COMT Val^108/158Met genotype affects the mu-opioid receptor system in the human brain: Evidence from ligand-binding, G-protein activation and preproenkephalin mRNA expression

Recent data from [¹¹C]carfentanil ligand-PET indicate that in the human brain, the availability of mu-opioid (MOP) receptor binding sites is affected by the Val^108/158Met polymorphism of the catechol-O-methyltransferase (COMT) gene. This prompted us to validate the impact of COMT Val^108/158Met on MOP receptors in human post-mortem brain. [³H]DAMGO receptor autoradiography was performed in frontal cortex, basal ganglia, thalamus and cerebellum (8 Met/Met, 6 Met/Val, 3 Val/Val). With respect to genotype, numbers of MOP binding sites in COMT Met^108/158 homozygous and Val^108/158Met heterozygous cases were higher than in Val^108/158 homozygous. Differences were significant in the caudate nucleus (Val/Met vs. Val/Val), nucleus accumbens (Val/Met vs. Val/Val) and the mediodorsal nucleus of the thalamus (Met/Met vs. Val/Val). In the thalamus, this was corroborated by DAMGO-stimulated [ ³⁵S]GTPγS autoradiography. Moreover, stepwise multiple regression taking into account various covariables allowed to confirm the COMT genotype as the most predictive factor in this structure. As a mechanism how COMT might exert its action on MOP receptors, it has been suggested that at least in striatopallidal circuits COMT Val^108/158Met impacts on enkephalin, which is capable of reciprocally regulating MOP receptor expression. Thus, we assessed preproenkephalin mRNA by in situ hybridization. In the striatum, mRNA levels were significantly higher in COMT Met^108/158 homozygous cases indicating that MOP binding sites and enkephalin are regulated in parallel. Moreover, the transcript was not detectable in the thalamus. Thus, mechanisms other than an enkephalin-dependent receptor turnover must be responsible for COMT-related differences in MOP binding site availability in the human brain.