Limbic brain structures are important sites of κ-opioid receptor-mediated actions in the rat: a [14C]-2-deoxyglucose study

The [1-14C]-2-deoxyglucose technique was employed to evaluate the regional pattern of alterations in glucose utilization in the rat brain, pituitary and spinal cord induced by the selective kappa-opioid agonist U-50,488H (trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl) cyclohexyl]-benzeneacetamide). Within the dose range used (0.5-5 mg/kg), U-50,488H produced a dose-dependent attenuation of nociceptive thresholds and a place aversion in the place conditioning test, allowing for a correlation of the regional pattern of changes in glucose utilization with certain behavioral responses. The regional changes in glucose utilization induced by U-50,488H in the brain were most pronounced in components of the limbic forebrain circuit such as the anterior thalamic nuclei, mammillary body, frontal cortex, lateral septal nucleus, nucleus accumbens and lateral habenular nucleus as well as in the brainstem tegmental nuclei and the dorsal and median raphe nucleus (components of the limbic midbrain area). Glucose utilization was decreased in the frontal cortex and increased in the other regions. An increase in glucose utilization also was observed in the central gray pons. Increases in glucose utilization in the pituitary were restricted to the intermediate lobe. In the lumbar part of the spinal cord, glucose metabolism was enhanced in the region around the central canal and in the ventral horn. The changes in glucose metabolism observed in these structures suggest that the aversive (dysphoric) effects of U-50,488H may be due to the altered activity of the limbic structures of the forebrain and midbrain which have been implicated in emotional and affective processes. The increased activity in the intermediate lobe of the pituitary, furthermore, might reflect a stress component in the effects of this drug. Since the dorsal raphe nucleus and the region of the central gray pons have been implicated in both analgesia and pain processes a supraspinal site of antinociceptive action of U-50,488H, in addition to a spinal site of action, must be considered.