The dissociation of sedative from spinal antinociceptive effects followingadministration of a novel alpha-2-adrenoceptor agonist, MPV-2426, in the locus coeruleus in the rat

Background: MPV-2426 is a novel alpha-2-adrenoceptor agonist developed for spinal pain therapy. In the present study we characterized its sedative and antinociceptive properties following microinjections into the brainstem an d intrathecally at the lumbar spinal cord level. Methods: Sedative effects of MPV-2426 were assessed in a locomotion measuri ng device following unilateral microinjection into the locus coeruleus (LC) of the brainstem or 1-2 mm rostral to the LC in rats. Antinociceptive effe cts induced by MPV-2426 in the brainstem, and for comparison intrathecally at the lumbar spinal cord level, were determined with a tail-flick test. De xmedetomidine was used as the reference alpha-2-adrenoceptor agonist. Results: MPV-2426 produced a dose-related hypolocomotive/sedative effect, w hich was significantly stronger following microinjection into the LC than 1 -2 mm rostral to the LC. The sedation induced by MPV-2426 was reversed by a tipamezole (1 mg/kg s.c.), an alpha-2-adrenoceptor antagonist. The sedative potency of dexmedetomidine, the reference alpha-2-adrenoceptor agonist, wa s stronger and less dependent on the exact injection site in the brainstem. Following microinjections at sedative doses in the brainstem, only dexmede tomidine produced a significant antinociceptive effect in the tail-flick te st. When microinjected into the lumbar spinal cord, MPV-2426 and dexmedetom idine had an equally strong antinociceptive effect in the tail-flick test. Conclusion: The results indicate that the sedative potency of MPV-2426 is c onsiderably weaker than that of dexmedetomidine. Additionally, the spread o f MPV-2426 within the central nervous system is more limited than that of d exmedetomidine. This could explain why MPV-2426 is sedative only when injec ted into the LC while antinociceptive effect is obtained when it is injecte d intrathecally at the lumbar spinal cord level. (C) Acta Anaesthesiologica Scandinavica 44 (2000).