Abstract
α2-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 α2aARs (D79N-α2a). The α2AR-selective antagonist SK&F 86466 and the mixed I1/α2AR-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-α2a(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-α2a (1.1 nmol; 0.7–1.7) mice. Clonidine produced antinociception in WT but not D79N-α2a 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 α2ARs. The comparable moxonidine potency between D79N-α2a and WT mice suggests that receptors other than α2a mediate moxonidine-induced antinociception. Conversely, absence of clonidine efficacy in D79N-α2amice implies that α2aAR activation enables clonidine-induced antinociception. When clinically administered, moxonidine induces fewer side effects relative to clonidine; moxonidine-induced antinociception appears to involve a different α2AR subtype than clonidine-induced antinociception. Therefore, moxonidine may prove to be an effective treatment for pain with an improved side effect profile.
Footnotes
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Send reprint requests to: Dr. George L. Wilcox, Department of Pharmacology, University of Minnesota, 6-210 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455. E-mail: george{at}umn.edu
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↵1 This work was supported by National Institutes of Health Grants R01-DA01933 and R01-DA04274 and NIDA ADAMHA Training Grant T32A07234.
- Abbreviations:
- ACE
- angiotensin-converting enzyme
- AR
- adrenergic receptor
- I1
- imidazoline1
- % MPE
- percent maximum possible effect
- NE
- norepinephrine
- 6-OHDA
- 6-hydroxydopamine
- SP
- Substance P
- WT
- wild-type
- Received October 26, 1998.
- Accepted February 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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