Functional blockage of the cannabinoid receptor type 1 evokes a kappa-opiate-dependent analgesia.
Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Cannabinoids and opioids are endogenous modulator of pain sensation, but therapies based in these compounds are not completely exploited because of their side effects. To test the role of cannabinoid receptor type 1 (CB1-R) inhibition in nociception, we performed a subchronic administration of the CB1-R antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) in mice. This treatment provoked analgesia in peripheral thermal and visceral models of pain. Analysis of genes encoded for the opioid system in the spinal cord showed an increase in the expression of genes encoded for the κ-opioid system in AM281-injected mice compared with vehicle-injected ones. Furthermore, systemic administration of nor-binaltorphimine, a κ-opioid receptor antagonist, blocked AM281-induced analgesia. Finally, c-fos expression in the dorsal spinal cord and higher centers of pain processing after noxious stimulation were significantly lower in AM281-injected mice than in vehicle-injected animals, indicating that dynorphin could block nociceptive information transmission at the spinal cord level. These results indicate the existence of a cross-talk between opioid and cannabinoid systems in nociception. Furthermore, the results suggest that CB1-R antagonists could be useful as a new therapeutic approach for pain relief.
Sáez-Cassanelli
José L
JL
División de Neurociencias, Universidad Pablo de Olavide de Sevilla, Sevilla, Spain.
Fontanella
German H
GH
Delgado-García
José M
JM
Carrión
Angel M
AM
D000698:Analgesia; D000701:Analgesics, Opioid; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006358:Hot Temperature; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011597:Psychomotor Performance / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077285:Rimonabant; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D000701:Analgesics, Opioid; D009025:Morpholines; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D017473:Receptors, Opioid, kappa; D000077285:Rimonabant; C109925:AM 281