Precipitated kappa-opioid receptor agonist withdrawal increases glutamate in rat locus coeruleus

Extracellular fluid levels of excitatory amino acids (glutamate, Glu; and aspartate, Asp) in the locus coeruleus and the behavioral signs during naloxone-precipitated withdrawal from kappa-opioid receptor agonists, butorphanol and (5 alpha,7 alpha,8 beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-benzeneacetamide (U-69,593), were investigated by in vivo microdialysis. Increases in levels of Glu, but not of Asp, were noted after naloxone (12 or 48 nmol/5 mu l, locus coeruleus)-precipitated withdrawal in the rats which had been intracerebroventricularly infused with butorphanol (26 nmol/1 mu l/h) or U-69,593 (26 nmol/10 mu l/h) for 3 days. The Glu levels in the locus coeruleus increased following administration of naloxone before and during the first 15-min sample after the precipitation of withdrawal in the butorphanol- or U-69,593-dependent rats. Furthermore, behavioral evidence of withdrawal (teeth-chattering, wet-dog shakes, etc.) was detected following the naloxone challenge in the butorphanol- and U-69,593-infused rats, but not in saline-infused controls. These results provide direct evidence to support the role of excitatory amino acids within the locus coeruleus in butorphanol or U-69,593 withdrawal.