The role of spinal neuropeptides and prostaglandins in opioid physical dependence.
This study examined the role of spinal calcitonin gene-related peptide (CGRP), substance P, and prostaglandins in the development and expression of opioid physical dependence. Administration of escalating doses (5 - 100 mg kg-1, i.p.) of morphine for 7 days markedly elevated CGRP and substance P- immunoreactivity in the dorsal horn of the rat spinal cord. Naloxone (2 mg kg-1, i.p.) challenge decreased both CGRP and substance P immunoreactivity and precipitated a robust withdrawal syndrome. Acute intrathecal pre-treatment with a CGRP receptor antagonist, CGRP(8 - 37) (4, 8 microg), a substance P receptor antagonist, SR 140333 (1.4, 2.8 microg), a cyclo-oxygenase (COX) inhibitor, ketorolac (30, 45 microg), and COX-2 selective inhibitors, DuP 697 (10, 30 microg) and nimesulide (30 microg), 30 min before naloxone challenge, partially attenuated the symptoms of morphine withdrawal. CGRP(8 - 37) (8 microg), but no other agents, inhibited the decrease in CGRP immunoreactivity. Chronic intrathecal treatment with CGRP(8 - 37) (4, 8 microg), SR 140333 (1.4 microg), ketorolac (15, 30 microg), DuP 697 (10, 30micro g), and nimesulide (30 microg), delivered with daily morphine injection significantly attenuated both the symptoms of withdrawal and the decrease in CGRP but not substance P immunoreactivity. The results of this study suggest that activation of CGRP and substance P receptors, at the spinal level, contributes to the induction and expression of opioid physical dependence and that this activity may be partially expressed through the intermediary actions of prostaglandins.
Trang
Tuan
T
Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada, K7L 3N6.
Sutak
Maaja
M
Quirion
Remi
R
Jhamandas
Khem
K
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology; D009021:Morphine Dependence / Q000378:metabolism*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009479:Neuropeptides / Q000378:metabolism*; D010147:Pain Measurement; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000037:antagonists & inhibitors / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D016861:Cyclooxygenase Inhibitors; D009292:Narcotic Antagonists; D009479:Neuropeptides; D011453:Prostaglandins; D013373:Substance P; D009270:Naloxone; D009020:Morphine; D015740:Calcitonin Gene-Related Peptide