6-o-monoacetylmorphine and naltrindole-benzofuran

CD-1 mice were treated intravenously with streptozotocin, 200 mg/kg, and tested 2 weeks later or treated with 60 mg/kg and tested 3 days later. Both treatments changed the tail flick response of heroin and 6-monoacetylmorphine (6 MAM) given intracerebroventricularly from a mu- to delta-opioid receptor-mediated action as determined by differential effects of opioid receptor antagonists. The response to morphine remained mu. Heroin and 6 MAM responses involved delta1 (inhibited by 7-benzylidenenaltrexone) and delta2 (inhibited by naltriben) receptors, respectively. These delta-agonist actions did not synergize with the mu-agonist action of morphine in the diabetic mice. The expected synergism between the delta agonist, [D-Pen2-D-Pen5]enkephalin (DPDPE), and morphine was not obtained in diabetic mice. Thus, diabetes disrupted the purported mu/delta-coupled response. In nondiabetic CD-1 mice, heroin and 6 MAM produced a different mu-receptor response (not inhibited by naloxonazine) from that of morphine (inhibited by naloxonazine). Also, these mu actions, unlike that of morphine, did not synergize with DPDPE. The unique receptor actions and changes produced by streptozotocin suggest that extrinsic in addition to genetic factors influence the opioid receptor selectivity of heroin and 6 MAM.

Topics: Analgesics, Opioid; Animals; Anti-Bacterial Agents; Benzylidene Compounds; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Heroin; Injections, Intraventricular; Male; Mice; Morphine; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu; Streptozocin; Time Factors

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.

Topics: Analgesics, Opioid; Animals; Benzylidene Compounds; beta-Endorphin; Dose-Response Relationship, Drug; Injections, Intraventricular; Injections, Spinal; Male; Mice; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Pain Measurement; Receptors, Opioid, delta; Spinal Cord

The purpose of this study was to determine which delta (delta) opioid receptor subtype, delta 1 or delta 2, was involved in producing the antinociceptive action of heroin and 6-monacetylmorphine (MAM) in Swiss Webster mice. Previous work from this laboratory established that heroin and MAM, given intracerebroventricularly (i.c.v.) in Swiss Webster mice, produce antinociception through activation of supraspinal delta receptors. Naltrindole, but not naloxone or nor-binaltorphimine, antagonizes the inhibitory action of heroin and MAM in the tail-flick test. Recent literature documents the occurrence of subtypes of the delta opioid receptor and the availability of selective antagonists. 7-Benzylidenenaltrexone (BNTX) antagonizes the antinociception induced by delta 1 receptor agonists without affecting that induced by delta 2 receptor agonists. Naltriben (NTB) selectively inhibits delta 2- but not delta 1-induced antinociception. In the present study BNTX and NTB were administered i.c.v. with heroin and MAM to determine the delta receptor subtype responsible for inhibition of the tail-flick response in Swiss Webster mice. The ED50 for heroin-induced antinociception was increased 19-fold by BNTX and was not altered by NTB administration. On the other hand, the ED50 value of MAM was increased 3-fold by NTB and was not altered by BNTX administration. These results suggest that heroin activated supraspinal delta 1 receptors and MAM acted on supraspinal delta 2 receptors to produce antinociception in Swiss Webster mice.

Topics: Animals; Benzylidene Compounds; Heroin; Male; Mice; Morphine Derivatives; Naltrexone; Pain; Receptors, Opioid, delta