title: Zomepirac: preclinical narcotic abuse liability evaluation.
abstract: 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate dihydrate (Zomepirac, Zomax) was assessed in a variety of preparations in which narcotic agonists and antagonists have distinctive profiles. Zomepirac failed to displace tritiated etorphine significantly at concentrations up to 200 mumol/l. It was active (3-7 X 10(-5) mol/l) on both the electrically stimulated guinea pig ileum and mouse vas deferens but was less efficacious than morphine; these effects were not reversed by narcotic antagonists. Zomepirac was inactive in some analgesic assays in mice: tail-flick (1-30 mg/kg s.c.); hot plate (1-100 mg/kg s.c.); Nilsen (1-50 mg/kg s.c.); it was also inactive (1-10 mg/kg s.c.) as an antagonist of morphine in the tail-flick assay. It was, however, active in the paraphenylquinone writhing assay; this action was not reversed by naloxone (1-10 mg/kg) Zomepirac (2.5-10 mg/kg s.c.) failed to suppress signs of withdrawal produced by morphine deprivation in dependent rhesus monkeys. The intraperitoneal infusion of high doses of zomepirac (50 mg/kg/24 h or more) in rats produced toxicity. However, lower doses failed to induce narcotic-like dependence over a 6-7-day infusion period. The compound failed to maintain intravenous drug self-administration responding in rhesus monkeys over a range of doses (0.1-3.2 mg/kg) although codeine did so. In rhesus monkeys trained to discriminate narcotic agonists (etorphine or ethylketazocine) from saline, zomepirac (1-10 mg/kg i.m.) failed to produce drug-appropriate responding. Thus, zomepirac appears to possess few, if any, of the characteristic actions of narcotics that are associated with their abuse liability.
mesh_terms: D000701:Analgesics, Opioid; D000818:Animals; D004192:Discrimination, Psychological / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009021:Morphine Dependence / Q000523:psychology; D009130:Muscle, Smooth / Q000187:drug effects; D011758:Pyrroles / Q000009:adverse effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism; D019966:Substance-Related Disorders / Q000209:etiology*; D014046:Tolmetin / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D011758:Pyrroles; D011957:Receptors, Opioid; C020549:zomepirac; D014046:Tolmetin