title: Role of pharmacokinetic effects in the potentiation of morphine analgesia by L-type calcium channel blockers in mice.
abstract: 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.
authors.affiliation: Department of Pharmacology, Wakayama Medical University, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Shiroh
authors.initials: S
authors.lastname: Kishioka
authors.forename: Takehiko
authors.initials: T
authors.lastname: Maeda
authors.forename: Yohji
authors.initials: Y
authors.lastname: Fukazawa
authors.forename: Chizuko
authors.initials: C
authors.lastname: Yamamoto
authors.forename: Masanobu
authors.initials: M
authors.lastname: Ozaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
mesh_terms: D000698:Analgesia / Q000379:methods*; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D004110:Diltiazem / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009553:Nimodipine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010812:Physical Stimulation; D014018:Tissue Distribution / Q000187:drug effects; D014700:Verapamil / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D009553:Nimodipine; D009020:Morphine; D014700:Verapamil; D004110:Diltiazem