A behavioral and 2-deoxyglucose autoradiographic study of the effects of cumulative morphine dose on naloxone precipitated withdrawal in the rat

Abstract We have studied regional cerebral metabolism by 2-deoxyglucose autoradiography in 67 brain structures of morphine-dependent rats during fixed dose naloxone precipitated withdrawal. Behavioral indices of withdrawal were studied simultaneously in the same animals used in the cerebral metabolism studies. The effects of cumulative morphine dose (470, 1145 and 2345 mg/kg) with fixed dose (0.5 mg/kg) naloxone precipitated withdrawal upon behavioral and cerebral metabolic measures of the severity of withdrawal were compared. All morphine dependent groups studied exhibited the known behavioral sequelae of naloxone precipitated withdrawal. Qualitative withdrawal signs exhibited by all dependent groups included tachypnea, ptosis, penile erection, ejaculation, diarrhea, urination, salivation, lacrimation, rhinorrhea, and irritability. Quantitative signs of withdrawal for 470, 1145 and 2345 mg/kg cumulative morphine dose groupds were as follows (mean ± S.D.): wet shakes/50 min5.8 ± 1.0; 4.4 ± 0.8; 8.4 ± 1.4; acute weight loss (g)14.0 ± 5.6; 3.4 ± 1.0; 6.8 ± 3.2; ‘jumping’ attempts/50 min10.2 ± 5.7; 25.7 ± 5.9; 3.8 ± 1.2. None of the behavioral measures of morphine withdrawal showed cumulative morphine dose dependency. Metabolic mapping (using 2-deoxyglucose) of functional activity during naloxone precipitated withdrawal revealed several brain regions with cumulative morphine dose dependent increases in glucose utilization. The percentage increase in glucose utilization for several rat brain structures for the 3 cumulative morphine morphine dose treatment groups were as follows: diagonal band 51, 63, 87, medial preoptic area 36, 45, 74; lateral preoptic area 24, 47, 77; globus pallidus 19, 53, 62; paraventricular hypothalamus 56, 98, 118; lateral hypothalamus 65, 84, 112; nucleus accumbens 36, 51, 79; medial septum 49, 50, 88; lateral septum 66, 58, 119; central nucleus amygdala 36, 50, 55; medial mammillary nucleus 25, 87, 103; lateral mammilliary nucleus 27, 82, 97; anteroventral thalamus 63, 87, 107; nucleus centromedianus 34, 68, 78; lateral habenula 93, 119, 158; ventral tegmental area 23, 31, 79; interpeduncular nucleus 59, 94, 121; dorsal raphe 21, 48, 86; median raphe 37, 48, 84. Numerous gray structures additionally analyzed failed to show cumulative morphine dose dependent functional activity changes during fixed dose naloxone precipitated withdrawal. Examples of such unaffected structures, representative of several CNS systems, were the frontal motor and cingulate cortices, anterior hypothalamic area, medial and lateral entorhinal cortices, the dentate gyrus and perforant pathway, medial nucleus of the amygdala, medial geniculate nucleus, red nucleus, the pontine reticular formation, and cranial nerve nuclei III, VII, VIII. Thus, in several brain regions, there were clear cumulative morphine dose dependent increases in glucose utilization. Standard behavioral analyses of withdrawal in the same animals failed to demonstrate clear dose dependency. Metabolic mapping of brain regions showing time and dose effects of opiate drug treatments may facilitate the identification of CNS structures participating in opiate withdrawal phenomena. Once such structures are identified, brain regions of interest can be specifically studied with respect to potential molecular mechanisms of opiate dependence and withdrawal.