title: alpha(2C)-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy.
abstract: The alpha(2A)-adrenergic receptor (AR) subtype mediates antinociception induced by the alpha(2)AR 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-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin and deltorphin II. Differential localization of alpha(2)-adrenergic (alpha(2A)-, alpha(2B)-(,) alpha(2C)-) and opioid (mu-, delta-, kappa-) subtypes suggests differential involvement of subtype pairs in opioid-adrenergic analgesic synergy. The present study applies a novel imidazoline(1)/alpha(2)-adrenergic receptor analgesic, moxonidine, to test for involvement of alpha(2B)- and alpha(2C)ARs in antinociception and antinociceptive synergy, because spinal antinociceptive activity of moxonidine shows minimal dependence on alpha(2A)AR. Intrathecal administration of moxonidine produced similar (2-3-fold) decreases in both mutant mice with a functional knockout of alpha(2A)AR (D79N-alpha(2A)AR) and alpha(2C)AR knockout (KO) mice. The potency of moxonidine was not altered in alpha(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 alpha(2)-receptor antagonist SK&F 86466 in both D79N-alpha(2A) mice and alpha(2C)KO mice, indicating that alpha(2)AR activation is required in the absence of either alpha(2A)- or alpha(2C)AR. Spinal administration of antisense oligodeoxynucleotides directed against the alpha(2C)AR decreased both alpha(2C)AR 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(2C)AR-KO mice. These results confirm that the alpha(2C)AR subtype contributes to spinal antinociception and synergy with opioids.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Fairbanks
authors.forename: Laura S
authors.initials: LS
authors.lastname: Stone
authors.forename: Kelley F
authors.initials: KF
authors.lastname: Kitto
authors.forename: H Oanh
authors.initials: HO
authors.lastname: Nguyen
authors.forename: Ivan J
authors.initials: IJ
authors.lastname: Posthumus
authors.forename: George L
authors.initials: GL
authors.lastname: Wilcox
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D004357:Drug Synergism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D011957:Receptors, Opioid / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects*; D013373:Substance P; D013564:Sympathetic Nervous System / Q000187:drug effects*
chemical_list: C547775:Adra2c protein, mouse; D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D000701:Analgesics, Opioid; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D018341:Receptors, Adrenergic, alpha-2; D011957:Receptors, Opioid; C060209:deltorphin II, Ala(2)-; D013373:Substance P; D003000:Clonidine