title: Spinal modulation of calcitonin gene-related peptide by endocannabinoids in the development of opioid physical dependence.
abstract: Studies implicate endocannabinoids in the acute and chronic actions of opioid drugs, including the genesis of physical dependence. Previous evidence suggests that spinal release of calcitonin gene-related peptide (CGRP) and activation of its receptors contribute to opioid physical dependence. The release of CGRP at the spinal level is modulated by cannabinoid (CB1)-receptors. Thus, this study examined whether CB1-receptor activity mediates changes in CGRP underlying development of opioid physical dependence. Systemic morphine administration for 5-days elevated CGRP-immunoreactivity in the rat spinal dorsal horn. In situ hybridization of dorsal root ganglion (DRG) neurons revealed an increase in CGRP mRNA during initial (day 1-3) but not later phase (day 4-5) of morphine treatment. CGRP-immunoreactivity in DRG neurons, however, was increased in the later phase of morphine treatment. Naloxone challenge to morphine-treated animals precipitated an intense withdrawal syndrome that depleted CGRP-immunoreactivity and increased Fos expression in the dorsal horn. The Fos-response primarily occurred in neurons that expressed CGRP receptor component protein (RCP) suggesting CGRP activity contributes to neuronal activation during precipitated withdrawal. Spinal slices obtained from morphine-treated animals showed higher levels of CGRP release than from saline controls. Intrathecal co-administration of CB1-receptor antagonists, AM-251 or SR141716A, with daily morphine attenuated the behavioral manifestations of withdrawal. Treatment with AM-251 also reduced the depletion of CGRP, suppressed Fos-induction, and prevented the increase in capsaicin-evoked spinal CGRP release. Altogether, this study suggests that endocannabinoid activity, expressed via CB1-receptors, contributes to the induction of opioid physical dependence through spinal modulation of CGRP.
authors.affiliation: Department of Pharmacology and Toxicology and Anesthesiology, Queen's University Kingston, Ont., Canada K7L 3N6.
authors.forename: Tuan
authors.initials: T
authors.lastname: Trang
authors.forename: Weiya
authors.initials: W
authors.lastname: Ma
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Chabot
authors.forename: Remi
authors.initials: R
authors.lastname: Quirion
authors.forename: Khem
authors.initials: K
authors.lastname: Jhamandas
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002186:Cannabinoids / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D004334:Drug Administration Schedule; D063388:Endocannabinoids; D005727:Ganglia, Spinal / Q000378:metabolism; D006358:Hot Temperature; D007158:Immunologic Techniques; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects; D009293:Opioid-Related Disorders / Q000209:etiology*; D010880:Piperidines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000523:psychology
chemical_list: D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D009292:Narcotic Antagonists; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D009270:Naloxone; C103505:AM 251; D009020:Morphine; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin