title: Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys.
abstract: There is evidence that blockade of Ca(2+) channels can modify the analgesia and respiratory depression produced by opioid drugs. The interaction between Ca(2+) channel blockade and drug-induced analgesia and respiratory depression was examined by administration of the L-type Ca(2+) channel blocker diltiazem together with various analgesic drugs. The antinociceptive effects of the drugs were evaluated using a warm-water (50 degrees C) tail-withdrawal assay in rhesus monkeys, and the respiratory depressant effects were evaluated using a pressure-displacement plethysmograph. Pretreatment with diltiazem (10-40 mg/kg, i.m.) 30 min before administration of morphine (0.3 to 10 mg/kg) or heroin (0.03 to 1.0 mg/kg) produced a dose-dependent potentiation of the opioid-induced analgesia. The analgesic potency of morphine and heroin was increased by approximately 0.5 log unit in the presence of 40 mg/kg diltiazem. However, diltiazem failed to alter the analgesic potencies of the mu-opioid receptor agonists, fentanyl, etonitazene, nalbuphine, the kappa-opioid receptor agonist, U-50,488 [(trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide ], or the non-opioid, clonidine. Respiratory frequency, minute volume, and tidal volume were suppressed by morphine, heroin, and fentanyl, but these effects were not modified by pretreatment with diltiazem (40 mg/kg). These results suggest that diltiazem selectively potentiates morphine- and heroin-induced analgesia without modifying the effects of these opioids on respiration.
authors.affiliation: Department of Pharmacology, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kishioka
authors.forename: M C
authors.initials: MC
authors.lastname: Ko
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005283:Fentanyl / Q000494:pharmacology; D003932:Heroin / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009266:Nalbuphine / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods; D011957:Receptors, Opioid / Q000819:agonists; D012119:Respiration / Q000187:drug effects*; D013997:Time Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D011957:Receptors, Opioid; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D003932:Heroin; D009020:Morphine; C084835:etonitazene; D004110:Diltiazem; D009266:Nalbuphine; D003000:Clonidine; D005283:Fentanyl