Modulation of the formalin-induced nociceptive response by diabetes: possible involvement of intracellular calcium

We examined the involvement of cytosolic calcium in the modulation of the formalin-induced nociceptive response by diabetes. Injection of formalin into the hindpaw of mice produced a biphasic nociceptive response consisting of immediate (first phase) and tonic (second phase) components. Although the duration of the first-phase response was significantly longer in diabetic mice than in non-diabetic mice, the second phase was significantly shorter in diabetic mice. The first-phase response was dose-dependently and significantly reduced by pretreatment with ryanodine, which blocks Ca(2+) release from Ca(2+)/caffeine-sensitive microsomal pools. The second-phase response was also significantly increased when diabetic mice were pretreated with ryanodine. However, ryanodine had no significant effect on either the first-phase or second-phase response in non-diabetic mice. On the other hand, pretreatment with thapsigargin, which inhibits Ca(2+) uptake into the inositol-1,4, 5-trisphosphate-sensitive microsomal Ca(2+) pool, significantly enhanced the first-phase response in non-diabetic mice. Furthermore, thapsigargin significantly and dose-dependently reduced the second phase of the formalin-induced nociceptive response in non-diabetic mice. Thapsigargin administered i.t. did not significantly affect either the first- or the second-phase response in diabetic mice. These results suggest that the change in the formalin-induced nociceptive response in diabetic mice may be due, at least in part, to the modification of nociceptive transmission in the spinal cord by intracellular calcium.