Differential effects of antisense oligodeoxynucleotides directed against g(zalpha) and g(oalpha) on antinociception produced by spinal opioid and alpha(2) adrenergic receptor agonists.

The present studies assessed the role of G(zalpha) and G(oalpha) in spinal alpha(2) adrenergic receptor agonist-induced antinociception, as well as in antinociceptive synergism between spinal morphine and clonidine. Mice were pretreated with a single intrathecal (i.t.) injection of artificial cerebrospinal fluid (ACSF), antisense oligodeoxynucleotide(s) (ODN) directed against G(zalpha) or G(oalpha), or nonsense ODN. After 48 h, the antinociceptive effects expressed as per cent maximal possible effect (% MPE) of either i.t. morphine alone, clonidine alone or coadministered morphine plus clonidine, were evaluated in the tail flick test. Antisense ODN to G(zalpha) attenuated clonidine- but not morphine-induced antinociception. The ED(50) (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) nmol. However, in the G(zalpha) antisense ODN pretreated mice, the highest dose clonidine tested (50 nmol) produced only 41+/-8.5% MPE. Antisense ODN to G(zalpha) also blocked antinociception produced by i.t. UK14, 304 (alpha(2) adrenergic receptor agonist) and [D-Pen(2), D-Pen(5)] enkephalin (DPDPE) (delta opioid receptor agonist), whereas it failed to attenuate i.t. Tyr-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(oalpha) attenuated both morphine and clonidine induced antinociception and did not affect synergism between the agonists. These results suggest that spinal G(o)alpha mediates antinociception produced by both clonidine and morphine while G(zalpha) mediates alpha(2) adrenergic and delta opioid receptor mediated antinociception, but not antinociception produced by mu or kappa opioid agonists.