Effects of nor-binaltorphimine on butorphanol dependence

Abstract

Butorphanol has been shown to act on μ-, δ- and κ-opioid receptors. However, the relative involvement of different opioid receptor subtypes in butorphanol dependence is not known. In the present study, nor-binaltorphimine, a long-acting non-peptide κ-opioid receptor antagonist, was employed to mask central κ-opioid receptors before and during the induction of butorphanol dependence in rats, so that the involvement of κ-opioid receptors could be elucidated. The results revealed that treatment with nor-binaltorphimine markedly blocked naloxone-precipitated withdrawal signs of escape behavior, teeth-chattering, wet shakes, ptosis, body weight loss, and hypothermia at all doses tested, and attenuated the withdrawal symptoms of forepaw tremors (24 nmol:P < 0.001) diarrhea (12 nmol: P < 0.05; 24 nmol: P < 0.01). In contrast, nor-binaltorphimine had no effect on yawning, ejaculation, nor urination in butorphanol-infused rats undergoing withdrawal. Three days of butorphanol infusion significantly increased K D values (in the cortex and striatum), decreased B max (in the cortex only) of [[su3H]U-69,593 bidning, and shifted K i of nor-binaltorphimine against [ 3H]U-69,593 (4.5 nM) binding in the cortex by more than 10-fold. Treatment with nor-binaltophimine blocked the effects of butorphanol on κ-opioid receptors. It is therefore concluded that κ-opioid receptors are involved in mediating escape behavior, teeth-chattering, wet shakes, forepaw tremors, ptosis, diarrhea, weight loss, and hypothermia in butorphanol-dependent rats undergoing withdrawal. Furthermore, κ-opioid receptors become desensitized to agonists (in the cortex and striatum), down-regulated (in the cortex), and supersensitive to antagonists in butorphanol-dependent rats.