Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys

Snjezana Lelas; Sandra Wegert; S. Victoria Otton; Edward M. Sellers; Charles P. France

doi:10.1016/S0376-8716(98)00169-0

Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys

Snjezana Lelas, Sandra Wegert, S. Victoria Otton, Edward M. Sellers, Charles P. France

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

The present study was conducted to investigate the role of cytochrome P450 in the discriminative-stimulus and antinociceptive effects of hydrocodone (HC) and hydromorphone (HM) in rhesus monkeys. In morphine-deprived monkeys, morphine dose-dependently reversed naltrexone-lever responding, an effect also produced by HC and HM. HC and HM also produced antinociception in a warm-water tail withdrawal procedure. Budipine and naltrexone shifted the dose-effect curves for the discriminative-stimulus effects of HC and HM to the right. In contrast, naltrexone, but not budipine (10.0 mg/kg) or quinidine (10.0 mg/kg), dose-dependently antagonized the antinociceptive effects of HC. Budipine and quinidine decreased the concentration of HM in plasma without significantly affecting the levels of HC, suggesting that these CYP2D6 inhibitors decreased the conversion of HC-HM. Thus, some behavioral effects of HC are not modified by a marked inhibition of CYP2D6, suggesting that these effects of HC are not due to its conversion to HM but, rather, that both HC and HM act directly on μ receptors. Copyright (C) 1999 Elsevier Science Ireland Ltd.

Original language	English (US)
Pages (from-to)	239-249
Number of pages	11
Journal	Drug and Alcohol Dependence
Volume	54
Issue number	3
DOIs	https://doi.org/10.1016/S0376-8716(98)00169-0
State	Published - May 3 1999
Externally published	Yes

Keywords

Antinociception
Drug discrimination
Hydrocodone
P450 enzymes
Rhesus monkey

ASJC Scopus subject areas

Psychiatry and Mental health
Pharmacology (medical)
Toxicology
Pharmacology

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title = "Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys",

abstract = "The present study was conducted to investigate the role of cytochrome P450 in the discriminative-stimulus and antinociceptive effects of hydrocodone (HC) and hydromorphone (HM) in rhesus monkeys. In morphine-deprived monkeys, morphine dose-dependently reversed naltrexone-lever responding, an effect also produced by HC and HM. HC and HM also produced antinociception in a warm-water tail withdrawal procedure. Budipine and naltrexone shifted the dose-effect curves for the discriminative-stimulus effects of HC and HM to the right. In contrast, naltrexone, but not budipine (10.0 mg/kg) or quinidine (10.0 mg/kg), dose-dependently antagonized the antinociceptive effects of HC. Budipine and quinidine decreased the concentration of HM in plasma without significantly affecting the levels of HC, suggesting that these CYP2D6 inhibitors decreased the conversion of HC-HM. Thus, some behavioral effects of HC are not modified by a marked inhibition of CYP2D6, suggesting that these effects of HC are not due to its conversion to HM but, rather, that both HC and HM act directly on μ receptors. Copyright (C) 1999 Elsevier Science Ireland Ltd.",

keywords = "Antinociception, Drug discrimination, Hydrocodone, P450 enzymes, Rhesus monkey",

author = "Snjezana Lelas and Sandra Wegert and Otton, {S. Victoria} and Sellers, {Edward M.} and France, {Charles P.}",

note = "Funding Information: Supported by NIDA Grants DA05018 and DA06889 and a Research Career Development Award to CPF (DA00211). Portions of these results were presented at the Annual Meeting of the College on Problems of Drug Dependence, Scottsdale, AZ, 1995 ( France et al., 1996 ). The authors wish to thank R. Gump and R. Fortier for their excellent technical assistance. ",

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T1 - Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys

AU - Lelas, Snjezana

AU - Wegert, Sandra

AU - Otton, S. Victoria

AU - Sellers, Edward M.

AU - France, Charles P.

N1 - Funding Information: Supported by NIDA Grants DA05018 and DA06889 and a Research Career Development Award to CPF (DA00211). Portions of these results were presented at the Annual Meeting of the College on Problems of Drug Dependence, Scottsdale, AZ, 1995 ( France et al., 1996 ). The authors wish to thank R. Gump and R. Fortier for their excellent technical assistance.

PY - 1999/5/3

Y1 - 1999/5/3

N2 - The present study was conducted to investigate the role of cytochrome P450 in the discriminative-stimulus and antinociceptive effects of hydrocodone (HC) and hydromorphone (HM) in rhesus monkeys. In morphine-deprived monkeys, morphine dose-dependently reversed naltrexone-lever responding, an effect also produced by HC and HM. HC and HM also produced antinociception in a warm-water tail withdrawal procedure. Budipine and naltrexone shifted the dose-effect curves for the discriminative-stimulus effects of HC and HM to the right. In contrast, naltrexone, but not budipine (10.0 mg/kg) or quinidine (10.0 mg/kg), dose-dependently antagonized the antinociceptive effects of HC. Budipine and quinidine decreased the concentration of HM in plasma without significantly affecting the levels of HC, suggesting that these CYP2D6 inhibitors decreased the conversion of HC-HM. Thus, some behavioral effects of HC are not modified by a marked inhibition of CYP2D6, suggesting that these effects of HC are not due to its conversion to HM but, rather, that both HC and HM act directly on μ receptors. Copyright (C) 1999 Elsevier Science Ireland Ltd.

AB - The present study was conducted to investigate the role of cytochrome P450 in the discriminative-stimulus and antinociceptive effects of hydrocodone (HC) and hydromorphone (HM) in rhesus monkeys. In morphine-deprived monkeys, morphine dose-dependently reversed naltrexone-lever responding, an effect also produced by HC and HM. HC and HM also produced antinociception in a warm-water tail withdrawal procedure. Budipine and naltrexone shifted the dose-effect curves for the discriminative-stimulus effects of HC and HM to the right. In contrast, naltrexone, but not budipine (10.0 mg/kg) or quinidine (10.0 mg/kg), dose-dependently antagonized the antinociceptive effects of HC. Budipine and quinidine decreased the concentration of HM in plasma without significantly affecting the levels of HC, suggesting that these CYP2D6 inhibitors decreased the conversion of HC-HM. Thus, some behavioral effects of HC are not modified by a marked inhibition of CYP2D6, suggesting that these effects of HC are not due to its conversion to HM but, rather, that both HC and HM act directly on μ receptors. Copyright (C) 1999 Elsevier Science Ireland Ltd.

KW - Antinociception

KW - Drug discrimination

KW - Hydrocodone

KW - P450 enzymes

KW - Rhesus monkey

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ER -

Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys

Abstract

Keywords

ASJC Scopus subject areas

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