Differential effects of antisense oligodeoxynucleotides directed against G(z alpha) and G(o alpha) on antinociception produced by spinal opioid and alpha(2) adrenergic receptor agonists

The present studies assessed the role of G(z alpha) and G(o alpha) in spina l alpha(2) adrenergic receptor agonist-induced antinociception, as well as in antinociceptive synergism between spinal morphine and clonidine. Mice we re pretreated with a single intrathecal (i.t.) injection of artificial cere brospinal fluid (ACSF), antisense oligodeoxynucleotide(s) (ODN) directed ag ainst G(z alpha) or G(o alpha), or nonsense ODN. After 48 h, the antinocice ptive effects expressed as per cent maximal possible effect (% MPE) of eith er i.t. morphine alone, clonidine alone or coadministered morphine plus clo nidine, were evaluated in the tail hick test. Antisense ODN to G(z alpha) a ttenuated clonidine- but not morphine-induced antinociception. The ED50 (95 % confidence interval) value for clonidine in ACSF pretreated mice was 6.3 (4.9-8.1) nmol, and in nonsense ODN pretreated mice, it was 4.2 (2.8-6.3) n mol. However, in the G(z alpha) antisense ODN pretreated mice, the highest dose clonidine tested (50 nmol) produced only 41 +/- 8.5% MPE. Antisense OD N to G(z alpha) also blocked antinociception produced by i.t. UK14,304 ( al pha(2) adrenergic receptor agonist) and [D-Pen(2), D-Pen(5)] enkephalin (DP DPE) (delta opioid receptor agonist), whereas it failed to attenuate i.t. T yr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO)- (mu opioid receptor agonist) and U50- 488 (kappa opioid receptor agonist) -induced antinociception. Pretreatment with antisense ODN to G(o alpha) attenuated both morphine and clonidine ind uced antinociception and did not affect synergism between the agonists. The se results suggest that spinal G(2)alpha mediates antinociception produced by both clonidine and morphine while G(o alpha) mediates alpha(2) adrenergi c and delta opioid receptor mediated antinociception, but not antinocicepti on produced by mu or kappa opioid agonists. (C) 2000 International Associat ion for the Study of Pain. Published by Elsevier Science B.V. All rights re served.