Spinal cannabinoids are anti-allodynic in rats with persistent inflammation.
Cannabinoid receptor (CB1) agonists strongly inhibit behavioral responses to acute noxious stimuli, but their effects on behavioral responses in persistent pain states are less clear. Here, we examined the effects of intrathecal (i.t.) administration of a CB1 agonist, WIN55,212-2, on mechanical allodynia (decreased withdrawal threshold) produced by injections of complete Freund's adjuvant (CFA) in the plantar surface of the rat hindpaw. We measured mechanical thresholds with calibrated von Frey filaments before and after CFA and used Fos expression as a marker of the activity of spinal cord neurons during inflammation and in response to a CB1 antagonist. One day post CFA-induced injury, mechanical sensitivity was significantly increased in the hindpaw ipsilateral to the CFA injection, as was the number of neurons that express Fos. Intrathecal injection of WIN55,212-2, significantly, reversed the allodynia at doses that had no effect on the mechanical threshold of the contralateral paw of CFA-treated or the withdrawal thresholds in naive animals. This effect was blocked by coadministration of the CB1 antagonist, SR141716A, with WIN55212-2. By itself, SR141716A, had no effect on mechanical thresholds in normal animals. In inflamed animals, SR141716A did not further reduce mechanical thresholds in the inflamed paw, but it significantly enhanced mechanical sensitivity 'contralateral' to the inflammation. Furthermore, i.t. injection of SR141716A increased Fos expression in both normal and inflamed animals, to a different extent in different laminae. In normal animals, the increase was primarily in laminae V-VI and in the ventral horn; in animals with persistent inflammation SR141716A increased the number of Fos neurons in laminae I-II and V-VI. These results demonstrate that WIN55212-2 reverses inflammation-induced allodynia at doses that do not produce analgesia and that SR141716A differentially affects the pattern of Fos expression in the spinal cord, depending on the presence or absence of inflammation. Taken together, these results suggest that the CB1 receptor system is tonically active in the spinal cord under normal conditions and that its activity is increased in response to injury.
Martin
William J
WJ
Department of Anatomy, University of California San Francisco, San Francisco, Box 0452, CA 94143, USA Department of Physiology, University of California San Francisco, San Francisco, CA 94143, USA W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA.
Loo
Carole M
CM
Basbaum
Allan I
AI
D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines; D002186:Cannabinoids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D009025:Morpholines / Q000627:therapeutic use; D009281:Naphthalenes / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009443:Neuritis / Q000188:drug therapy*; D017288:Pain Threshold / Q000187:drug effects*; D010880:Piperidines / Q000627:therapeutic use; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011720:Pyrazoles / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant; D013314:Stress, Mechanical
D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant