We studied the in vivo pharmacology of ICI 154,129, a new antagonist that is claimed to show selectivity for delta opiate receptors. At s.c. doses of 30 and 100 mg/kg, ICI 154,129 had no marked effect on the gastrointestinal transit of a charcoal meal in mice. In this test, ICI 154,129 reversed the inhibitory action of metkephamid (a proposed delta receptor agonist) but not that of levorphanol. ICI 154,129 was proconvulsant in the mouse picrotoxin potentiation test; the dose-response curve had a low ceiling and was biphasic. Naloxone (1 mg/kg, s.c.) enhanced the proconvulsant action of ICI 154,129 (40 mg/kg, s.c.) by an unknown mechanism.

Animals↗

PubMedDate not supplied

Studies on opioid peptides as endogenous anticonvulsants.

In both normal and hypophysectomized rats, electroconvulsive shock (ECS) produced a significant postictal rise in seizure threshold (S.T.) to flurothyl, a volatile convulsant. This ECS-induced increase in S.T. was markedly attenuated by naloxone (10 mg/kg s.c.), which itself did not alter basal S.T. A dose of bicuculline (0.1 mg/kg i.p.) which was slightly proconvulsant in the flurothyl test did not significantly alter the postictal rise in S.T. produced by ECS. With hypophysectomized rats, there was a 24% increase in basal S.T. to flurothyl challenge. Hypophysectomy had no influence on the postictal rise in S.T. produced by ECS, nor on the attenuation that occurs with naloxone. We propose that the postictal rise in S.T. reflects a change occurring centrally which prevents a static convulsive state, possibly through brain opioid peptides acting as endogenous anticonvulsants.

Animals↗

PubMedDate not supplied

Classification of opioids on the basis of their ability to antagonize bombesin-induced grooming in rats.

Bombesin (0.001-0.125 microgram) elicits dose-related excessive grooming when administered i.c.v. to rats. In contrast to the grooming produced by various other endogenous and exogenous agents, bombesin-induced grooming is not markedly affected by behaviorally non-depressant doses (determined by a novel method) of morphine (3 and 10 mg/kg, s.c.). The benzomorphan, ethylketocyclazocine (0.25-0.5 mg/kg, s.c.), does attenuate bombesin-induced grooming in a dose-related and stereospecific manner. In this study, we have classified 27 opioids on the basis of their ability to antagonize bombesin-induced grooming. The results of the classification indicate that a benzomorphan nucleus is required for activity in this test. Our test provides evidence that postulated benzomorphan binding sites are functionally active as pharmacologic receptors.

Animals↗

PubMedDate not supplied

Extraction and measurement of morphine: correlation of brain level and s.c. dose in drug-naive and morphine-tolerant rats.

A method was recently developed by Raffa et al (1) for rapid analysis of brain levels of morphine in rats given the drug subcutaneously. The technique combines the extraction procedure of Sprague and Takemori (2) and the HPLC methodology of Peterson et al (3). The purpose of the present work was verification of the accuracy of this technique and its application to an accompanying study in which the dissociation constants of morphine determined in drug-naive and morphine-tolerant rats were compared. Male, Sprague-Dawley rats (180-220 g) were given morphine sulfate s.c. 60 min prior to testing. Each rat in the "tolerant" group received two 75 mg morphine pellets subcutaneously which were removed 96 h later. Brain levels of morphine were measured a further 24 h later. Morphine levels in rat brain ranged from 52 to 1800 ng, corresponding to subcutaneous doses of 2.5 to 320 mg/kg. This range of brain levels agrees well with those obtained using different methods (4,5). We found no significant difference in brain levels of morphine in naive and tolerant rats given the same doses of morphine (10, 20, 40, and 80 mg/kg, s.c.). Thus, in the determination of dissociation constants for morphine, the same relation can be used for both naive and morphine-tolerant rats when converting administered dose to brain level.

Animals↗

PubMedDate not supplied

Estimation in vivo of the receptor constants of morphine in naive and morphine-tolerant rats.

The efficacy and dissociation constant of morphine in naive and morphine-tolerant rats were estimated by the method of partial irreversible blockade of a fraction of the receptor population with buprenorphine. The dissociation constant (KA) of morphine increased from 3.3 x 10(-5) M in naive to 1.4 x 10(-4) M in morphine-tolerant animals, indicating a decrease in the affinity of morphine for its receptor in the tolerant state. The efficacy of morphine (KA/A50 + 1) was constant in naive and tolerant animals (4.23 and 4.46, respectively). When the data were recalculated following conversion of administered dose to brain morphine concentration, the value of KA was 1.7 x 10(-7) M in naive and 7.7 x 10(-7) M in morphine-tolerant rats, while the efficacy was 2.5 and 3.4, respectively. In addition, the stimulus-effect relationship varied in the two states, with the curve in the tolerant animal being of different shape and broader range than in the naive rat. The present results suggest that (a) tolerance to opiate agonists may involve affinity changes and (b) post-receptor events leading to the measured effect may also be affected.

Analgesia↗