Enhanced binding of nor-binaltorphimine to kappa-opioid receptors in rats dependent on butorphanol.

Autoradiographic characterization of binding for brain kappa(1) ([(3)H]CI-977) and kappa(2) ([(3)H]bremazocine) in the presence of DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin), DPDPE ([D-Pen(2), D-Pen(5)]-enkephalin), and U-69,593 opioid receptors, in the presence of different concentrations of a selective unlabeled kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), was performed in rats in which dependence on or withdrawal from butorphanol had been established. Dependence was induced by a 72 hr intracerebroventricular (i.c.v.) infusion with butorphanol (26 nmol/microl/hr; butorphanol dependent). Butorphanol withdrawal was produced by terminating the infusion of butorphanol in dependent animals. Responses were studied 7 hr following termination (butorphanol withdrawal). IC(50) values from competition studies were estimated by fitting inhibition curves for both kappa(1)- and kappa(2)-opioid receptor assays. In both dependent and withdrawal groups, the IC(50) values obtained against [(3)H]CI-977 or [(3)H]bremazocine with nor-BNI were decreased (ratios of approximately 0.03-0.21 and approximately 0.05-0.42 vs. control, respectively) in brain regions, including frontal cortex, nucleus accumbens, claustrum, dorsal endopiriform nucleus, caudate putamen, parietal cortex, posterior basolateral amygdaloid nucleus, dorsomedial hypothalamus, hippocampus, posterior paraventricular thalamic nucleus, periaqueductal gray, substantia nigra, superficial gray layer of the superior colliculus, ventral tegmental area, and locus coeruleus, compared with control. These results indicate that, in butorphanol-dependent and butorphanol-withdrawal rats, the brain kappa(1)- and kappa(2)-opioid receptors developed a supersensitivity to antagonist binding.

Butorphanol dependence and withdrawal decrease hippocampal kappa 2-opioid receptor binding.

The present study examines the degree and distribution of alterations in the expression of kappa-opioid receptor subtypes using a model of chronic intracerebroventricular (i.c.v.) infusion of butorphanol. Autoradiographic characterization of binding for brain kappa(1) ([3H]CI-977)-, kappa(2) ([3H]bremazocine in the presence of DAMGO, DPDPE, and U-69,593)- and total kappa ([3H]bremazocine in the presence of only DAMGO and DPDPE)-opioid receptors was performed. Dependence was induced by a 72 h i.c.v. infusion with butorphanol (26 nmol/microl per hour) (butorphanol-dependent). Butorphanol withdrawal was produced by terminating the infusion of butorphanol in dependent animals. Responses were studied 7 h following termination (butorphanol-withdrawal). During both dependence and withdrawal phases, the binding signals for both kappa(1)- and kappa(2)-opioid receptors were significantly increased in certain regions, with especially marked increases in the frontal cortex, nucleus accumbens, parietal cortex, dorsomedial hypothalamus, ventral tegmental area and locus coeruleus. In contrast, a highly specific decrease in kappa(2)-, but increase in kappa(1)-, opioid receptor binding was noted in the hippocampus of rats in both butorphanol-dependent and-withdrawal groups. Therefore, alterations in kappa(1)- and kappa(2)-opioid receptors in the hippocampus may be differently involved in both adaptation to and recovery from chronic exposure to a mixed agonist/antagonist opioid analgesic. These results further illustrate the regional distribution of changes in binding characteristics of rat brain kappa(1)- and kappa(2)-opioid receptor subtypes in an established model of butorphanol dependence and withdrawal.