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 (δ) opioid receptors to produce antinociception in the tail flick test. More specifically, this action of heroin involves δ 1 and 6MAM involves δ 2 opioid receptors. Even though 6MAM given intrathecally (IT) in Swiss Webster mice also activates δ receptors to produce antinociception, the subtype of δ receptor in the spinal cord is not known. The present study addressed this question. First, in order to confirm the subtype selectivity of the δ opioid receptor antagonists in the spinal cord, 7-benzylidenenaltrexone (BNTX, a selective δ 1 receptor antagonist) and naltriben (a selective δ 2 receptor antagonist) were administered IT against the prototypic δ 1 and δ 2 peptide agonists [D-Pen 2,5]enkephalin (DPDPE) and [D-Ser 2,Leu 5]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 δ 1 and δ 2 opioid receptor subtype agonist actions. This differentiation was further demonstrated by administration of the antagonists IT against the antinociceptive action of β-endorphin given intracerebroventricularly. The antinociceptive action of β-endorphin is due to spinal release of met-enkephalin which results in spinal δ 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 δ 1 and δ 2 opioid receptor activity can be obtained with naltriben and BNTX, blockade of the individual δ receptor subtypes does not appear to alter IT 6MAM antinociception. Therefore, these results suggest that 6MAM, given IT, is acting on a δ opioid receptor but this receptor in the spinal cord appears to be different from the δ 2 receptor on which 6MAM acts in the brain.