N. Takeshita et I. Yamaguchi, INSULIN ATTENUATES FORMALIN-INDUCED NOCICEPTIVE RESPONSE IN MICE THROUGH A MECHANISM THAT IS DERANGED BY DIABETES-MELLITUS, The Journal of pharmacology and experimental therapeutics, 281(1), 1997, pp. 315-321
Although hypoglycemic doses of insulin (0.24-7.5 U/kg s.c.) did not si
gnificantly change acetic acid-induced writhing in mice, they dose-dep
endently 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 mu U/animal) mimicked the effects of the s.c. dose, but cau
sed little change in blood glucose levels. The antinociceptive activit
y 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 ketans
erin (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-hydroxytrypt
amine 3 receptor antagonist). Insulin also exerted antinociception in
streptozotocin-induced diabetic mice and genetically diabetic db/db mi
ce which, however, were less sensitive (ID(50)s around 7.5 U/kg) to th
e of insulin effect than normal mice. The results suggest that insulin
attenuates chronic rather than acute pains through a mechanism mediat
ed by dopamine, 5-hydroxytryptamine and opioids. The antinociceptive p
athway appears to be deranged by diabetes mellitus.