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Vol. 300, Issue 1, 282-290, January 2002

alpha 2C-Adrenergic Receptors Mediate Spinal Analgesia and Adrenergic-Opioid Synergy

Carolyn A. Fairbanks , Laura S. Stone , Kelley F. Kitto, H. Oanh Nguyen, Ivan J. Posthumus and George L. Wilcox

Departments of Pharmacology (C.A.F., L.S.S., K.F.K., H.O.N., I.J.P., G.L.W.) and Neuroscience (C.A.F., L.S.S., G.L.W.), University of Minnesota, Minneapolis, Minnesota

The alpha 2A-adrenergic receptor (AR) subtype mediates antinociception induced by the alpha 2AR agonists clonidine, dexmedetomidine, norepinephrine, and 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14,304) as well as antinociceptive synergy of UK-14,304 with opioid agonists [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin and deltorphin II. Differential localization of alpha 2-adrenergic (alpha 2A-, alpha 2B-, alpha 2C-) and opioid (µ-, delta -, kappa -) subtypes suggests differential involvement of subtype pairs in opioid-adrenergic analgesic synergy. The present study applies a novel imidazoline1/alpha 2-adrenergic receptor analgesic, moxonidine, to test for involvement of alpha 2B- and alpha 2CARs in antinociception and antinociceptive synergy, because spinal antinociceptive activity of moxonidine shows minimal dependence on alpha 2AAR. Intrathecal administration of moxonidine produced similar (2-3-fold) decreases in both mutant mice with a functional knockout of alpha 2AAR (D79N-alpha 2AAR) and alpha 2CAR knockout (KO) mice. The potency of moxonidine was not altered in alpha 2BKO mice, indicating that this subtype does not participate in moxonidine-induced spinal antinociception. Moxonidine-mediated antinociception was dose dependently inhibited by the selective alpha 2-receptor antagonist SK&F 86466 in both D79N-alpha 2A mice and alpha 2CKO mice, indicating that alpha 2AR activation is required in the absence of either alpha 2A- or alpha 2CAR. Spinal administration of antisense oligodeoxynucleotides directed against the alpha 2CAR decreased both alpha 2CAR immunoreactivity and the antinociceptive potency of moxonidine. Isobolographic analysis demonstrates that moxonidine-deltorphin antinociceptive synergy is present in the D79N-alpha 2A mice but not in the alpha 2CAR-KO mice. These results confirm that the alpha 2CAR subtype contributes to spinal antinociception and synergy with opioids.

0022-3565/02/3001-0282$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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