Involvement of cannabinoid (CB1)-receptors in the development and maintenance of opioid tolerance.
Sustained exposure to opioid agonists such as morphine increases levels of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn, a response implicated in the development of opioid tolerance and physical dependence. Recent evidence suggests that both the opioid-induced increase in CGRP and the development of opioid physical dependence are suppressed by blockade of spinal cannabinoid (CB1)-receptors. The present study examined whether CB1-receptor activity also has a role in the development of opioid tolerance. In rats implanted with spinal catheters, repeated acute injections of morphine (15 microg) delivered over 4 h resulted in a rapid decline of thermal and mechanical antinociception and a significant loss of analgesic potency, reflecting development of acute opioid tolerance. In another set of experiments, chronic administration of spinal morphine (15 microg) once daily for 5 days produced a similar loss of analgesic effect and a marked increase in CGRP-immunoreactivity in the superficial laminae of the dorsal horn. Consistent with the in vivo findings, primary cultures of adult dorsal root ganglion (DRG) neurons exposed to morphine for 5 days showed a significant increase in the number of CGRP-immunoreactive neurons. Co-administration of acute or chronic morphine with a CB1-receptor antagonist/inverse agonist, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM-251), inhibited the development of both acute and chronic analgesic tolerance. In animals already exhibiting tolerance to morphine, intervention with AM-251 restored morphine analgesic potency. Co-administration with AM-251 attenuated the morphine-induced increase in CGRP-immunoreactivity in the spinal cord and in DRG cultured neurons. Collectively, the results of this study suggest that activity of endocannabinoids, mediated via CB1-receptors, contributes to both the development and maintenance of opioid tolerance by influencing the opioid-induced increase in spinal CGRP.
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Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Sutak
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Jhamandas
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D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines; D011720:Pyrazoles; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000502:physiology*; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000096:biosynthesis
D000701:Analgesics, Opioid; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D018015:Receptors, Calcitonin Gene-Related Peptide; C103505:AM 251; D009020:Morphine