Male ICR mice were rendered diabetic by i.v. injection of streptozotocin. The nociceptive behavioral responses to i.t. injection of somatostatin (SST) but nor substance P (SP) were attenuated in diabetic mice compared with that in non-diabetic mice. Spantide, a SP receptor antagonist, enhanced the nociceptive response induced by i.t. SST in diabetic mice. Pretreatment of mice with SP reduced the SST-induced nociceptive response in non-diabetic mice. These results suggest that a endogenous antinociceptive system may exist which links SP with SST-mediated nociceptive transmission in the spinal cord. Furthermore, this endogenous antinociceptive system may be enhanced in diabetic mice.