Attenuation of ascending nociceptive signals to the rostroventromedial medulla induced by a novel alpha(2)-adrenoceptor agonist, MPV-2426, following intrathecal application in neuropathic rats

Background: In the current study, the potency and spread of the antinocicep tion induced by MPV-2426, a novel alpha(2)-adrenoceptor agonist, was charac terized in neuropathic and non-neuropathic animals, Methods: Neuropathy was induced by unilateral ligation of two spinal nerves in the rat. After lumbar intrathecal or systemic administration of MPV-242 6, thermally and mechanically evoked responses of nociceptive neurons of th e rostroventromedial medulla were recorded during pentobarbitone anesthesia . To obtain a behavioral correlate of neurophysiologic findings, nocifensor reflex responses evoked by thermal and mechanical stimuli were assessed in unanesthetized neuropathic and control animals, Results: After intrathecal administration, MPV-2426 and dexmedetomidine pro duced a dose-related antinociceptive effect, independent of the submodality of the noxious test stimulus or the pathophysiologic condition. This antin ociceptive effect was spatially restricted to the inputs from the lower hal f of the body, and it was reversed by atipamezole, an alpha(2)-adrenoceptor antagonist. After systemic administration in non-neuropathic animals, MPV- 2426 had no antinociceptive effect on responses to rostroventromedial medul la neurons, whereas systemically administered dexmedetomidine produced a do se-related suppression of nociceptive signals to the rostroventromedial med ulla. independent of the site of test stimulation, In a behavioral study, i ntrathecal MPV-2426 produced a dose-dependent suppression of nocifensor res ponses evoked by noxious mechanical or heat stimuli, whereas systemic admin istration of MPV-2426 had no effects. Conclusions: Intrathecal MPV-2426 has spatially limited antinociceptive pro perties in neuropathic and non-neuropathic conditions because of its action on spinal alpha(2)-adrenoceptors, These properties may be advantageous whe n designing therapy for spatially restricted pain problems.