Acute and chronic effects of nitrendipine on naloxone precipitated morphine withdrawal in mice

There is growing evidence indicating that neuronal calcium channels play an important role in the mechanism of morphine dependence. In this study, the effects of acute and chronic administration of nitrendipine on naloxone precipitated morphine withdrawal signs were investigated. Mice were rendered dependent to morphine by subcutaneous injection of morphine over a period of 5 days. In chronic studies, nitrendipine [25 and 50 mg/kg, i.p.], or vehicle injections were given once a day during the morphine treatment, and the last injection of nitrendipine was given 24 h before the morphine withdrawal. For acute studies, nitrendipine [25 and 50 mg/kg, i.p.] was given 1 h after the last dose of morphine [1 h before naloxone]. A single injection of nitrendipine at 25 mg/kg was ineffective in blocking most signs of morphine withdrawal, however, at 50 mg/kg nitrendipine blocked signs such as hair raising, sniffing, diarrhea and number of jumping. The concurrent injections of nitrendipine with morphine prevented most signs of morphine withdrawal. In agreement with previous findings, these results suggest that alterations in voltage-sensitive calcium channels play a role in the adaptations that occur on chronic treatment with morphine

Pharmacologic characteriztion of bronchospasm induced by substance P [SP] and SP fragments in guinea - pig

Using pharmacologic approach, neurokinin receptor-mediated bronchoconstrictor responses in anesthetized guinea-pigs was characterized. Thus, the bronchospastic effects of substance P [SP] and SP fragments [all administrated intravenously] before and after giving vehicle or selective neurokinin receptor antagonists were compared. Ranking order of potency of SP or SP fragments for induction of bronchoconstriction was: SP4-11 >> SP5-11 = SP3-11 = SP2-11 > SP = SP6-11 [the number of amino acid in the sequence of SP fragments are shown by superscript]. The neurokinin 1 [NK1] receptor antagonists [CP 96,345 or CP 99,994, 3 mg kg-1, iv] did not change baseline values of pulmonary flow resistance [RL] and dynamic pulmonary elastance [EL] and did not eliminate bronchopulmonary responses to these peptides but decreased changes in RL and EL in response to SP and SP fragments. The neurokinin 2 [NK2] receptor antagonist SR 48,968 [1 mg kg-1, iv] failed to induce a rightward shift in dose-response curves to SP or SP fragments except to SP4-11. Combinations of NK1 and NK2 receptor antagonists shifted dose-response curves to SP and SP fragments more than that of NK1 receptor antagonists alone. These findings reveal that SP-induced bronchoconstriction is mediated by its C-terminal sequence and this response is mainly via NK1 receptors. Moreover, bronchopulmonary responses to SP and its C-terminal fragments are complex and there may be interactions between NK1 and NK2 receptors in the lungs