Dissociation of the α 2-adrenergic antinociception from sedation following microinjection of medetomidine into the locus coeruleus in rats

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Abstract
It is well established that α-adrenoceptor agonists have sedative and antinociceptive properties. In the current behavioral study we tried to find out if the α-adrenergic sedative and antinociceptive effects can be dissociated. We tested the hypothesis that α adrenergic sedation is mediated by the locus coeruleus (LC) and antinociception by spinal α-adrenoceptors. Also, we addressed the possibility that intracerebral injection of an α-agonist might produce its antinociceptive effect by an action directly at the spinal cord. Medetomidine, an α-adrenergic agonist, or atipamezole, an α-adrenergic antagonist, were microinjected bilaterally into the LC through chronic cannulae in unanesthetized Han-Wistar rats. The effect on locomotor activity (/vigilancc). tail-flick and hot-plate response, and on formalin-induced pain behavior was determined. Medetomidine microinjected into the LC (1–10 μg/cannula) produced dose-dependently hypolocomotion (/sedation), increase of response latencies in the hot-plate and the tail-flick tests, and a decrease in the formalin-induced pain behavior. Hypolocomotion (/sedation) was obtained at a lower medetomidine dose (1 μg/cannula) than antinociception (3–10 μg/cannula). The lowest medetomidine dose used (1 μg/cannula), which induced significant hypolocomotion (/sedation), produced either no antinociception (hot-plate and tail-flick tests) or even a slight hyperalgesia (formalin test). The hypolocomotion (/sedation) but not antinociception (tail-flick test) induced by systemic administration of medetomidine (100 μg/kg s.c.) could be reversed by atipamezole (10 μg/cannula) microinjected into the LC. Only a high systemic dose of atipamezole (1 mg/kg s.c.) reversed the antinociceptive effects of medetomidine. Microinjection of medetomidine into the LC (3 μg/cannula) produced antinociception (tail-flick test) also in spinal rats. which effect was completely reversed by atipamezole (l mg/kg s.c.). Following administration of medetomidine at the dose of 1 μg/cannula into the central or cortical nucleus of the amygdala (control sites) there was no significant effect on locomotor activity, hot-plate response, or formalin-induced pain. The results indicate that α-adrenergic sedative and pain-modulating effects can be dissociated following microinjection of medetomidine into the LC. The antinociceptive effect of the supraspinally microinjected medetomidine in Han-Wistar rats could be explained by direct activation of the spinal α-adrenoceptors, whereas the sedation/hypolocomotion could he explained by an action on the α-adrenoceptors located in the LC, or its immediate vicinity.