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

Abstract

It is well established that alpha 2-adrenoceptor agonists have sedative and antinociceptive properties. In the current behavioral study we tried to find out if the alpha 2-adrenergic sedative and antinociceptive effects can be dissociated. We tested the hypothesis that alpha 2-adrenergic sedation is mediated by the locus coeruleus (LC) and antinociception by spinal alpha 2-adrenoceptors. Also, we addressed the possibility that intracerebral injection of an alpha 2-agonist might produce its antinociceptive effect by an action directly at the spinal cord. Medetomidine, an alpha 2-adrenergic agonist, or atipamezole, an alpha 2-adrenergic antagonist, were microinjected bilaterally into the LC through chronic cannulae in unanesthetized Han-Wistar rats. The effect on locomotor activity (/vigilance), tail-flick and hot-plate response, and on formalin-induced pain behavior was determined. Medetomidine microinjected into the LC (1-10 micrograms/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 microgram/cannula) than antinociception (3-10 micrograms/cannula). The lowest medetomidine dose used (1 microgram/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 micrograms/kg s.c.) could be reversed by atipamezole (10 micrograms/cannula) microinjected into the LC. Only a high systemic dose of atipamezole (1 mg/kg s.c.) reversed the antinociceptive effects of medetomidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic clonidine activates neurons of the dorsal horn, but not the locus ceruleus (A6) or the A7 area, after a formalin test: the importance of the dorsal horn in the antinociceptive effects of clonidine

“…The bilateral suppression of LC discharge activity led to a reduction in forebrain electroencephalographic activity [16]. The LC has been reported to be a major site for the hypnotic effects of α-2-agonists [17][18][19]. In this study, systemic clonidine produced hypnotic responses in rats and decreased the neural activity of the LC.…”

The mechanism of action of α 2 adrenoceptor blockers as revealed by effects on open field locomotion and escape reactions in the shuttle-box

“…Various agonists acting on 2 adrenoceptors decrease locomotor activity in various conditions, an effect that can be reversed by 2 adrenoceptor antagonists (Heal et al 1989;Antonelli et al 1991;Wilckens et al 1992;Pirke et al 1993;Pertovaara et al 1994). 2 Adrenoceptor antagonists have been shown to increase activity and exploration in an open field (idazoxan: Siviy et al 1990;yohimbine : Anden et al 1982), and may potentiate the burst of activity elicited by apomorphine (Dickinson et al 1988).…”

“…Norepinephrine acting through these receptors affects arousal (Sirvio et al 1993), selective attention (Rowe et al 1996), locomotor behavior (Pertovaara et al 1994), food intake (Leibowitz 1988), conflict behaviour (punished drinking; Fontana and Commissaris 1992), muricidal behavior (Hong et al 1987), playfulness in juvenile rats (Siviy et al 1994), behavior in male-female interactions (Cutler, 1993), male rivalry aggression (Haller et al 1994(Haller et al , 1995Haller 1995a,b), feline affective aggression (Barrett et al 1987) and flight (Saha et al 1993b), and may be effective in the treatment of human depression as well (Hanock et al 1995).…”

Regulation of Neuropathic Hypersensitivity by α2‐Adrenoceptors in the Pontine A7 Cell Group

“…The present results extend these earlier findings by showing that a 2 -adrenoceptors in A7 have the capacity to attenuate neuropathic hypersensitivity via disinhibition of descending noradrenergic pathways. In our earlier study, an a 2 -adrenoceptor agonist in A6 increased sustained pain in non-neuropathic animals, probably due to suppression of noradrenergic feedback inhibition [8]. Based on this earlier finding, it was expected that fadolmidine in A6 increased hypersensitivity in nerve-injured animals, which it did not.…”

“…However, there is evidence indicating that heteroreceptors (i.e., a 2 -adrenoceptors on non-adrenergic cells) play a significant role in presumably pontine as well as spinal a 2 -adrenoceptor functions [6]. Microinjections of a 2 -adrenoceptor agonists into A6 of healthy animals have produced partly contradictory results that have varied from antinociception towards brief noxious stimuli [7] to hyperalgesia towards sustained noxious stimulation [8].Peripheral nerve injury induces various plastic changes in pain pathways that are associated with chronic pain and hypersensitivity. Among peripheral nerve injury-induced changes are those described in pain modulation originating in A6 that may have a role in maintenance of neuropathic hypersensitivity [9][10][11].…”