BW 373U86: Behavioral pharmacology of a putative non-peptide, systemically-active delta opioid agonist.

Abstract

The experiments described in this thesis were designed to evaluate the opioid-receptor-mediation of the discriminative stimulus (S$\sp{\rm D}),$ analgesic and convulsant effects produced by BW 373U86 (($\pm$)-4-((R*)-$\alpha$-((2S*5R*)-4-Allyl-2,5-dimethyl-$ 1$-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride) using the apparent pA$\sb2$ method. Potencies were determined for the selective opioid antagonists, naltrindole (NTI) and naltrexone (NTX) in antagonizing morphine (MOR), bremazocine (BREM) and BW 373U86 (BW). The S$\sp{\rm D}$ effects of MOR, BREM and BW were established in separate groups of pigeons. None of the training drugs substituted for each other. With the exception of ethylketazocine, none of the compounds tested including the prototypic $\delta$ agonists substituted for BW. NTX was 30-fold more potent in antagonizing MOR than BW. NTI was 1000-fold more potent in antagonizing BW than MOR. NTI did not antagonize BREM. These data indicated that the S$\sp{\rm D}$ effects of MOR, BREM and BW were mediated through different receptors. Convulsant effects of BW were evaluated in mice. NTI was 10-fold more potent than NTX in antagonizing BW. None of the opioid compounds tested, including the prototypic $\delta$ agonists, produced a convulsive syndrome that was similar to BW-induced convulsions. Pretreatment with BW produced a dose-related downward shift in the BW dose-effect curve. The downward shift produced by pretreatment with 10.0 mg/kg BW did not return to baseline levels for 8 days. This downward shift was prevented by both NTI and NTX. The analgesic effects of MOR, BREM and BW were evaluated in the writhing assay in mice. NTX was more potent in antagonizing MOR than BW. NTI was more potent in antagonizing BW than MOR; NTI did not antagonize BREM. The analgesic effects of MOR, BREM and BW were most likely mediated through different receptors. The fact that the convulsant and S$\sp{\rm D}$ effects of BW were not shared with prototypic $\delta$ agonists suggested that BW may be producing its effects through a subtype of $\delta$ receptor. Support for this notion was also provided by the fact that the potency of NTI was different in antagonizing the analgesic effects of BW, (D-Ala2) deltorphin II and (D-Pen$\sp2,$D-Pen$\sp5$) enkephalin.