Role of intracellular calcium in acute thermal pain perception

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The role of intracellular calcium in acute thermal nociception was investigated in the mouse hot-plate test. Intracerebroventricular (i.c.v.) administration of TMB-8, a blocker of Ca ++ release from intracellular stores, produced hypernociception. By contrast, i.c.v. pretreatment with thapsigargin, a depletor of Ca ++ intracellular stores, produced an increase of the mouse pain threshold. Furthermore, non-analgesic doses of thapsigargin prevented the hypernociception produced by TMB-8. In mice undergoing treatment with heparin, an InsP 3-receptor antagonist, or ryanodine, a ryanodine receptor (RyR) antagonist, a dose-dependent reduction of the pain threshold was observed. Pretreatment with d- myo inositol, compound which produces InsP 3, and 4-chloro- m-cresol, a RyR agonist, induced an antinociceptive effect. The heparin hypernociception was prevented by d- myo inositol, but not by l- myo inositol, used as negative control. In the same experimental conditions, the antinociception induced by d- myo inositol was prevented by a non-hyperalgesic dose of heparin. Similarly, the reduction of pain threshold produced by ryanodine was reversed by non-analgesic doses of 4-chloro- m-cresol, whereas the antinocicpetion induced by 4-chloro- m-cresol was prevented by non-hyperalgesic doses of ryanodine. The pharmacological treatments employed did not produce any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate that a variation of intracellular calcium contents at a supraspinal level is involved in the modulation of acute thermal nociception. In particular, the stimulation of both InsP 3- and Ry-receptors appears to play an important role in the induction of antinociception in mice, whereas a blockade of these receptors is involved in an hypernociceptive response to acute thermal pain.