Enhanced binding of nor‐binaltorphimine to κ‐opioid receptors in rats dependent on butorphanol

Abstract

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.

EVALUATION OF CARDIORESPIRATORY, BLOOD GAS, AND LACTATE VALUES DURING EXTENDED IMMOBILIZATION OF WHITE RHINOCEROS (CERATOTHERIUM SIMUM)

“…In these butorphanolwithdrawn rats, κ-opioid receptors levels and κ opioid receptor gene expression were significantly increased as compared to morphine-withdrawn rats suggesting an important role for κ opioid receptors in physical dependence to butorphanol in rats (Fan et al, 2003a;Tanaka et al, 2005). Furthermore, in butorphanol-dependent and butorphanol-withdrawn rats, κ1 and κ2 receptor subtypes developed a supersensitivity to nor-binaltorphimine in an autoradiographic binding study (Fan et al, 2003b). In rats physically dependent on butorphanol, natural withdrawal typically begins to appear 6-8 h after the termination of chronic butorphanol treatment which was also associated with changes in κ opioid receptor binding (Fan et al, 2002a;Fan et al, 2002b).…”

Butorphanol dependence increases hippocampal κ‐opioid receptor gene expression

“…κ‐Opioid receptors have been shown to be down‐regulated in the cortex of butorphanol‐dependent rats (Jaw et al, 1993b). A mechanism by which to explain increases in κ‐opioid receptor binding during withdrawal from dependence on butorphanol invokes increases in binding affinity, rather than receptor number, as has been demonstrated by Fan et al (2003b) and Wongchanapai et al (1998). The increases in κ‐opioid receptor mRNA levels may be caused by cellular counteradaptations to increase the turnover rate of κ‐opioid receptors (Jaw et al, 1993b).…”

“…Specifically, significant changes were noted in only seven of 21 regions, and, of these, the average change was only 35% above control, and no single region exceeded 41% of control values. Previous competitive binding studies (Wongchanapai et al, 1998; Fan et al, 2003b) have noted that dependence on butorphanol appeared to change the biochemical properties of κ‐opioid receptors, resulting in an increase in the antagonist binding affinity of κ‐opioid receptors. Together, the observed changes in κ‐opioid receptor binding characteristics and protein levels are consistent with behavioral observations that naloxone‐precipitated withdrawal from dependence on butorphanol is more dramatic than that observed in rats undergoing withdrawal in the absence of opioid antagonist challenge.…”

“…infusion with butorphanol for 72 hr produces physical dependence and a withdrawal syndrome that begins to appear 6–8 hr after the cessation of chronic butorphanol administration (Jang et al, 1999; Fan et al, 2002a). From behavioral, functional, and biochemical studies, it has been shown that κ‐opioid receptors are especially involved in the development of dependence on butorphanol and the expression of many withdrawal signs in rats (Jaw et al, 1993a, b; Ho et al, 1997; Park et al, 2000; Fan et al, 2002a, b, 2003a, b). In a previous study, the binding signals for both κ 1 ‐ and κ 2 ‐opioid receptors were significantly increased in the frontal cortex, nucleus accumbens, parietal cortex, dorsomedial hypothalamus, ventral tegmental area, and locus coeruleus in both rats dependent on butorphanol and those in withdrawal from such dependence (Fan et al, 2002b).…”

Kappa opioid antagonists: Past successes and future prospects

“…pituitary-axis, 101 modulation of morphine-induced reward, 102 instrumental learning in the spinal cord, 103 decrease of THC-induced place aversion, 104 reversal of kappa opioid agonist -induced increases of [ 35 S]GTP ␥ S binding, 105 enhanced binding in butorphanol-dependent rats, 106 enhancement of noradrenalin release, 107 kappa opioid inhibitory tone, 108 the enhancement of allodynia, 109 antagonism of kappa opioid agonist induced hypothermia, 110 antagonism of the effects of kappa agonist anticonvulsant effects in the maximum electroshock seizure model, 111 increases in the activity of tuberohypophysial dopamine neurons in male Long-Evans rats, 112 effects on the heart, 113-115 attenuation of the discriminative stimulus effects of kappa agonists in squirrel monkeys, 116 and attenuation of kappa agonistinduced food-reinforced responding in pigeons 78 , 117 and rats. 118 GNTI has been studied for its effects on systems including: the enhancement of allodynia, 109 antagonism of the effects of kappa opioid agonists in schedule controlled behavior in rhesus monkeys, 67 and antagonism of the discriminative stimulus effects of salvinorin A (a kappa opioid agonist) in rhesus monkeys.…”