Modulation by alpha-difluoromethyl-ornithine and aminoguanidine of pain threshold, morphine analgesia and tolerance.
The effects of alpha-difluoromethyl-ornithine (DFMO) and aminoguanidine, which might influence the metabolism of endogenous agmatine, on pain threshold, morphine analgesia and tolerance were investigated in mice. In the mouse acetic acid writhing test, intracerebroventricular (i.c.v.) injection of DFMO or aminoguanidine significantly elevated the pain threshold as indicated by a decrease in the number of writhings. DFMO or aminoguanidine obviously increased the analgesic effect of morphine in the mouse acetic acid writhing test and the mouse heat radiation tail-flick assay. These effects of DFMO and aminoguanidine were antagonized by idazoxan (3 mg/kg, i.p.), which is a selective antagonist of the imidazoline receptor. In the mouse heat radiation tail-flick assay, aminoguanidine significantly prolonged the tail-flick latency of animals, suggesting that the pain threshold was elevated. Furthermore, both DFMO and aminoguanidine enhanced morphine analgesia and inhibited acute morphine tolerance in the mouse heat radiation tail-flick assay. Neither DFMO nor aminoguanidine inhibited the activity of nitric oxide synthase in different brain areas in mice in vivo. These results indicate that the substances involved in the metabolism of endogenous agmatine could modulate the pain threshold, morphine analgesia and tolerance, indicating the possible role of endogenous agmatine in the pharmacological effects of morphine.
Lu
Gang
G
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Su
Rui-Bin
RB
Li
Jin
J
Qin
Bo-Yi
BY
D019342:Acetic Acid; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000376:Agmatine / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004361:Drug Tolerance; D000518:Eflornithine / Q000494:pharmacology*; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006358:Hot Temperature; D019329:Idazoxan / Q000494:pharmacology; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects*
D000317:Adrenergic alpha-Antagonists; D000701:Analgesics, Opioid; D006146:Guanidines; D000376:Agmatine; D009020:Morphine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D019342:Acetic Acid; C004479:pimagedine; D019329:Idazoxan; D000518:Eflornithine