Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially mediated by augmented excitatory amino acid input.

Single-cell activity was recorded in the locus coeruleus (LC) of morphine-dependent, halothane-anesthetized rats. Systemic administration of the opiate antagonist naloxone (0.1 mg/kg, i.v.) robustly increased the activity of LC neurons. Local microinjection of naloxone or of its hydrophilic derivative, naloxone methiodide, into LC (10 mM, 20-40 nl) did not activate LC neurons in dependent rats. Intracerebroventricular or intracoerulear injection of kynurenate, a broad-spectrum antagonist of excitatory amino acids (EAAs), substantially but incompletely attenuated the activation of LC cells induced by intravenous naloxone-precipitated withdrawal (more than 50% blockade). Intracoerulear microinjections of the non-NMDA-receptor antagonist 6-cyano-7-dinitroquinoxaline-2,3-dione (CNQX) or the selective NMDA-receptor antagonist AP5 significantly reduced the withdrawal-induced excitation. AP5 was the least effective among all antagonists tested. Similar microinjections of kynurenate or CNQX almost completely suppressed the excitation of LC neurons induced by electrical stimulation of a rear footpad. LC responses to footpad stimulation (mediated by endogenous EAAs) or iontophoretically applied glutamate were not modified by the chronic morphine treatment. These results indicate that a substantial part of LC hyperactivity during opiate withdrawal is mediated by an augmented EAA input to LC.