Spinal delta opioid receptor subtype activity of 6-monoacetylmorphine in Swiss Webster mice

Heroin and 6-monoacetylmorphine (6MAM) given intracerebroventricularly in Swiss Webster mice, act on supraspinal delta (delta) opioid receptors to produce antinociception in the tail flick test. More specifically, this action of heroin involves delta 1 and 6MAM involves delta 2 opioid receptors. Even though 6MAM given intrathecally (IT) in Swiss Webster mice also activates delta receptors to produce antinociception, the subtype of delta receptor in the spinal cord is not known. The present study addressed this question. First, in order to confirm the subtype selectivity of the delta opioid receptor antagonists in the spinal cord, 7-benzylidenenaltrexone (BNTX, a selective delta 1 receptor antagonist) and naltriben (a selective delta 2 receptor antagonist) were administered IT against the prototypic delta 1 and delta 2 peptide agonists [D-Pen2,5]enkephalin (DPDPE) and [D-Ser2,Leu5]enkephalin-Thr (DSLET), respectively. DPDPE-induced antinociception was inhibited by BNTX, but not naltriben. The opposite selectivity occurred for DSLET; naltriben, but not BNTX, administered IT inhibited IT DSLET-induced antinociception. Therefore, the antagonists differentiated between spinal delta 1 and delta 2 opioid receptor subtype agonist actions. This differentiation was further demonstrated by administration of the antagonists IT against the antinociceptive action of beta-endorphin given intracerebroventricularly. The antinociceptive action of beta-endorphin is due to spinal release of met-enkephalin which results in spinal delta 2 receptor activation. This antinociception was reduced by IT naltriben, but not BNTX, administration. The antagonists were then administered against IT 6MAM-induced antinociception. Neither BNTX nor naltriben given alone, each at twice the usual dose, altered IT 6MAM-induced antinociception. When the antagonists were administered together, each at the usual dose, the antinociceptive action of 6MAM was inhibited. Thus, even though a differentiation between spinal delta 1 and delta 2 opioid receptor activity can be obtained with naltriben and BNTX, blockade of the individual delta receptor subtypes does not appear to alter IT 6MAM antinociception. Therefore, these results suggest that 6MAM, given IT, is acting on a delta opioid receptor but this receptor in the spinal cord appears to be different from the delta 2 receptor on which 6MAM acts in the brain.