Insulin attenuates formalin-induced nociceptive response in mice through a mechanism that is deranged by diabetes mellitus.
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 microU/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.
Takeshita
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Basic Research Group, Tsukuba Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Ibaraki, Japan.
Yamaguchi
I
I
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005260:Female; D005557:Formaldehyde / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009270:Naloxone / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology; D013311:Streptozocin; D013469:Sulpiride / Q000494:pharmacology; D000077526:Tropisetron
D000700:Analgesics; D001786:Blood Glucose; D007211:Indoles; D007328:Insulin; D005557:Formaldehyde; D009270:Naloxone; D013311:Streptozocin; D000077526:Tropisetron; D013469:Sulpiride; D007650:Ketanserin; D010869:Pindolol