am-1241 and Diabetic-Neuropathies

Influence of a relatively specific inhibitor cyclooxygenase (COX)-2, celecoxib, a relatively specific inhibitor of neuronal nitric oxide synthase (NOS), 7-Ni, and a relatively selective inhibitor of inducible NOS, L-NIL, on the action of a preferentially selective CB1 cannabinoid receptor agonist, Met-F-AEA and a selective CB2 cannabinoid receptor agonist, AM 1241 was investigated, in a streptozotocin (STZ)-induced neuropathy.. Studies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli - the modification of the classic paw withdrawal test described by Randall-Selitto. Diabetes was induced by a single administration of STZ.. In a diabetic neuropathic pain model, pretreatment with celecoxib, L-NIL and 7-Ni, significantly increased the antihyperalgesic activity of both Met-F-AEA and AM 1241.. The results of this study seemed to indicate that the interaction between cannabinoid, COX-2 and NOS(s) systems might exist. Concomitant administration of small doses of CB1 and/or CB2 receptor agonists and COX-2 or NOS inhibitors can be effective in the alleviation of diabetic neuropathic pain.

Topics: Animals; Arachidonic Acids; Cannabinoids; Celecoxib; Cyclooxygenase Inhibitors; Diabetic Neuropathies; Drug Synergism; Hyperalgesia; Indazoles; Lysine; Male; Neuralgia; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Pain Measurement; Rats; Rats, Wistar; Streptozocin

The effect of CB-1 and CB-2 receptor agonists, as well as an influence of a non-selective inhibitor of nitric oxide synthase (NOS), L-NOArg, and an inhibitor acting preferentially on cyclooxygenase-1 (COX-1), indomethacin, on the action of cannabinoid receptor agonists in a streptozotocin (STZ)-induced neuropathic model was investigated. When administered alone, a non-selective cannabinoid receptor agonist, WIN 55,212-2, a potentially selective CB-1 cannabinoid receptor agonist, Met-F-AEA, and a selective CB-2 cannabinoid receptor agonist, AM1241, dose-dependently reduced STZ-induced hyperalgesia. The results of the present study also demonstrated that inhibitors of COX and NOS increase antihyperalgesic activity of low doses of CB-1 and CB-2 receptor agonists. Hypothetical consequences of this phenomenon are discussed.

Topics: Analgesics; Animals; Arachidonic Acids; Benzoxazines; Cannabinoids; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Drug Synergism; Hyperalgesia; Indomethacin; Male; Morpholines; Naphthalenes; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Streptozocin