfa et al., antinociception produced by morphine (Welch et al., 1989), 1994); however, potential antagonistic factors that may be active whereas this opiate inhibits the acute release of CGRP in the cord against tolerance, such as neuropeptide FF (Lake et al., 1991) or (Pohl et al., 1989). Recently, we reported that increases in CGRP- like immunostaining and reductions in specific [“‘I]hCGRP bind- Received July 10, 1995; revised Jan. 1 I, 1996; acccptcd Jan. 17, 1996. ing in the superficial laminae of the dorsal horn were correlated This research was supported by Medical Rcsearch Council of Canada grants to with the development of tolerance to the spinal antinociceptive K.J. and R.O. D.v.R. held a studentshio from the Fonds DOW la Formation de Chercheurs e< I’Aide ?I la Recherche. R.d. is a Chercheur-Boursier from the Fonds action of morphine (M6nard et al., 1995a) and [o-Pen’,o-Pen’]- de la Recherche en SantC du Qukbec. Travel was supported by the Ontario-Quebec enkephalin (Mknard et al., 1995b) acting as p and S agonist, Foundation. respectively. These alterations in spinal CGRP markers were not Correspondence should be addressed to Dr. RBmi Quirion, Douglas Hospital Research Centre, 6875 La&k Boulevard, Verdun, QuCbec, Canada H4H 1R3. observed in markers of various other sensory neuropeptides (SP, Copyright 0 1996 Society for Neuroscience 0270.6474/96/162342-10$05.00/O galanin, neurotensin, and neuropeptide Y). To examine the sig- MBnard et al. Morphine Tolerance and CGRP J. Neurosci., April 1, 1996, 76(7):2342-2351 2343 22 - mo 7.5pg --)- mo+E-37 2.Opg 20 I * mo+E-37 l.Opg * saline 72 18 * z 18 g 14 Esi 12 ii 10 8 J 6 22 ---e mo 7.5pg A mo+E-37 0.5yg 20 * mo+E-37 0.25pg * saline 18 16 14 12 10 8 Figure I. Time course of the antinociceptive effect of a 7 d continuous intrathecal morphine (mo: 7.5 kg/hr) infusion 6 alone and with CGRP,,, (mo + 8-37: 0.25, 0.50, 1.0, and 2.0 &hr) in the tail-immersion test. CGRP,-a, at day 5 in 4 the 0.5 wg/hr group and days 5 and 7 in the 1.0 and 2.0 &hr groups significantly inhibited the development of tolerance to mornhine-induced antinociceution. Data shown reuresent 0 1 3 5 7 mean ~' i SEM of 8-12 animals per group. *p < 0.05 indicates a significant difference from corresponding value in the mor- DAYS phine group. nificance of morphine-induced changes in spinal CGRP systems in gift of Dr. J. M. Polak (Royal Postgraduate Medical School, London, the development of tolerance, we have now investigated the UK). Bovine serum albumin (BSA), bacitracin, leupeptin, chymostatin, action of the CGRP receptor antagonist CGRP,-,, (Dennis et al., goat anti-rabbit IgG, pcroxidase anti-peroxidase (PAP), 3,3’ diamino benzidine tetrahydrochloride (DAB), and HEPES buffer were obtained 1990) on this phenomenon, using a continuous spinal morphine from Sigma Chemicals (St. Louis, MO), whereas miniosmotic pumps infusion model of tolerance. The potential efficacy of the CGRP (model 2001) were purchased from Alzet (Palo Alto, CA). Morphine blocker was evaluated in antinociceptive tests involving thermal sulfate was obtained from BDH Pharmaceuticals (Toronto, Ontario, (tail immersion/tail flick) and mechanical (paw pressure) nocicep- Canada). All other chemicals wcrc of analytical grade and purchased tive stimuli. Our results reveal that CGRP,-,, is most effective in from Fisher Scientific (Montreal, Quebec, Canada). preventing the development of tolerance to the analgesic proper- lntrathecul infusion. Under pcntobarbital or halothane anesthesia, rats were implanted with indwelling polyethylene catheters (PE-10) as de- ties of spinally infused morphine. scribed in detail elsewhere (Gouarderes et al., 1993a). For intrathecal MATERIALS AND METHODS infusions, a 7.5 cm catheter was inserted through a slit into the cisternal membrane and advanced gently to reach the lumbar (L4) subarachnoid A4uterials. Adult male Sprague-Dawley rats (300-325 gm) obtained from space. The catheter was connected previously to a short piece of PE-60 Charles River (St. Constant, Quebec, Canada) were used in the study. for attachment of the intrathecal catheter to the flow moderator of an Animals were maintained according to the guidelines of the Canadian Alzet infusion pump. Alzet miniosmotic pumps (model 2001) filled with Council on Animal Care and were given free access to food and water. saline 0.90/o, morphine sulfate (7.5 or 10 &hr), hCGRP (1.0 pg/hr), [“‘I]hCGRP (2000 Ci/mmol), microscales, and Hyperfilms were obtained from Amersham Canada (Oakville, Ontario). Unlabeled hCGRP and hCGRP,m,, (0.5 and 1.0 pg/hr), morphine (7.5 bg/hr) plus hCGRP (1.0 hCGRP,-,, were synthesized in our laboratories (Institut Nationale pg/hr), or morphine (7.5 or 10 &hr) plus hCGRP,-,, (0.5-2.0 pglhr) dc la Rechcrche Scientifique-Sante, Pointe Claire, Quebec, Canada). were implanted subcutaneously, below the back region of the neck, and hCGRP,m,, has been characterized extensively as a highly selective, connected to the intrathecal catheter. Solutions were released continu- potent, and stable CGRP receptor blocker under various in vitro and in ously at the lumbar level (flow rate, 1 ml/hr) for a 7 d period. Because of viva conditions. It is currently the most potent CGRP antagonist available the length of the intrathecal catheter, it is well established that significant (Quirion et al., 1992).
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