Separation of the convulsions and antidepressant-like effects produced by the delta-opioid agonist SNC80 in rats

Abstract

Rationale-Delta-opioid agonists produce a number of behavioral effects, including convulsions, anti-nociception, locomotor stimulation, and antidepressant-like effects. The development of these compounds as treatments for depression is limited by their convulsive effects. Therefore, determining how to separate the convulsive and antidepressant-like characteristics of these compounds is essential for their potential clinical use.Objective-The present study tests the hypothesis that the rate of delta-opioid agonist administration greatly contributes to the convulsive properties, but not the anti-depressant-like effects, of delta-opioid agonists.Materials and methods-The delta-opioid agonist SNC80 (1, 3.2, and 10 mg kg −1 or vehicle) was administered to Sprague-Dawley rats by intravenous infusion over different durations of time (20 s, 20, or 60 min). Convulsions were measured by observation prior to determining antidepressantlike effects in the forced swim test.Results-Slowing the rate of SNC80 administration minimized delta agonist-induced convulsions without altering the effects of SNC80 in the forced swim test.Conclusions-These data suggest that delta agonist-induced antidepressant properties are independent of convulsive effects, and that it may be possible to eliminate the convulsions produced by delta agonists, further promoting their potential clinical utility.

NIH 11082 produces anti-depressant-like activity in the mouse tail-suspension test through a delta-opioid receptor mechanism of action

“…= 0.75 (0.26 − 2.20) mg/kg; Aceto et al, in press). While NIH 11082 did produce anti-hyperalgesic effects in the rat Freund's adjuvant arthritic model, it was ineffective in the tail-flick and hot plate tests, which are nociceptive assays that are sensitive to muopioid receptor antagonists (Traynor et al, 2005;Aceto et al, in press). …”

“…This compound produced antinociceptive activity in the paraphenylquinone mouse writhing assay (ED 50 (95% CL) = 1.9 (0.7-5.3 mg/kg), but showed virtually no activity by itself in the tail-flick and hotplate tests (Traynor et al, 2005;Aceto et al, in press). Naltrindole, a selective delta-opioid receptor antagonist, blocked the analgesic action of NIH 11082, while neither the kappa opioid selective antagonist nor-BNI nor the mu-opioid receptor antagonist beta-FNA reduced this effect (Aceto et al, in press).…”

“…Similarly, increasing levels of endogenous delta-opioid peptides with enkephalinase inhibitors such as RB101 revealed antidepressant-like effects in both mice and rats (Baamonde et al, 1992;Tejedor-Real et al, 1998). In addition, the nonpeptidic delta-opioid receptor agonists SNC80 ( (+)-4-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1piperazinyl)-3-methoxybenzyl)N,N-diethylbenzamide) and (+)BW373U86 ((+)-4-[(alpha-R*)-alpha-[(2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,Ndiethylbenzamide) to rats elicited naltrindole-sensitive antidepressant-like properties, as assessed in the forced swim test (Broom et al, 2002a;Jutkiewicz et al, 2004;Jutkiewicz et al, 2005). Conversely, chronic administration of the potent, nonselective opioid receptor antagonist naltrexone to humans induced a self-reported mental depression in a placebocontrolled open study (Hollister et al, 1981), suggesting a general role for opioid systems in depression.…”

“…A promising opioid candidate that can elicit potential therapeutic effects and is apparently devoid of provoking seizures (Traynor et al, 2005) is NIH 11082 ((−)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride). This compound produced antinociceptive activity in the paraphenylquinone mouse writhing assay (ED 50 (95% CL) = 1.9 (0.7-5.3 mg/kg), but showed virtually no activity by itself in the tail-flick and hotplate tests (Traynor et al, 2005;Aceto et al, in press).…”

“…Naltrindole, a selective delta-opioid receptor antagonist, blocked the analgesic action of NIH 11082, while neither the kappa opioid selective antagonist nor-BNI nor the mu-opioid receptor antagonist beta-FNA reduced this effect (Aceto et al, in press). However, NIH 11082 has low binding affinity (K i = 140 nM) and lacks potency and efficacy in the GTPγS assay for the delta-opioid receptor (Traynor et al, 2005). Thus, the effects of this drug are mediated through an allosteric site of action, the release of endogenous delta-opioid receptor ligands, or other indirect mechanisms of action.…”