Delta 9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism.
Although Delta(9)-tetrahydrocannabinol (THC) produces analgesia, its effects on nociceptive primary afferents are unknown. These neurons participate not only in pain signaling but also in the local response to tissue injury. Here, we show that THC and cannabinol induce a CB(1)/CB(2) cannabinoid receptor-independent release of calcitonin gene-related peptide from capsaicin-sensitive perivascular sensory nerves. Other psychotropic cannabinoids cannot mimic this action. The vanilloid receptor antagonist ruthenium red abolishes the responses to THC and cannabinol. However, the effect of THC on sensory nerves is intact in vanilloid receptor subtype 1 gene knock-out mice. The THC response depends on extracellular calcium but does not involve known voltage-operated calcium channels, glutamate receptors, or protein kinases A and C. These results may indicate the presence of a novel cannabinoid receptor/ion channel in the pain pathway.
Zygmunt
Peter M
PM
Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University Hospital, SE-221 85 Lund, Sweden. Peter.Zygmunt@klinfarm.lu.se
Andersson
David A
DA
Hogestatt
Edward D
ED
D000344:Afferent Pathways / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001681:Biological Assay; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology; D002187:Cannabinol / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D005260:Female; D006499:Hepatic Artery / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010146:Pain; D011619:Psychotropic Drugs / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000187:drug effects* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D002186:Cannabinoids; C469526:Cnr2 protein, rat; D011619:Psychotropic Drugs; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol; D002187:Cannabinol; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D002118:Calcium