α2C-Adrenergic Receptors Mediate Spinal Analgesia and Adrenergic-Opioid Synergy

The α 2A -adrenergic receptor (AR) subtype mediates antinociception induced by the α 2 AR agonists clonidine, dexmedetomidine, norepinephrine, and 5-bromo- N -(4,5-dihydro-1 H -imidazol-2-yl)-6-quinoxalinamine (UK-14,304) as well as antinociceptive synergy of UK-14,304 with opioid agonists [d-Ala 2 , N -Me-Phe 4 ,Gly 5 -ol]-enkephalin and deltorphin II. Differential localization of α 2 -adrenergic (α 2A -, α 2B - , α 2C -) and opioid (μ-, δ-, κ-) subtypes suggests differential involvement of subtype pairs in opioid-adrenergic analgesic synergy. The present study applies a novel imidazoline 1 /α 2 -adrenergic receptor analgesic, moxonidine, to test for involvement of α 2B - and α 2C ARs in antinociception and antinociceptive synergy, because spinal antinociceptive activity of moxonidine shows minimal dependence on α 2A AR. Intrathecal administration of moxonidine produced similar (2–3-fold) decreases in both mutant mice with a functional knockout of α 2A AR (D79N-α 2A AR) and α 2C AR knockout (KO) mice. The potency of moxonidine was not altered in α 2B KO mice, indicating that this subtype does not participate in moxonidine-induced spinal antinociception. Moxonidine-mediated antinociception was dose dependently inhibited by the selective α 2 -receptor antagonist SK&F 86466 in both D79N-α 2A mice and α 2C KO mice, indicating that α 2 AR activation is required in the absence of either α 2A - or α 2C AR. Spinal administration of antisense oligodeoxynucleotides directed against the α 2C AR decreased both α 2C AR immunoreactivity and the antinociceptive potency of moxonidine. Isobolographic analysis demonstrates that moxonidine-deltorphin antinociceptive synergy is present in the D79N-α 2A mice but not in the α 2C AR-KO mice. These results confirm that the α 2C AR subtype contributes to spinal antinociception and synergy with opioids.