European journal of pharmacology
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Intrathecally administered mu-opioid (morphine; DAMGO ([D-Ala2,N-MePhe4,Gly5-ol]enkephalin)) and delta-opioid (DPDPE ([D-Pen2,D-Pen5] enkephalin); DADLE ([D-Ala2,D-Leu5]enkephalin)) receptor preferring agonists were systematically challenged with the competitive opiate antagonists naloxone or naltrindole in the rat. Naloxone produced a dose-dependent reduction in agonist effect with the intrathecal IC50 being similar for all agonists (2.1-5.4 micrograms). In contrast, the naltrindole antagonist profile was (IC50 in micrograms) DPDPE (4.0); morphine (23.5); DADLE (> 30) and DAMGO (> 30). Three points are emphasized: (1) antagonism of DPDPE and not DAMGO by naltrindole suggests two distinct opioid sites; (2) a similar potency for naloxone against these agonists suggests that the agonists may act upon spinal sites for which naloxone has comparable affinity or that they may act upon separate sites which are functionally coupled and that the action of naloxone on one or the other site is responsible for the antagonism; and (3) given the modest cross-tolerance between DADLE and mu agonists, the failure of naltrindole to antagonize DADLE suggests that in the rat this peptide acts through a delta site different from that acted upon by DPDPE.
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Abecarnil, a beta-carboline acting at benzodiazepine receptors, has been shown to have anxiolytic and anticonvulsant properties in a number of models. It has reduced muscle relaxant and incoordinating effects in comparison to diazepam. Given the wide clinical application of diazepam to prevent alcohol withdrawal seizures, a genetic animal model was employed to compare abecarnil with diazepam for its anti-withdrawal effects. ⋯ Similar results were seen in an experiment where withdrawal handling-induced convulsions were assessed after a single high-dose ethanol injection. Abecarnil and diazepam also reduced the smaller handling-induced convulsion scores seen in naive WSP mice. Single doses of abecarnil or diazepam did not lead to a rebound elevation of handling-induced convulsion scores suggestive of a withdrawal reaction.
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The effects of Ca2+ channel antagonists on the capsaicin-induced cough reflex in guinea pigs were studied. Intraperitoneal injection of nifedipine, verapamil and flunarizine in doses that ranged from 0.3 to 3.0 mg/kg decreased the number of coughs in a dose-dependent manner. ⋯ Pretreatment with a low dose of nifedipine (0.3 mg/kg), which by itself had no significant effect on the number of coughs, markedly increased the antitussive effects of morphine, dihydrocodeine and dextromethorphan. These data suggest that Ca2+ channels play an important role in the regulation of the cough reflex.
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Induction of anaphylactic shock in mice by i.v. antigen challenge (bovine serum albumin, 100 micrograms) or i.v. treatment with the mast cell degranulator compound 48/80 resulted in 80 and 90% mortality rate, respectively. Inhibition of nitric oxide (NO) synthesis from L-arginine by co-injection of the L-arginine analog NG-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg) reduced the mortality rate by 40 and 20% in the antigen- and compound 48/80-induced shock models. ⋯ This beneficial effect was reversed by addition of L-arginine (120 mg/kg) but not D-arginine (120 mg/kg). These results suggest NO production as a possible mechanism involved in the pathophysiology of anaphylactic shock.