Dose effects of naloxone on fixed morphine dependence: simultaneous behavioral and 2-deoxyglucose study in the rat

Abstract

We have simultaneously studied regional cerebral glucose utilization (RCGU) and behavior during naloxone precipitated morphine withdrawal. For RCGU studies, 25 brain regions were analyzed that previously had been shown to participate in morphine withdrawal. Four established behavioral signs of morphine withdrawal were recorded: wet shakes, jumping, weight loss, and autonomic signs. Using a 10 4 range of naloxone dose (0.0005–5.0 mg/kg), dose dependent effects were found for 3 behaviors: jumping, weight loss and autonomic signs. The incidence of wet shakes did not correlate with naloxone dose. Increases in RCGU in several specific brain sites were also naloxone dose dependent. Naloxone dose dependent increases in RCGU during precipitated morphine withdrawal may be divided into 3 classes of responses: Class I structures (paraventricular, ventromedial, and lateral hypothalamus) exhibited their largest RCGU increases between 0.005 and 0.05 mg/kg of naloxone; Class II structures (preoptic areas, basal ganglia, anterior and intralaminar thalamic nuclei, mammillary nuclei, and certain midbrain regions) showed gradual RCGU increases across the 10 4 range of naloxone dose; and, Class III structures (diagonal band, medial and lateral septum, and the central amygdaloid nucleus) displayed large RCGU increases across 0.5–5.0 mg/kg of naloxone. Regression analysis of RCGU vs behavior showed correlations between Class I responses and autonomic signs ( p<0.010); weight loss was correlated with all 3 classes of naloxone dose dependent RCGU responses during withdrawal ( p<0.05). The strong positive correlation among these RCGU increases and certain morphine withdrawal behaviors supported the use of RCGU measurements in specific brain sites as a sensitive and objective biochemical indicator of the presence and severity of morphine dependence. In addition, this study demonstrates the changes in RCGU in different brain regions are heterogeneous with respect to naloxone dose and appear reproducibly along a continuum from mild to severe withdrawal.