CALMODULIN INHIBITORS INDUCE SPINAL ANALGESIA IN RATS

Calcium is an important intracellular messenger that interacts with Ca 2+-binding proteins, such as calmodulin (CaM), to activate several int racellular enzymes. The involvement of Ca2+ in the transmission of noc iceptive signals has been demonstrated at the spinal level. Specifical ly, spinal sensitization induced by persistent nociceptive stimulation seems to be related to an increase of cytosolic calcium and the subse quent activation of several enzymes, some of which are Ca2+/CaM depend ent. In order to elucidate the possible implication of calmodulin in t hese pain processes, we have studied the effect of two calmodulin inhi bitors (W-7 and calmidazolium) on the formalin and tail-flick tests in rats after their intrathecal administration. Antinociceptive effects were observed in both tests by injecting 0.12-1 mu mol/rat of calmidaz olium and 0.25-2 mu mol/rat of W-7. Calmidazolium was more potent than W-7 in inhibiting both phases of the formalin test, whereas lower dos es of W-7 in comparison to calmidazolium affected the tail-flick laten cies. In addition, both drugs induced, at high doses, a muscular flacc idity of the hindlimbs that impaired normal walking in the rats. This effect caused a significant reduction of the rotarod performance when 1 mu mol/rat of calmidazolium or 2 mu mol/rat of W-7 were injected. Ov erall, our results show that calmodulin inhibitors are capable of prod ucing spinal analgesia on phasic and tonic noxious stimuli in rats, th us rendering them a promising potential as analgesics.