Nor-binaltorphimine precipitates withdrawal and excitatory amino acid release in the locus ceruleus of butorphanol--but not morphine-dependent rats.

The relative involvement of kappa opioid receptors in the mediation of behavioral and neurochemical responses to withdrawal from chronic drug treatment with the opioid analgesic butorphanol was studied using in vivo microdialysis to detail extracellular fluid concentrations of glutamate and aspartate within the locus ceruleus. Sprague-Dawley rats were rendered opioid dependent after 3 days of intracerebroventricular (i.c.v.) infusion of butorphanol (26 nmol/microl/hr) or morphine (26 nmol/microl/hr) and after i.c.v. infusion of saline vehicle (1 microl/hr). Acute withdrawal was precipitated by i.c.v. injection of the selective kappa opioid receptor antagonist nor-binaltorphimine (48 nmol/5 microl) after the 3-day period of infusion. Behavioral signs of withdrawal were detected after nor-binaltorphimine only in butorphanol-dependent rats. Basal levels of glutamate and aspartate were not different between treatment groups. Nor-binaltorphimine in the butorphanol-dependent rats increased glutamate to 227% and aspartate to 158% in the initial 15-min sample (P < 0.01). Nor-binaltorphimine did not increase glutamate or aspartate concentrations in the morphine-dependent or saline-treated groups. These results indicate a significantly greater participation of kappa opioid receptors in the development of butorphanol, rather than morphine, dependence and identify a differential neurochemical response to butorphanol withdrawal within a defined brain region, the locus ceruleus.