Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is accumulating evidence that kappa opioid agonists attenuate cocaine's behavioral effects, and we recently reported that the kappa opioid agonists ethylketocyclazocine (EKC) and U50-488 decreased cocaine self-administration by rhesus monkeys. In the present study, we first examined the effects of acute intramuscular administration of six kappa opioid agonists on responding maintained by food under an FR30 schedule. Each kappa agonist produced dose-dependent decreases in schedule controlled behavior, and the relative potencies were enadoline >/= bremazocine > Mr2033 >/= cyclazocine = spiradoline > PD117302. We then studied the effects of chronic administration of these kappa agonists in monkeys responding under a second order schedule of food delivery and cocaine self-administration. The effects of 10 days of intravenous treatment with three arylacetamides [enadoline (0.00032-0.0032 mg/kg/hr), (-) spiradoline (0.0032-0.018 mg/kg/hr), PD117302 (0.032-0.32 mg/kg/hr)] and three benzomorphans [bremazocine (0.00032-0.0032 mg/kg/hr), Mr2033 (0.0032-0.032 mg/kg/hr), cyclazocine (0.001-0.10 mg/kg/hr)] were compared with saline treatment. Enadoline (0.001 and 0.0032 mg/kg/hr), bremazocine (0.0032 mg/kg/hr) and Mr2033 (0.01 and 0.0032 mg/kg/hr) significantly decreased cocaine self-administration (0.01 mg/kg/injection) (P < .05-.01). Cyclazocine (0.001-0.10 mg/kg/hr), (-) spiradoline (0.0032-0.018 mg/kg/hr) and PD117302 (0.032-0.32 mg/kg/hr) had no significant effects on cocaine self-administration across the dose-range studied. When gradually increasing doses of enadoline (0.00032-0.01 mg/kg/hr) or Mr2033 (0.0032-0.032 mg/kg/hr) were administered over 28 consecutive days, cocaine self-administration was dose-dependently decreased in all monkeys. Food-maintained responding was usually decreased at doses that decreased cocaine self-administration. Adverse side effects (emesis and sedation) were transient, and laboratory indices of hematology and blood chemistry were normal throughout chronic enadoline and Mr2033 treatment. These data extend our earlier findings with EKC and U50,488 and suggest that kappa opioid agonists may be a useful approach to the development of new pharmacological treatments for cocaine dependence. The extent to which undesirable side effects may limit their clinical usefulness remains to be determined.
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PMID:Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys. 969 38

Kappa opioid agonists inhibit dopamine release from mesolimbic dopaminergic neurons and attenuate some behavioral effects of cocaine in rodents. Evidence that kappa opioid agonists may act as functional antagonists of cocaine led us to examine their interactions with cocaine's abuse-related effects in rhesus monkeys. In cocaine self-administration studies, four arylacetamides (U50,488, enadoline, (-) spiradoline and PD117302) and four benzomorphans (ethylketocyclazocine [EKC], bremazocine, Mr2033 and cyclazozine) each were administered as continuous infusions over 10 days. EKC, Mr2033, bremazocine, U50,488 and enadoline produced significant dose-dependent and sustained decreases in cocaine self-administration and also decreased food-maintained responding at some doses. Emesis and sedation were occasionally observed during the first two days of kappa agonist treatment, but tolerance developed rapidly to these effects. Cyclazocine, PD117302 and spiradoline did not significantly alter cocaine self-administration. The behavioral effects of EKC and U50,488 were antagonized by both the kappa opioid antagonist nor-binaltorphimine and the non-selective opioid antagonist naloxone. In general, compounds with mixed activity at both kappa and mu opioid receptors (e.g. EKC, Mr2033) decreased cocaine self-administration more consistently and with fewer or less severe undesirable side effects than more selective kappa agonists (e.g. U50,488, spiradoline). Although several kappa agonists decreased cocaine self-administration, EKC and U50,488 did not consistently block the discriminative stimulus effects of cocaine in monkeys trained to discriminate cocaine from saline. The extent to which kappa agonist-induced decreases in cocaine self-administration reflect an antagonism of cocaine's abuse-related effect remains to be determined.
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PMID:Interactions between kappa opioid agonists and cocaine. Preclinical studies. 1091 26