Vol. 286, Issue 2, 780-787, August 1998

Role of Intracellular Calcium in Modification of Mu and Delta Opioid Receptor-Mediated Antinociception by Diabetes in Mice¹

Masahiro Ohsawa, Hiroshi Nagase and Junzo Kamei

Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hoshi University, Ebara, Japan (M.O., J.K.), and Basic Research Laboratories, Toray Industries, Kamakura, Japan (N.H.)

We examined the effects of calcium modulators on mu and delta opioid receptor agonist-induced antinociception in both diabetic and nondiabetic mice. In nondiabetic mice, intracerebroventricular (i.c.v.) pretreatment with calcium and thapsigargin, which increase intracellular calcium, reduced [D-Ala²,N-MePhe⁴,Gly-ol⁵]-enkephalin (DAMGO)-induced antinociception by shifting its dose-response curve to the right. However, in diabetic mice i.c.v. pretreatment with calcium and thapsigargin did not affect DAMGO-induced antinociception. In contrast i.c.v. administration of agents that decrease intracellular calcium, such as EGTA and ryanodine, enhanced DAMGO-induced antinociception in both diabetic and nondiabetic mice. In contrast with DAMGO i.c.v. pretreatment with calcium and thapsigargin enhanced ()-TAN67-induced antinociception in nondiabetic mice by shifting its dose-response curve to the left. However, ()-TAN67-induced antinociception in diabetic mice was not affected by pretreatment with calcium or thapsigargin. Moreover i.c.v. pretreatment with EGTA, but not with ryanodine, reduced ()-TAN67-induced antinociception in nondiabetic mice. In diabetic mice i.c.v. pretreatment with both EGTA and ryanodine reduced ()-TAN67-induced antinociception. These results suggest that cytosolic calcium has different effects on mu and delta opioid receptor agonist-induced antinociception. Further, these results suggest that the modification of mu and delta opioid receptor agonist-induced antinociception by diabetes in mice may be due to increased levels of intracellular calcium.