Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys.
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 mu receptors.
Lelas
S
S
Department of Pharmacology and Neuroscience Center of Excellence, Louisiana State University Medical Center, New Orleans 70112, USA.
Wegert
S
S
Otton
S V
SV
Sellers
E M
EM
France
C P
CP
D000701:Analgesics, Opioid / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004193:Discrimination Learning / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006853:Hydrocodone / Q000378:metabolism / Q000494:pharmacology*; D004091:Hydromorphone / Q000378:metabolism / Q000494:pharmacology*; D008253:Macaca mulatta; D010147:Pain Measurement / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000187:drug effects
D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D010880:Piperidines; D017450:Receptors, Opioid, mu; D006853:Hydrocodone; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; C026710:budipine; D004091:Hydromorphone