The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jan 1984
Comparative StudyIn vivo studies on spinal opiate receptor systems mediating antinociception. II. Pharmacological profiles suggesting a differential association of mu, delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat.
The intrathecal administration of mu (morphine) and delta (D-Ala2-D-Leu5-enkephalin) but not kappa agonists (ethylketocyclazocine, bremazocine and U50488H) or partial agonists (nalbuphine and buprenorphine) produced a dose-dependent inhibition of all cutaneous thermal (hot plate and tail-flick) responses in the rat. In contrast, on visceral chemical tests (writhing), mu and kappa agonists but not delta agonists exerted a powerful suppression of the response. Whereas the ED50 of morphine on the cutaneous thermal tests did not differ from that observed on the visceral chemical test, agents with significant mu and delta activity (metkephamid and beta-endorphin) showed a prominent reduction in activity on the writhing as compared with the hot plate and tail-flick. ⋯ Kappa ligands were selectively resistant to antagonism with naloxone pA2 values for those agonists ranging from 5.9 to 6.6. These observations suggest that there are three discriminable populations of receptors in the spinal cord whose activation results in a selective modulation of the response of the animal to noxious stimuli. In addition, the selective effects of the delta agonists on cutaneous thermal and kappa agonists on visceral chemical suggest a differential coding of spinal afferents through which these stimuli are transmitted.
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J. Pharmacol. Exp. Ther. · Dec 1983
Central alpha receptors and their role in digoxin cardiotoxicity.
The purpose of this study was to determine the role of alpha receptors in the inotropic and cardiotoxic actions of digoxin. Pentobarbital-anesthetized dogs were pretreated centrally with either prazosin, a selective alpha-1 antagonist, or yohimbine, a selective alpha-2 antagonist. Cardiac rhythm, blood pressure and contractile force were monitored during a 60-min period after pretreatment and during a continuous i.v. infusion of digoxin (2.5 micrograms/kg/min). ⋯ Central alpha-1 blockade with prazosin increased the lethal dose of digoxin only at the largest dose (100 micrograms/kg i.c.v.) and its effects may be attributed to nonspecific central activity. BHT-933 (5 micrograms/kg i.c.v.), a selective alpha-2 agonist, enhanced the toxic effects of digoxin by decreasing both the arrhythmogenic and lethal dose of digoxin. These results suggest a central alpha-2 receptor mediation of the cardiotoxic actions of digoxin.
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Central cardiovascular and respiratory effects of dermorphin were studied in conscious rats. Intracerebroventricular administration (0.1 or 1 nM) of dermorphin increased the systolic and diastolic blood pressure whereas a high dose (50 nM) decreased blood pressure. Dermorphin at 1 nM increased respiratory rate but caused hypoxia, acidosis and hypercapnia; at 50 nM, respiratory rate was suppressed. ⋯ Neither blood pressure nor respiratory depression was altered by the muscarinic blocker. Naloxone (1 mg/kg) reversed the respiratory, cardiovascular and sympathetic effects of dermorphin as well as the catalepsy. These data show that dermorphin has central autonomic effects which are naloxone reversible and mediated by both sympathetic and parasympathetic pathways.
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J. Pharmacol. Exp. Ther. · Mar 1983
Relative involvement of mu, kappa and delta receptor mechanisms in opiate-mediated antinociception in mice.
The antinociceptive properties of morphine (mu), ethylketazocine (kappa), nalorphine (kappa), [D-Ala2, D-Leu5]enkephalin (delta) and [D-Ala2, Met5]enkephalinamide (mu, delta) were assessed using the radiant heat tail-flick and acetic acid-induced writhing assays in mice. The apparent pA2 values for the interaction of naloxone with morphine were the same regardless of the nociceptive stimulus employed or the route of administration of morphine. The apparent pA2 values for the interactions of naloxone with ethylketazocine and nalorphine in the writhing test differed significantly from that for the interaction of morphine and naloxone. ⋯ The apparent pA2 values for the interactions of naloxone with [D-Ala2, D-Leu5] enkephalin differed from those for morphine-naloxone interactions on the writhing test. The highly selective mu antagonist beta-funaltrexamine antagonized the agonist actions of morphine and [D-Ala2, D-Leu5]enkephalin, and, in a previous study, beta-funaltrexamine antagonized the antinociceptive actions of [D-Ala2, Met5]enkephalinamide, but not those of nalorphine. It was concluded that agonist interaction with mu or kappa receptors can result in antinociceptive effects in the acetic acid-induced writhing test, and that an agonist interaction with mu, but not kappa, receptors results in antinociceptive action on the radiant heat tail-flick test, and furthermore, that a possible combination of mu and delta receptor interaction can result in antinociceptive activity in both tests.