IngentaConnect The dissociation of sedative from spinal antinociceptive effects ...

Abstract:

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 and intrathecally at the lumbar spinal cord level.

Methods:

Sedative effects of MPV-2426 were assessed in a locomotion measuring device following unilateral microinjection into the locus coeruleus (LC) of the brainstem or 1–2 mm rostral to the LC in rats. Antinociceptive effects induced by MPV-2426 in the brainstem, and for comparison intrathecally at the lumbar spinal cord level, were determined with a tail-flick test. Dexmedetomidine was used as the reference alpha-2-adrenoceptor agonist.

Results:

MPV-2426 produced a dose-related hypolocomotive/ sedative effect, which 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 atipamezole (1 mg/kg s.c.), an alpha-2-adrenoceptor antagonist. The sedative potency of dexmedetomidine, the reference alpha-2-adrenoceptor agonist, was stronger and less dependent on the exact injection site in the brainstem. Following microinjections at sedative doses in the brainstem, only dexmedetomidine produced a significant antinociceptive effect in the tail-flick test. When microinjected into the lumbar spinal cord, MPV-2426 and dexmedetomidine had an equally strong antinociceptive effect in the tail-flick test.

Conclusion:

The results indicate that the sedative potency of MPV-2426 is considerably weaker than that of dexmedetomidine. Additionally, the spread of MPV-2426 within the central nervous system is more limited than that of dexmedetomidine. This could explain why MPV-2426 is sedative only when injected into the LC while antinociceptive effect is obtained when it is injected intrathecally at the lumbar spinal cord level.

Keywords: Alpha-2-adrenergic analgesia; sedation; locus coeruleus; dexmedetomidine; spinal cord analgesia

Language: English

Document Type: Original article

Affiliations: 1: Department of Pharmacology and Toxicology and 2: Department of Physiology, Institute of Biomedicine, 3: Department of Anaesthesia, Institute of Clinical Medicine, University of Helsinki, Helsinki, and 4: Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland

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