Anti-OPRM1 (aa 1-110) polyclonal antibody

Among endogenous signaling networks involved in both rewarding and homeostatic mechanisms of obesity, a relevant role is played by the endocannabinoid (ECS) and the opioid (EOS) systems. We here studied the transcriptional regulation of ECS and EOS genes in the hypothalamus of Diet-induced obesity rats, a preclinical model of obesity, as well as in humans with obesity and healthy controls. A significant and selective increase in type 1 cannabinoid receptor gene (Cnr1) expression was observed at the beginning of obesity development (5 weeks on high fat diet) as well as after 21 weeks of high diet exposure. After 5 weeks on high fat diet, selective up-regulation of mu opioid receptor gene (Oprm1) expression was also observed. Consistently, epigenetic studies showed a selective and significant decrease in DNA methylation at specific CpG sites at both gene promoters in overweight rats, but only after 5 weeks on high fat diet. Moreover, significantly lower levels of DNA methylation were observed at selected CpG sites of both receptor gene promoters, analyzed in peripheral blood mononuclear cells from younger (<30 years old) humans with obesity, as well as in those with shorter time length from disease onset. Taken together, we here provide evidence of selective, synergistic and time-dependent transcriptional regulation of CNR1 and OPRM1 genes in overweight rats, as well as in human subjects. These alterations in genes regulation could contribute to the development of the obese phenotype, and we thus suggest CNR1 and OPRM1 epigenetic modulation as possible biomarkers of obesity development. Due to the reversible nature of the epigenetic hallmark, our data might also open new avenue to early environmental strategies of intervention.

Blockade of the p-opioid receptor (MOR) by naltrexone reduces relapse risk in a subpopulation of alcohol-dependent patients. Previous positron-emission-tomography (PET) studies using the MOR ligand [C-11]carfentanil have found increased MOR availability in abstinent alcoholics, which may reflect either increased MOR expression or lower endogenous ligand concentration. To differentiate between both effects, we investigated two cohorts of alcoholic subjects using either post-mortem or clinical PET analysis. Post-mortem brain tissue of alcohol-dependent subjects and controls (N = 43/group) was quantitatively analyzed for MOR ([H-3]DAMGO)-binding sites and OPRMI mRNA in striatal regions. [C-11]carfentanil PET was performed in detoxified, medication free alcohol-dependent patients (N = 38), followed by a randomized controlled study of naltrexone versus placebo and follow-up for I year (clinical trial number. NCT00317031). Because the functional OPRMI variant rs179997I:A>G affects the ligand binding, allele carrier status was considered in the analyses. MOR-binding sites were reduced by 23-51% in post-mortem striatal tissue of alcoholics. In the PET study, a significant interaction of OPRMI genotype, binding potential (BPND) for [C-11]carfentanil in the ventral striatum, and relapse risk was found. Particularly in G-allele carriers, lower striatal BPND was associated with a higher relapse risk. Interestingly, this effect was more pronounced in the naltrexone treatment group. Reduced MOR is interpreted as a neuroadaptation to an alcohol-induced release of endogenous ligands in patients with severe alcoholism. Low MOR availability may explain the ineffectiveness of naltrexone treatment in this subpopulation. Finally, low MOR-binding sites are proposed as a molecular marker for a negative disease course.