Opioid receptors and butorphanol dependence

Butorphanol, a mixed opioid agonist/antagonist, is considered to be a relatively safe drug when used within the therapeutic dose range. However, diversional uses of butorphanol involving high dose have been documented. In the present review, the relative involvement of μ, δ, and κ-opioid receptors in butorphanol physical dependence in rats is discussed. Physical dependence was produced by continuous intracerebroventricular (icv) infusion of butorphanol (26 nmol/h) for 72 h in male Sprague-Dawley rats. Multiple icv injections of β-funaltrexamine (β-FNA, a μ-antagonist, 12, 24, or 48 nmol/5 μl), naltrindole (NTI, a δ-antagonist, 0.1, 1, or 10 nmol/5 μl), or nor-binaltorphimine (nor-BNI, a κ-antagonist, 12, 24, or 48 nmol/5 μl) significantly attenuated the development of butorphanol dependence. Furthermore, icv administration of both NTI (24, 48, or 100 nmol/5 μl) and nor-BNI (3, 10, 20, 48 or 100 nmol/5 μl) precipitated withdrawal behaviors, whereas, β-FNA (12, 24, 48, or 100 nmol/5 μl) was unable to elicit withdrawal signs in butorphanol-dependent rats. The results indicate that the development of butorphanol dependence is due to effects of butorphanol on central μ-, δ-, and κ-opioid receptors.