DISSOCIATION OF THE ALPHA(2)-ADRENERGIC ANTINOCICEPTION FROM SEDATIONFOLLOWING MICROINJECTION OF MEDETOMIDINE INTO THE LOCUS-COERULEUS IN RATS

It is well established that alpha(2)-adrenoceptor agonists have sedati ve and antinociceptive properties. In the current behavioral study we tried to find out if the alpha(2)-adrenergic sedative and antinocicept ive effects can be dissociated. We tested the hypothesis that alpha(2) -adrenergic sedation is mediated by the locus coeruleus (LC) and antin ociception by spinal alpha(2)-adrenoceptors. Also, we addressed the po ssibility that intracerebral injection of an alpha(2)-agonist might pr oduce its antinociceptive effect by an action directly at the spinal c ord. Medetomidine, an alpha(2)-adrenergic agonist, or atipamezole, an alpha(2)-adrenergic antagonist, were microinjected bilaterally into th e LC through chronic cannulae in unanesthetized Han-Wistar rats. The e ffect on locomotor activity (/vigilance), tail-flick and hot-plate res ponse, and on formalin-induced pain behavior was determined. Medetomid ine microinjected into the LC (1-10 mu g/cannula) produced dose-depend ently hypolocomotion (/sedation), increase of response latencies in th e hot-plate and the tail-flick tests, and a decrease in the formalin-i nduced pain behavior. Hypolocomotion (/sedation) was obtained at a low er medetomidine dose (1 mu g/cannula) than antinociception (3-10 mu g/ cannula). The lowest medetomidine dose used (1 mu g/cannula), which in duced significant hypolocomotion (/sedation), produced either no antin ociception (hot-plate and tail-flick tests) or even a slight hyperalge sia (formalin test). The hypolocomotion (/sedation) but not antinocice ption (tail-flick test) induced by systemic administration of medetomi dine (100 mu g/kg s.c.) could be reversed by atipamezole (10 mu g/cann ula) microinjected into the LC. Only a high systemic dose of atipamezo le (1 mg/kg s.c.) reversed the antinociceptive effects of medetomidine . Microinjection of medetomidine into the LC (3 mu g/cannula) produced antinociception (tail-flick test) also in spinal rats, which effect w as completely reversed by atipamezole (1 mg/kg s.c.). Following admini stration of medetomidine at the dose of 1 mu g/cannula into the centra l or cortical nucleus of the amygdala (control sites) there was no sig nificant effect on locomotor activity, hot-plate response, or formalin -induced pain. The results indicate that alpha(2)-adrenergic sedative and pain-modulating effects can be dissociated following microinjectio n of medetomidine into the LC. The antinociceptive effect of the supra spinally microinjected medetomidine in Han-Wistar rats could be explai ned by direct activation of the spinal alpha(2)-adrenoceptors, whereas the sedation/hypolocomotion could be explained by an action on the al pha(2)-adrenoceptors located in the LC, or its immediate vicinity.