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Vol. 290, Issue 1, 403-412, July 1999

Moxonidine, a Selective alpha 2-Adrenergic and Imidazoline Receptor Agonist, Produces Spinal Antinociception in Mice1

Carolyn A. Fairbanks and George L. Wilcox

Departments of Pharmacology (C.A.F., G.L.W.) and Neuroscience (G.L.W.), University of Minnesota, Minneapolis, Minnesota

alpha 2-Adrenergic receptor (AR)-selective compounds produce antihypertensive and antinociceptive effects. Moxonidine alleviates hypertension in multiple species, including humans. This study demonstrates that intrathecally administered moxonidine produces antinociception in mice. Antinociception was detected via the (52.5°C) tail-flick and Substance P (SP) nociceptive tests. Moxonidine was intrathecally administered to ICR, mixed C57BL/6 × 129/Sv [wild type (WT)], or C57BL/6 × 129/Sv mice with dysfunctional alpha 2aARs (D79N-alpha 2a). The alpha 2AR-selective antagonist SK&F 86466 and the mixed I1/alpha 2AR-selective antagonist efaroxan were tested for inhibition of moxonidine-induced antinociception. Moxonidine prolonged tail-flick latencies in ICR (ED50 = 0.5 nmol; 0.3-0.7), WT (0.17 nmol; 0.09-0.32), and D79N-alpha 2a (0.32 nmol; 0.074-1.6) mice. Moxonidine inhibited SP-elicited behavior in ICR (0.04 nmol; 0.03-0.07), WT (0.4 nmol; 0.3-0.5), and D79N-alpha 2a (1.1 nmol; 0.7-1.7) mice. Clonidine produced antinociception in WT but not D79N-alpha 2a mice. SK&F 86466 and efaroxan both antagonized moxonidine-induced inhibition of SP-elicited behavior in all mouse lines. SK&F 86466 antagonism of moxonidine-induced antinociception implicates the participation of alpha 2ARs. The comparable moxonidine potency between D79N-alpha 2a and WT mice suggests that receptors other than alpha 2a mediate moxonidine-induced antinociception. Conversely, absence of clonidine efficacy in D79N-alpha 2a mice implies that alpha 2aAR activation enables clonidine-induced antinociception. When clinically administered, moxonidine induces fewer side effects relative to clonidine; moxonidine-induced antinociception appears to involve a different alpha 2AR subtype than clonidine-induced antinociception. Therefore, moxonidine may prove to be an effective treatment for pain with an improved side effect profile.

0022-3565/99/2901-0403$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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