DEXMEDETOMIDINE INJECTION INTO THE LOCUS-CERULEUS PRODUCES ANTINOCICEPTION

Background: alpha(2)-Adrenergic agonists such as clonidine and dexmede tomidine are known to produce sedation and analgesia in humans. The se dative effect of these agents is thought to occur through supraspinal pathways, involving the locus ceruleus (LC) and its projections in rat s, While the antinociceptive response to cu,agonists, given intratheca lly, is mediated predominantly in the spinal cord, other sites of acti on have not been systematically studied. The authors examined whether alpha(2)-adrenergic receptors in the LC mediate an antinociceptive eff ect. Methods: For administration of different drugs into the LC, guide cannulas were placed with their tips in the LC in male Sprague-Dawley rats, Dexmedetomidine (3.5 mu g/0.2 mu l) was microinjected into the LC through the cannula, or given systemically by intraperitoneal injec tion (50 mu g/kg). The antinociceptive effect of dexmedetomidine was m easured using the tail-flick latency response, To determine the sites through which dexmedetomidine injection into the LC produces antinocic eption, the authors examined whether this response could be perturbed by the specific alpha(2)-adrenergic antagonists atipamezole and L659,0 66 and pertussis toxin administered either into the LC or intrathecall y before injection of dexmedetomidine systemically or directly into th e LC. To eliminate the possibility that drug administered in one site (LC or intrathecal) could reach the other site, the dispositional char acteristics of radiolabeled dexmedetomidine (LC) or atipamezole (intra thecal) were studied. Results: Dexmedetomidine placed into the LC prod uces a dose-dependent increase in the tail-nick latency. This anti-noc iceptive effect was blocked by pertussis toxin and by the a, antagonis ts atipamezole and L659,066 placed in the LC, intrathecal administrati on of atipamezole and pertussis toxin also blocked the antinociceptive effect of dexmedetomidine placed in the LC. H-3-dexmedetomidine intro duced into the LC did not reach the spinal. cord in pharmacologically active concentrations; also, intrathecally administered H-3-atipamezol e did not reach the LC in appreciable amounts, The systemic administra tion of dexmedetomidine produced an increase in tail-flick latency, an d this effect was attenuated by the injection of atipamezole and L695, 066 into the LC. Conclusions: Part of the mechanism by which dexmedeto midine produces an antinociceptive effect is by an action directly on the LC, demonstrated by these studies in which antinociception produce d by injection of this drug into the LC can be blocked by specific alp ha(2) antagonists injected into the LC, Furthermore, the action of dex medetomidine In the LC in turn may result in an increase in activation of alpha(2) adrenoceptors in the spinal cord, because the antinocicep tive effect of LC dexmedetomidine injection also can be blocked by int rathecal injection of atipamezole and pertussis toxin.