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Vol. 300, Issue 1, 282-290, January 2002
2C-Adrenergic Receptors Mediate Spinal Analgesia
and Adrenergic-Opioid Synergy
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 
2A-adrenergic receptor (AR) subtype mediates
antinociception induced by the 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 2-adrenergic (2A-,
2B-, 2C-) and opioid (µ-,
-, 
-) subtypes suggests differential involvement of subtype pairs
in opioid-adrenergic analgesic synergy. The present study applies a
novel imidazoline1/2-adrenergic receptor
analgesic, moxonidine, to test for involvement of 2B- and 2CARs in antinociception and antinociceptive
synergy, because spinal antinociceptive activity of moxonidine shows
minimal dependence on 2AAR. Intrathecal administration
of moxonidine produced similar (2-3-fold) decreases in both mutant
mice with a functional knockout of 2AAR
(D79N-2AAR) and 2CAR knockout (KO) mice.
The potency of moxonidine was not altered in 2BKO mice,
indicating that this subtype does not participate in moxonidine-induced
spinal antinociception. Moxonidine-mediated antinociception was dose
dependently inhibited by the selective 2-receptor
antagonist SK&F 86466 in both D79N-2A mice and
2CKO mice, indicating that 2AR activation
is required in the absence of either 2A- or
2CAR. Spinal administration of antisense
oligodeoxynucleotides directed against the 2CAR decreased both 2CAR immunoreactivity and the
antinociceptive potency of moxonidine. Isobolographic analysis
demonstrates that moxonidine-deltorphin antinociceptive synergy is
present in the D79N-2A mice but not in the
2CAR-KO mice. These results confirm that the
2CAR subtype contributes to spinal antinociception and synergy with opioids.
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