Role of Pharmacokinetic Effects in the Potentiation of Morphine Analgesia by L-Type Calcium Channel Blockers in Mice
The present study was designed to investigate the pharmacokinetic interaction of morphine with three classes of L-type calcium channel blockers (CCB) and its relationship to morphine-induced mechanical antinociception in mice. The CCB classes were benzothiazepine (diltiazem), dihydropyridine (nimodi...
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Language: | English |
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Elsevier
2004-01-01
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Series: | Journal of Pharmacological Sciences |
Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861319324910 |
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author | Norifumi Shimizu Shiroh Kishioka Takehiko Maeda Yohji Fukazawa Chizuko Yamamoto Masanobu Ozaki Hiroyuki Yamamoto |
author_facet | Norifumi Shimizu Shiroh Kishioka Takehiko Maeda Yohji Fukazawa Chizuko Yamamoto Masanobu Ozaki Hiroyuki Yamamoto |
author_sort | Norifumi Shimizu |
collection | DOAJ |
description | The present study was designed to investigate the pharmacokinetic interaction of morphine with three classes of L-type calcium channel blockers (CCB) and its relationship to morphine-induced mechanical antinociception in mice. The CCB classes were benzothiazepine (diltiazem), dihydropyridine (nimodipine), and phenylalkylamine (verapamil). Each of the three classes of L-type CCB (diltiazem, 40 and 80 mg/kg; nimodipine, 40 mg/kg; verapamil, 40 mg/kg), when administered prior to morphine (4 mg/kg, s.c.), potentiated the analgesic effect of morphine and markedly increased the level of morphine in serum. Pretreatment with diltiazem (40 and 80 mg/kg) and verapamil (40 mg/kg) also increased morphine level in the brain. However, these drugs produced less increase in morphine level in the brain than they produced in serum (i.e., they decreased the brain-to-serum ratio of morphine). Pretreatment with nimodipine (40 mg/kg) did not affect the morphine level in the brain and also decreased the brain-to-serum ratio of morphine. When morphine (3.2 – 100 mg/kg, s.c.) was injected alone, the brain-to-serum ratio of morphine was constant, regardless of the morphine dose. These results suggest that increases in morphine concentration in peripheral blood may be, at least in part, involved in the ability of L-type CCBs to potentiate the analgesic effect of morphine. Keywords:: morphine analgesia, diltiazem, nimodipine, verapamil, pharmacokinetics |
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language | English |
last_indexed | 2024-04-13T13:43:49Z |
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series | Journal of Pharmacological Sciences |
spelling | doaj.art-c47d0d5179d940368fdc86ea66916cca2022-12-22T02:44:32ZengElsevierJournal of Pharmacological Sciences1347-86132004-01-01943240245Role of Pharmacokinetic Effects in the Potentiation of Morphine Analgesia by L-Type Calcium Channel Blockers in MiceNorifumi Shimizu0Shiroh Kishioka1Takehiko Maeda2Yohji Fukazawa3Chizuko Yamamoto4Masanobu Ozaki5Hiroyuki Yamamoto6Department of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, JapanDepartment of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, Japan; Corresponding author. FAX: +81-73-446-3806 E-mail: kishioka@wakayama-med.ac.jpDepartment of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, JapanDepartment of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, JapanDepartment of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, JapanDepartment of Toxicology, Niigata University of Pharmacy and Applied Life Science, 5-13-2 Kamishineicho, Niigata City, Niigata 950-2076, JapanDepartment of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, JapanThe present study was designed to investigate the pharmacokinetic interaction of morphine with three classes of L-type calcium channel blockers (CCB) and its relationship to morphine-induced mechanical antinociception in mice. The CCB classes were benzothiazepine (diltiazem), dihydropyridine (nimodipine), and phenylalkylamine (verapamil). Each of the three classes of L-type CCB (diltiazem, 40 and 80 mg/kg; nimodipine, 40 mg/kg; verapamil, 40 mg/kg), when administered prior to morphine (4 mg/kg, s.c.), potentiated the analgesic effect of morphine and markedly increased the level of morphine in serum. Pretreatment with diltiazem (40 and 80 mg/kg) and verapamil (40 mg/kg) also increased morphine level in the brain. However, these drugs produced less increase in morphine level in the brain than they produced in serum (i.e., they decreased the brain-to-serum ratio of morphine). Pretreatment with nimodipine (40 mg/kg) did not affect the morphine level in the brain and also decreased the brain-to-serum ratio of morphine. When morphine (3.2 – 100 mg/kg, s.c.) was injected alone, the brain-to-serum ratio of morphine was constant, regardless of the morphine dose. These results suggest that increases in morphine concentration in peripheral blood may be, at least in part, involved in the ability of L-type CCBs to potentiate the analgesic effect of morphine. Keywords:: morphine analgesia, diltiazem, nimodipine, verapamil, pharmacokineticshttp://www.sciencedirect.com/science/article/pii/S1347861319324910 |
spellingShingle | Norifumi Shimizu Shiroh Kishioka Takehiko Maeda Yohji Fukazawa Chizuko Yamamoto Masanobu Ozaki Hiroyuki Yamamoto Role of Pharmacokinetic Effects in the Potentiation of Morphine Analgesia by L-Type Calcium Channel Blockers in Mice Journal of Pharmacological Sciences |
title | Role of Pharmacokinetic Effects in the Potentiation of Morphine Analgesia by L-Type Calcium Channel Blockers in Mice |
title_full | Role of Pharmacokinetic Effects in the Potentiation of Morphine Analgesia by L-Type Calcium Channel Blockers in Mice |
title_fullStr | Role of Pharmacokinetic Effects in the Potentiation of Morphine Analgesia by L-Type Calcium Channel Blockers in Mice |
title_full_unstemmed | Role of Pharmacokinetic Effects in the Potentiation of Morphine Analgesia by L-Type Calcium Channel Blockers in Mice |
title_short | Role of Pharmacokinetic Effects in the Potentiation of Morphine Analgesia by L-Type Calcium Channel Blockers in Mice |
title_sort | role of pharmacokinetic effects in the potentiation of morphine analgesia by l type calcium channel blockers in mice |
url | http://www.sciencedirect.com/science/article/pii/S1347861319324910 |
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