title: Increased locus coeruleus glutamate levels are associated with naloxone-precipitated withdrawal from butorphanol in the rat.
abstract: Extracellular fluid levels of glutamate were measured in the locus coeruleus during butorphanol (a mixed agonist at mu-, delta-, and kappa-opioid receptors) withdrawal by using microdialysis in conscious butorphanol-dependent Sprague-Dawley rats. Guide cannulae were implanted chronically and rats were given intracerebroventricular (i.c.v.) infusions of butorphanol (26 nmol/1 microliter/hr) or saline (1 microliter/hr) for 3 days. Microdialysis probes (2 mm tip) were inserted into the locus coeruleus 24 hr before precipitation of withdrawal by i.c.v. injection of naloxone (48 nmol/5 microliters). A separate series of rats was rendered dependent by peripheral injection of butorphanol (20 mg/kg, s.c., b.i.d.) for 5 days and naloxone (5 mg/kg, i.p.) was given to precipitate withdrawal. Single injections of butorphanol (26 nmol/5 microliters, i.c.v.) had no effect on the extracellular fluid levels of glutamate, compared to rats injected with vehicle. Behavioral evidence of withdrawal was detected following naloxone challenge in butorphanol-dependent rats (both i.c.v. and s.c. models), but not in non-dependent, vehicle-treated rats. Significant increases (P < 0.05) in levels of glutamate were noted after naloxone-precipitated withdrawal only in the butorphanol group. The glutamate levels in the locus coeruleus increased from 8.37 +/- 2.01 before, to 21.93 +/- 4.58 microM in the first 15 min sample following i.c.v. injections of 48 nmol/5 microliters naloxone and from 10.84 +/- 1.74 before, to 26.01 +/- 6.19 microM in the 15-30 min sample following i.p. injections of 5 mg/kg naloxone in the butorphanol-dependent rats, respectively. These results provide direct evidence to support the role of excitatory amino acids within the locus coeruleus in butorphanol withdrawal.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216, USA.
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Feng
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.forename: R W
authors.initials: RW
authors.lastname: Rockhold
authors.forename: I K
authors.initials: IK
authors.lastname: Ho
mesh_terms: D000818:Animals; D002077:Butorphanol / Q000008:administration & dosage / Q000494:pharmacology*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome
chemical_list: D009270:Naloxone; D018698:Glutamic Acid; D002077:Butorphanol