A novel delta opioid agonist, BW373U86, in squirrel monkeys responding under a schedule of shock titration.

The squirrel monkey titration procedure was used to assess the antinociceptive effects of the novel delta opioid agonist (+/-)-4-(a-R*)-a(2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxyb enzyl)- N,N-diethylbenzamide (BW373U86). Under this procedure shock increased every 15 sec from 0.01 to 2.0 mA in 30 steps. Five responses terminated the shock for 15 sec, after which the shock resumed at a lower intensity. The intensity at which the monkeys maintained the shock 50% of the time (median shock level, MSL) was determined. BW373U86 (1.0-30.0 mg/kg i.m.) increased MSL, but these increases were not dose-dependent and lasted only 15 min or less. Doses of BW373U86 that increased MSL often produced tremors and/or convulsions immediately after administration. When 1.0 mg/kg of naltrindole, a delta opioid antagonist, was given in combination with BW373U86, doses of BW373U86 up to 30 mg/kg no longer increased MSL nor did tremors and/or convulsions occur. Doses of BW373U86 (0.01-0.3 mg/kg i.m.) that did not increase MSL when administered alone shifted the dose-effect curve for the mu agonist l-methadone to the left. These shifts were antagonized dose-dependently by naltrindole. In monkeys that were tolerant to morphine, BW373U86 (0.03-0.1 mg/kg i.m.) shifted the morphine dose-effect curve leftward. In addition, BW373U86 altered the effects of the partial opioid agonists, buprenorphine, nalbuphine, butorphanol and levallorphan such that doses of these drugs that did not increase MSL when administered alone, often did so in the presence of BW373U86. Taken together, these findings indicate that BW373U86 has a delta agonist profile in the squirrel monkey; however, its antinociceptive effects in the shock titration procedure may be due to its toxic effects.

Discontinuation of sustained sucrose-feeding aggravates morphine withdrawal.

Sprague-Dawley rats were allowed ad lib access to a 20% sucrose solution in addition to their normal diet to investigate the relationship between the prolonged consumption of a high carbohydrate diet and opioid function as evidenced by opioid dependence and withdrawal. Morphine dependence, assayed by tailflick, was induced, followed by naloxone-precipitated withdrawal, gauged by weight loss. Sucrose-fed animals developed lowered pain thresholds prior to dependence induction relative to those of control animals, but failed to exhibit any differences from controls in the development of dependence. Weight loss during withdrawal was increased by the discontinuation of sustained sucrose-feeding. In addition, the induction of dependence first decreased, then increased the animals' preference for sucrose. It is concluded that changes in opioid function caused by sustained sucrose-feeding are insufficient to affect the development of tolerance to morphine analgesia, but do aggravate the symptoms of precipitated withdrawal when access to sucrose is denied prior to the injection of naloxone.

Relationships between sustained sucrose-feeding and opioid tolerance and withdrawal.

This study examines the effect of sustained sucrose consumption on the development of tolerance to morphine analgesia (20 mg/kg IP injections) and subsequent, naloxone-precipitated withdrawal (2 mg/kg IP). Food intakes are also measured. Sprague-Dawley rats were allowed ad lib access to a 20% sucrose solution in addition to their normal diet. Pain thresholds and intakes were monitored for two weeks, then morphine tolerance was induced, followed by precipitated withdrawal. Tolerance was assayed by the tailflick method, and withdrawal was gauged by weight loss. The animals given access to sucrose developed lowered pain thresholds prior to tolerance induction relative to those of control animals, but they failed to exhibit any differences from controls in tolerance development of severity of withdrawal. The induction of tolerance first decreased, then increased sucrose consumption and steadily decreased chow consumption. Naloxone-precipitated withdrawal decreased chow consumption, but failed to affect the ingestion of the sucrose solution. It is concluded that changes in opioid function caused by sustained sucrose-feeding are insufficient to affect the development of tolerance to morphine analgesia; however, tolerance induction biphasically alters sucrose consumption.