Changes in the brain κ-opioid receptor levels of rats in withdrawal from physical dependence upon butorphanol

Abstract

Changes in κ-opioid receptor levels have been implicated in the development of physical dependence upon and withdrawal from the mixed agonist–antagonist opioid, butorphanol. Immunoblotting analysis was performed to determine the levels of κ- and μ-opioid receptors in brain regions of rats in withdrawal from dependence upon butorphanol or morphine. Physical dependence was induced by a 72 h i.c.v. infusion with either butorphanol or morphine (26 nmol/μl/h). Withdrawal was subsequently precipitated by i.c.v. challenge with naloxone (48 nmol/5 μl/rat), administered 2 h following cessation of butorphanol or morphine infusion. Immunoblotting analysis of κ-opioid receptors from butorphanol-withdrawal rats showed significant increases in 11 of 21 brain regions examined, including the nucleus accumbens, amygdala, dorsomedial hypothalamus, hypothalamus, paraventricular thalamus, thalamus, presubiculum, and locus coeruleus, when compared with saline treated, non-dependent controls. In addition, significant reductions were found in the hippocampus and in cortical brain regions, including the parietal cortex and temporal cortex from butorphanol-withdrawal rats. These findings contrasted with those from morphine-withdrawal rats, in which the only changes noted were increases in the thalamus and paraventricular thalamus. Changes in the levels of the μ-opioid receptor protein were observed in 11 of 21 brain regions examined in morphine-withdrawal rats, but only in three of 21 in butorphanol-withdrawal rats. These results implicate a substantive and largely unique role for κ-opioid receptors in mediation of the development of physical dependence upon, and the expression of withdrawal from, butorphanol, as opposed to the prototypical opioid analgesic, morphine.