Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade

S. L. Walsh, A. E. Chausmer, E. C. Strain, G. E. Bigelow

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Rationale: Butorphanol exerts activity at mu, kappa, and delta opiate receptors in rats and monkeys but produces predominant mu-like effects in humans. Objectives: 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. Materials and 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)143-155
Number of pages13
Issue number1
StatePublished - Jan 2008

Bibliographical note

Funding Information:
Acknowledgments The authors thank the staff at the Behavioral Pharmacology Research Unit at Johns Hopkins University and the staff at the Human Behavioral Science Center at the University of Kentucky for their assistance with the conduct of this study, data analysis and manuscript preparation. This project was supported by funding from the National Institute on Drug Abuse (R01DA100753 SLW; R01DA016718 SLW; K02 DA00332 ECS). The authors did not have any financial conflicts of interest related to this study. This study complies with the current laws of the USA.


  • Agonist
  • Antagonist
  • Drug abuse
  • Human
  • Opiate
  • Opioid
  • Opioid receptor

ASJC Scopus subject areas

  • Pharmacology


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