Antinociceptive effect of U-50488H, a κ-opioid agonist, in streptozotocin-induced diabetic mice

We compared the antinociceptive activity of a κ-opioid agonist, U-50488H, in streptozotocin-induced diabetic mice with that in non-diabetic mice. Subcutaneously administered U-50488H (3 and 10 mg kg -1 ) showed a more potent antinociceptive effect, as evaluated by the tail-pressure method, in diabetic mice than in non-diabetic mice. Increased antinociceptive activity of U-50488H observed in diabetic mice was also observed in mice given U-50488H intrathecally (3 and 10 μg). However, there were no differences observed between diabetic and non-diabetic mice given U-50488H intracerebroventricularly (3 and 10 μg). Although the antinociceptive effect of U-50488H (3 mg kg -1 , s.c.) in non-diabetic mice was increased by treatment with PD135158 (100 ng, i.c.v.), a cholecystokinin B (CCKB) antagonist, the antinociceptive activity of U-50488H which was enhanced in diabetic mice was not influenced by PD135158. Moreover, the increased antinociceptive activity of U-50488H (3 mg kg, S.C.) in diabetic mice diminished when desulfated octapeptide of cholecystokinin (3-100 ng, i.c.v.), a CCK B agonist, was administered. These results suggested that diabetic mice were selectively hyper-responsive to spinal κ-opioid receptor-mediated antinociception. The function of the analgesia inhibitory system in which cholecystokinin is used as a transmitter might be diminished in diabetic mice.