TY - JOUR T1 - Insulin Attenuates Formalin-Induced Nociceptive Response in Mice through a Mechanism that Is Deranged by Diabetes Mellitus JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 315 LP - 321 VL - 281 IS - 1 AU - Nobuaki Takeshita AU - Isamu Yamaguchi Y1 - 1997/04/01 UR - http://jpet.aspetjournals.org/content/281/1/315.abstract N2 - Although hypoglycemic doses of insulin (0.24-7.5 U/kg s.c.) did not significantly change acetic acid-induced writhing in mice, they dose-dependently attenuated formalin-induced nociceptive responses, and their effects were more potent on the second phase (ID50 = .62 U/kg) than on the first (ID50 > 7.5 U/kg). Intracerebroventricular doses of insulin (250-1000 μU/animal) mimicked the effects of the s.c. dose, but caused little change in blood glucose levels. The antinociceptive activity of insulin (0.75 U/kg, s.c.) in the formalin test was significantly inhibited by naloxone (10 mg/kg i.p., an opiate receptor antagonist), sulpiride (10 mg/kg i.p., a dopamine 2 receptor antagonist), pindolol (1 mg/kg i.p., a 5-hydroxytryptamine 1 receptor antagonist) and ketanserin (1 mg/kg i.p., a 5-hydroxytryptamine 2 receptor antagonist), but not by 3-tropanyl-indole-3-carboxylate (1 mg/kg i.p., a 5-hydroxytryptamine 3 receptor antagonist). Insulin also exerted antinociception in streptozotocin-induced diabetic mice and genetically diabetic db/db mice which, however, were less sensitive (ID50s around 7.5 U/kg) to the of insulin effect than normal mice. The results suggest that insulin attenuates chronic rather than acute pains through a mechanism mediated by dopamine, 5-hydroxytryptamine and opioids. The antinociceptive pathway appears to be deranged by diabetes mellitus. The American Society for Pharmacology and Experimental Therapeutics ER -