Abstract
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 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 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.
Footnotes
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This study was supported by National Institutes of Health Grants R01-DA-01933 and R01-DA-11236 to G.L.W. National Institute on Drug Abuse training Grant T32A07234 supported C.A.F.
Abbreviations
- AR
- adrenergic receptor
- KO
- knockout
- OE
- over-expresser
- WT
- wild-type
- SP
- substance P
- ODN
- oligodeoxynucleotide
- CL
- confidence limits
- I1 imidazoline1
- -ir, immunoreactivity
- DRG
- dorsal root ganglion
- UK-14,304
- 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine
- Received June 19, 2001.
- Accepted September 12, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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