The objective of this project is to investigate the mechanism of butorphanol tartrate (STADOL)-induced pharmacological responses and to determine how tolerance to and physical dependence upon butorphanol develop. Butorphanol is a potent non-scheduled opioid analgesic, yet case reports of butorphanol abuse and studies reported in the literature and our laboratory have demonstrated that butorphanol also possesses a substantial physical dependence liability under certain circumstances. The proposed project is designed to systematically assess how butorphanol produces pharmacological responses and how different opioid receptors, e.g. mu-, delta-, and kappa-receptors, are involved in butorphanol tolerance and dependence. Morphine sulfate will be compared as a reference compound when appropriate.
Six specific aims are proposed. They are:
Aim I. Characterization of the development of tolerance to and physical dependence upon butorphanol using continuous intracerebroventricular (i.c.v.) infusion of butorphanol via osmotic mini-pumps.
Aim II. Identification of the opioid receptors involved in development of tolerance to butorphanol using pharmacologic agents.
Aim III. Identification of the opioid receptors involved in development of physical dependence upon butorphanol using pharmacologic agents.
Aim I V. Studies of changes in binding characteristics of different opioid receptors during the development of tolerance to and physical dependence upon butorphanol.
Aim V. Correlations of the role(s) of different opioid receptors in the development of tolerance to and physical dependence upon butorphanol by testing correlations between the results obtained pharmacologically and biochemically.
Aim V I. Comparative studies of the phenomena of tolerance to and physical dependence upon butorphanol and of how butorphanol tolerance-dependence affects different opioid receptors during systemic administration (s.c.) of butorphanol. The proposed project should reveal the mechanism of action of butorphanol, assess the addictive potential of butorphanol, suggest certain precautions to be considered during usage of butorphanol, provide more rationale for the treatment of butorphanol abuse, and provide awareness of the abuse potential of butorphanol.