Increased locus coeruleus glutamate levels are associated with naloxone-precipitate withdrawal from butorphanol in the rat

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Abstract
Extracellular fluid levels of glutamate were measured in the locus coeruleus during butorphanol (a mixed agonist at μ-, δ-, and κ-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/l μl/hr) or saline (1 μl/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 μl). 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 μl, 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 nondependent, 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 μM in the first 15 min sample following i.c.v. injections of 48 nmol/5 μl naloxone and from 10.84±1.74 before, to 26.01±6.19 μM 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.