Mu- and delta-opioid receptor antagonists precipitate similar withdrawal phenomena in butorphanol and morphine dependence

Abstract

The relative involvement of mu- and delta-opioid receptors in the mediation of butorphanol-, as compared to morphine-, dependence was examined with the use of highly selective antagonists at mu- and delta-opioid receptors. Extracellular fluid levels of glutamate (Glu) and aspartate (Asp) were measured within the pontine locus coeruleus following precipitation of withdrawal from dependence on either butorphanol or morphine in conscious Sprague-Dawley rats. Dependence was induced by intracerebroventricular (i.c.v.) infusion of butorphanol (26 nmol/mu l/h), morphine (26 nmol/mu l/h) or saline vehicle (1 mu l/h) for 3 days by means of an osmotic minipump. Microdialysis probes (2 mm tip) were inserted into the locus coeruleus 24 h before precipitation of withdrawal by i.c.v. injection of either the mu-opioid receptor antagonist, D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; 48 nmol/5 mu l or 48 nmol/5 mu l), or the delta-opioid receptor antagonist, naltrindole (17-cyclopropy;methyl-6,7-dehydro-4,5-epoxy-3, 14-dihydroxy-6,7,2'3'-indolmorphinan hydrochloride; 48 nmol/5 mu l or 100 nmol/5 mu l). Baseline levels of Glu ranged from 9.59 + or - 1.27 to 12.84 + or - 3.01 mu M in the various treatment groups. Levels of Asp were similar. Precipitation of withdrawal by CTOP elicited significant increases of Glu and Asp in both morphine- and butorphanol-dependent rats. Maximal increases in Glu of 425% and 258% above baseline levels were elicited in the first 15 min microdialysis sample following i.c.v. injection of CTOP in morphine- and butorphanol-dependent rats, respectively. Behavioral signs of withdrawal were greater in morphine than butorphanol-dependent groups. The i.c.v. treatment with naltrindole elicited increases in Glu and Asp that were similar, although less marked, than those precipitated by CTOP treatment. Administration of naltrindole produced equivalent signs of withdrawal in both morphine- and butorphanol-dependent rats. Withdrawal from dependence on both morphine and butorphanol is characterized by elevations in coerulear levels of excitatory amino acids. Responses elicited following the use of selective mu- and delta-opioid receptor antagonists to precipitate withdrawal suggest that the role played by these receptors in mediation of the signs and symptoms of withdrawal do not differ greatly between butorphanol- and morphine-dependent rats.