Selective and segmentally restricted antinociception induced by MPV-2426, a novel alpha-2-adrenoceptor agonist
Research field:Central nervous system
Authors:Kalmari J, Onttonen T, Pertovaara A
Address of presenting
author:		Jaakko Kalmari
Department of Physiology
Institute of Biomedicine
POB 9
University of Helsinki
FIN-00014 Helsinki
Finland
E-mail:jaakko.kalmari@helsinki.fi
Phone:+358-9-191 8552
Fax:+358-9-191 8681
Text of abstract Introduction
MPV-2426 or radolmidine is a novel alpha-2-adrenoceptor agonist developed for spinal pain therapy. It has been shown that MPV-2426 has less cardiovascular side-effects following intrathecal (i.t.) administration (Eisenach et al. 1999) and it produces less sedation following intracerebral injection (Xu et al. 2000) than older alpha-2-adrenoceptor agonists clonidine and dexmedetomidine. However, the antinociceptive potency of MPV-2426 following i.t. administration is in the same range as that of dexmedetomidine both under experimental pathophysiological as well as physiological conditions (Onttonen & Pertovaara, 2000; Pertovaara & Wei, 2000). In the present study we determined the segmental distribution and selectivitiy of the antinociceptive effect induced by MPV-2426 following i.t. administration in the rat.

Methods
The experiments were performed in lightly anesthetized rats with an i.t. catheter for administration of drugs into the lumbar spinal cord level. To determine segmental distribution of antinociception, the withdrawal latency of the tail and forepaw from a hot water bath was measured. To assess selectivity of reflex modulation, the effect of i.t. MPV-2426 on the innocuous H-reflex was determined.

Results
In the hot water immersion test MPV-2426 produced a dose-dependent (0.3-3.0 ug) prolongation of tail withdrawal latency, whereas the effect on forepaw withdrawal was short of significance. Dexmedetomidine, the reference alpha-2-adrenoceptor agonist, produced a significant dose-related prolongation of both the tail and forepaw withdrawal (0.3 and 1.0 ug). MPV-2426 (1.0 and 3.0 ug) produced no significant change in the amplitude of the H-reflex or M-response induced by electrical stimulation of the tibial nerve, nor any change in the modulation of the H-reflex amplitude induced by conditioning sural nerve stimulation. The antinociception induced by MPV-2426 was completely reversed by atipamezole (1 mg/kg s.c.), an alpha-2-adrenoceptor antagonist.

Conclusions
MPV-2426 produces a selective and segmentally more restricted antinociceptive effect than dexmedetomidine due to action on spinal alpha-2-adrenoceptors. These properties of MPV-2426, together with its minor cardiovascular and sedative side-effects, might be beneficial when designing a segmentally restricted spinal pain therapy.

References
Eisenach, J.C., Lavand´homme, P., Tong, C., Cheng, J.K., Pan, H.L., Virtanen, R., Nikkanen, H. & James, R. 1999. Anesthesiology 91.1425-36.
Onttonen, T. & Pertovaara, A. 2000. Anesthesiology in press
Pertovaara, A. & Wei, H. 2000. Anesthesiology 92.1082-92.
Xu, M., Wei, H., Kontinen, V.K., Kalso, E. & Pertovaara, A. 2000. Acta Anaesthesiol Scand in press

Keywords:antinociception, alpha-2-adrenoceptor agonist, H-reflex, radolmidine

Created 2000-04-16