TY - JOUR
T1 - α2C-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy
AU - Fairbanks, Carolyn A.
AU - Stone, Laura S.
AU - Kitto, Kelley F.
AU - Oanh Nguyen, H.
AU - Posthumus, Ivan J.
AU - Wilcox, George L.
PY - 2002
Y1 - 2002
N2 - The α2A-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 (α2A-, α2B-, α2C-) and opiod (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 α2B- and α2CARS in antinociception and antinociceptive synergy, because spinal antinociceptive activity of moxonidine shows minimal dependence on α2AAR. Intrathecal administration of moxonidine produced similar (2-3-fold) decreases in both mutant mice with a functional knockout of α2AAR (D79N-α2AAR) and α2CAR knockout (KO) mice. The potency of moxonidine was not altered in α2BKO mice, indicating that this subtype does not participate in moxonidine-induced spinal antinociception. Moxonidine-mediated antinociception was dose dependently inhibited by the selective α2-receptor antagonist SK&F 86466 in both D79N-α2A mice and α2CKO mice, indicating that α2AR activation is required in the absence of either α2A - or α2CAR. Spinal administration of antisense oligodeoxynucleotides directed against the α2CAR decreased both α2CAR immunoreactivity and the antinociceptive potency of moxonidine. Isobolographic analysis demonstrates that moxonidine-deltorphin antinociceptive synergy is present in the D79N-α2A mice but not in the α2CAR-KO mice. These results confirm that the α2CAR subtype contributes to spinal antinociception and synergy with opioids.
AB - The α2A-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 (α2A-, α2B-, α2C-) and opiod (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 α2B- and α2CARS in antinociception and antinociceptive synergy, because spinal antinociceptive activity of moxonidine shows minimal dependence on α2AAR. Intrathecal administration of moxonidine produced similar (2-3-fold) decreases in both mutant mice with a functional knockout of α2AAR (D79N-α2AAR) and α2CAR knockout (KO) mice. The potency of moxonidine was not altered in α2BKO mice, indicating that this subtype does not participate in moxonidine-induced spinal antinociception. Moxonidine-mediated antinociception was dose dependently inhibited by the selective α2-receptor antagonist SK&F 86466 in both D79N-α2A mice and α2CKO mice, indicating that α2AR activation is required in the absence of either α2A - or α2CAR. Spinal administration of antisense oligodeoxynucleotides directed against the α2CAR decreased both α2CAR immunoreactivity and the antinociceptive potency of moxonidine. Isobolographic analysis demonstrates that moxonidine-deltorphin antinociceptive synergy is present in the D79N-α2A mice but not in the α2CAR-KO mice. These results confirm that the α2CAR subtype contributes to spinal antinociception and synergy with opioids.
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U2 - 10.1124/jpet.300.1.282
DO - 10.1124/jpet.300.1.282
M3 - Article
C2 - 11752127
AN - SCOPUS:0036139448
SN - 0022-3565
VL - 300
SP - 282
EP - 290
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -