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The α_2A-adrenergic receptor (AR) subtype mediates antinociception induced by the α₂AR 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 α₂-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 imidazoline₁/α₂-adrenergic receptor analgesic, moxonidine, to test for involvement of α_2B- and α_2CARs in antinociception and antinociceptive synergy, because spinal antinociceptive activity of moxonidine shows minimal dependence on α_2AAR. Intrathecal administration of moxonidine produced similar (2–3-fold) decreases in both mutant mice with a …