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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Main Authors: Norifumi Shimizu, Shiroh Kishioka, Takehiko Maeda, Yohji Fukazawa, Chizuko Yamamoto, Masanobu Ozaki, Hiroyuki Yamamoto
Format: Article
Language:English
Published: Elsevier 2004-01-01
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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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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