Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade.
BACKGROUND
Butorphanol exerts activity at mu, kappa, and delta opiate receptors in rats and monkeys but produces predominant mu-like effects in humans.


OBJECTIVE
The aim of this study was to determine if the kappa receptor-mediated actions of butorphanol could be unmasked or enhanced by giving it in combination with naltrexone, an opioid antagonist with higher affinity for mu vs kappa receptors.


METHODS
Ten healthy adult inpatient volunteers (eight men, two women), with opioid abuse histories, completed this double-blind, randomized, placebo-controlled study. Naltrexone (0, 1, 3, 10, or 30 mg, p.o.) was administered 1 h before butorphanol (0, 6, or 12 mg/70 kg, i.m.) during 15 test sessions. An array of physiological (e.g., vital signs, urine output, and subject- and observer-rated) measures was collected before and for 4 h after drug administration.


RESULTS
Naltrexone alone produced no direct effects. Butorphanol alone produced typical mu-, but not kappa-, related physiological effects (e.g., miosis, respiratory depression) and produced mood and drug effects considered typical of both mu (e.g., "liking," "good drug effects") and kappa agonists (e.g., increases in perceptual disturbances). Naltrexone pretreatment led to significant butorphanol-induced diuresis (i.e., increased urine output and decreased urine osmolality). Naltrexone generally produced a dose-dependent blockade of subjective responses.


CONCLUSIONS
These data suggest that naltrexone antagonism unveiled the kappaergic activity of butorphanol as measured by diuresis, while subjective responses generally attributed to mu vs kappa receptors were not dissociable. Moreover, these data demonstrate that butorphanol exerts physiologically relevant kappa agonist activity at these supraanalgesic doses in humans.
Walsh
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SL
Department of Behavioral Science & Center on Drug and Alcohol Research, College of Medicine, University of Kentucky, Lexington, KY, USA. sharon.walsh@uky.edu
Chausmer
A E
AE
Strain
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EC
Bigelow
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GE
D000328:Adult; D000339:Affect / Q000187:drug effects; D001143:Arousal / Q000187:drug effects; D002077:Butorphanol / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006556:Heroin Dependence / Q000503:physiopathology; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D010465:Perception / Q000187:drug effects; D011292:Premedication; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects*
D009292:Narcotic Antagonists; D009294:Narcotics; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D002077:Butorphanol