Articles: narcotic-antagonists.
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Comparative Study
Synthesis, opioid receptor binding, and bioassay of naltrindole analogues substituted in the indolic benzene moiety.
A series of analogues of the delta opioid receptor antagonist naltrindole (1) possessing a phenyl, phenoxy, or benzyloxy group at the 4'-, 5'-, 6'-, or - 7'-positions (4-15) and a 2-(2-pyridinyl)ethenyl group at the 5'-position (16) on the indolic benzene ring were synthesized through Fischer indolization of naltrexone. Compounds 4-16 were evaluated for their affinities in opioid receptor binding assays in rat or guinea pig brain membranes and for their opioid antagonist and agonist activities in vitro on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. All of the compounds displayed delta selectivity in binding to the delta, mu, and kappa opioid receptors. ⋯ The overall affinity and activity profile of compound 14 is, therefore, that of a nonpeptide ligand possessing mixed mu agonist/delta antagonist properties. Recently there has been considerable interest in such compounds possessing mu agonist/delta antagonist activities because of their potential therapeutic usefulness as analgesics with low propensity to produce tolerance and dependence side effects. The results of the present study suggest that morphinan derivatives related to 16 and 14 may provide useful leads for the development of potent nonpeptide ligands possessing delta agonist or mixed delta antagonist/mu agonist activities.
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J Pain Symptom Manage · Jul 1998
Clinical TrialPain tolerance in opioid addicts on and off naltrexone pharmacotherapy: a pilot study.
Under certain experimental and clinical conditions, opioid antagonists have been demonstrated to have analgesic properties. In this open-label, nonrandomized, within-subject comparison, the effect of chronic treatment with the antagonist, naltrexone, on tolerance for experimental pain was evaluated in a small sample of male opioid addicts (N = 10) receiving naltrexone maintenance. ⋯ Intra-subject comparison revealed that eight of the ten subjects were more pain tolerant (median + 20 sec) while receiving naltrexone. It is suggested that either midbrain opioid system upregulation in the presence of naltrexone or underlying individual differences in pain tolerance in persons with addictive disease provide potential explanations for these findings.
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Rats were kindled by repeated injections of pentylenetetrazole (PTZ; 37.5 mg/kg; i.p.) in the presence or absence of the opioid receptor antagonist naloxone. Naloxone (10 mg/kg; i.p.) applied 30 min before each PTZ application had no major effect on the seizure development, although a slight decrease in the seizure expression of fully kindled animals could be observed. In the kindled animals, a pronounced but transient increase in c-fos mRNA level was observed in several brain areas after the injection of PTZ. ⋯ Brosz, Naloxone ameliorates the learning deficit induced by pentylenetetrazole kindling in rats, Eur. J. Neurosci. 6 (1994) 1512-1515].
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Acute displacement of opioids from their receptors by administration of large doses of opioid antagonists during general anesthesia is a new approach for detoxification of patients addicted to opioids. The authors tested the hypothesis that mu-opioid receptor blockade by naloxone induces cardiovascular stimulation mediated by the sympathoadrenal system. ⋯ Despite barbiturate-induced anesthesia, acute mu-opioid receptor blockade in patients addicted to opioids induces profound epinephrine release and cardiovascular stimulation. These data suggest that long-term opioid receptor stimulation changes sympathoadrenal and cardiovascular function, which is acutely unmasked by mu-opioid receptor blockade. Because of the attendant cardiovascular stimulation, acute detoxification using naloxone should be performed by trained anesthesiologists or intensivists.
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Comparative Study
Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose.
To determine whether naloxone administered i.v. to out-of-hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (s.q.). ⋯ There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. The slower rate of absorption via the s.q. route was offset by the delay in establishing an i.v.