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 x 129/Sv [wild type (WT)], or C57BL/6 x 129/Sv mice with dysfunctional α(2a)ARs (D79N-α(2a)). The α2AR-selective antagonist SKandF 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-α(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-α(2a) (1.1 nmol; 0.7-1.7) mice. Clonidine produced antinociception in WT but not D79N-α(2a) mice. SKandF 86466 and efaroxan both antagonized moxonidine-induced inhibition of SP-elicited behavior in all mouse lines. SKandF 86466 antagonism of moxonidine-induced antinociception implicates the participation of α2ARs. The comparable moxonidine potency between D79N- α(2a) and WT mice suggests that receptors other than α(2a) mediate moxonidine-induced antinociception. Conversely, absence of clonidine efficacy in D79N-α(2a) mice implies that α(2a)AR 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.
|Original language||English (US)|
|Number of pages||10|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jul 1999|