Nefopam but not physostigmine affects the thermoregulatory response in mice via alpha(2)-adrenoceptors

Abstract

Nefopam, a non-opioid, centrally acting benzoxazocine analgesic, proved to be as efficient in treatment of postanaesthetic thermoregulatory shivering as clonidine or meperidine. However, its exact mechanism of action is still unclear. Potent anti-shivering activity was also demonstrated for physostigmine primarily based on cholinergic but probably also different additional mechanisms of action. Hypothesizing an involvement of alpha(2)-adrenoceptors we studied their role in nefopam- and physostigmine-mediated thermoregulation in a mouse model of nonshivering thermogenesis. To differentiate possible alpha(2)-adrenoceptor subtype-specific interactions, we analysed wildtype mice and mice with deletion of the alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptor (knock out). Ten mice of each genotype (n = 40) were administered saline, saline plus atipamezole, 1 mg/kg nefopam, 25 mg/kg nefopam, 25 mg/kg nefopam plus atipamezole, physostigmine and physostigmine plus atipamezole intraperitoneally. Each mouse was randomly subjected to each of the seven different treatments. Afterwards, the mice were positioned into a plexiglas chamber where rectal temperature and mixed expired carbon dioxide were measured during following whole body cooling. Thermoregulatory threshold temperature of nonshivering thermogenesis and maximum response intensity were analysed. Nefopam decreased the thermoregulatory threshold temperature in wildtype, alpha(2B)- and alpha(2C)-adrenoceptor mice. This effect was partially abolished by additional administration of the alpha(2)-adrenoceptor antagonist atipamezole. In alpha(2A)-adrenoceptor knock out mice, nefopam did not affect the thermoregulatory threshold. In contrast, physostigmine decreased the thermoregulatory threshold in wildtype and all alpha(2)-adrenoceptor knock out mice independently from additional atipamezole administration. Our results indicate an important role of the alpha(2A)-adrenoceptor in the thermoregulatory response induced by nefopam but not by physostigmine in mice.