Opioid-related discriminative stimulus, antinociceptive and respiratory depressant effects of substituted 3-hydroxy-N-phenethyl-5-phenylmorphans

Abstract

<b>Abstract ID 18116</b> <b>Poster Board 4</b> <b>Aim:</b> Delta opioid receptor (DOR) signaling mechanisms have been proposed to decrease the side effect liability associated with morphine-like prescription opioids. We evaluated this proposition by determining the acute effects of six novel opioid agonists in assays of morphine discrimination in rats, and antinociception, operant performance and respiratory function in nonhuman primates. <b>Methods:</b> 6 novel 3-hydroxy-N-phenethyl-5-phenylmorphans (C9-alkyl substituted compounds with varying stereochemistry) were synthesized at the NIDA and NIAAA IRP. In vitro assays using commercially available kits (e.g. HitHunter for cAMP accumulation) indicated the compounds have no efficacy at kappa opioid receptors (KOR), no to low efficacy at DOR, and some inhibitory effects at DOR or KOR. The compounds had efficacy ranging from low (105) to moderate (76a, 111, 90b) to high (76b, 142) at mu opioid receptors (MOR). In behavioral studies, full dose-effect functions for all six compounds were first determined in rats (n=7-9) trained to discriminate 3 mg/kg morphine from saline. Next, effects in squirrel monkeys (n=3-5/group) were determined using cumulative dosing procedures in two assays. In one set of studies, tail-withdrawal latency from 52^oC water (antinociception) and effects on food-maintained operant responding (behavioral disruption) were concurrently evaluated. In other studies, whole body plethysmography in the presence of normal air and air mixed with 5% CO₂ was used to obtain respiratory parameters (breathing frequency, tidal volume, minute volume). <b>Results:</b> Four compounds (76b, 105, 142, and 111) fully substituted for morphine in discrimination studies; one compound (76a) partially substituted (&gt;70% drug-lever responding), and one compound (90b) did not generalize from the morphine stimulus (∼25% drug -lever responding). All morphine-like discriminative stimulus effects were attenuated by pretreatment with 0.1 mg/kg naltrexone. In squirrel monkeys, compounds 76b and 142 had antinociceptive effects, behaviorally disruptive, and ventilatory effects similar to those of morphine. The remaining compounds had similarly disruptive effects on food-maintained operant responding but produced only limited effects on ventilation. Only three of the four (111, 90b, and 76a) had moderate to full antinociceptive effects. <b>Conclusion:</b> These data demonstrate that the presence of agonist or antagonist activity at DOR may have greater influence on the effects of partial MOR agonists (76a, 111, and 90b) than on either full agonists (76b, 142) or very low efficacy agonists (105). Supported by NIH Grant DA047574