Repeated administration with δ9- tetrahydrocannabinol regulates µ-opioid receptor density in the rat brain

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Abstract
Several studies have demonstrated reciprocal, as well as synergistic interactions between cannabinoid and opioid systems. The aim of this study was to explore the time-related effects of repeated administration of δ9-tetrahydrocannabinol on µ-opioid receptor autoradiography in various brain regions of the rat. To this aim, the effects of δ9-tetrahydrocannabinol (δ9-THC, 5 mg/kg/day; i.p.) were examined after 1, 3, 7 and 14 days of repeated administration on regions containing µ-opioid receptors: (i) forebrain [caudate-putamen, nucleus accumbens (core and shell) and piriform cortex]; (ii) amygdala (medial pars and cortical posteromedial pars), hypothalamus (ventromedial and dorsomedial nuclei, zona incerta), hippocampal regions (CA1, CA2, CA3, dentate girus), hindbrain (substantia nigra and ventral tegmental area); and (iii) thalamus, including 12 thalamic nuclei. In most of these regions, repeated cannabinoid administration increases µ-opioid receptor density; however, the onset, degree of magnitude reached and time-related effects produced by administration with δ9-tetrahydrocannabinol are dependent upon the brain region examined. It appears that the major increase in µ-opioid receptor density occurs 1 and 3 days after δ9-THC administration. In some regions, this increase is maintained and, for most of the brain areas examined, this effect is no longer significant by 14 days of administration, suggesting tolerance to cannabinoid treatment. Taken together, the results of this study suggest that cannabinoids produce a time-related differential responsiveness in µ-opioid receptor density in several brain areas that may be relevant to an understanding of the alterations associated with cannabinoid exposure.