RESUMEN
BACKGROUND AND PURPOSE: µ-Opioid receptors, pro-opiomelanocortin and pro-enkephalin are highly expressed in the nucleus tractus solitarii (NTS) and µ receptor agonists given to the NTS dose-dependently increased BP. However, the molecular mechanisms of this process remain unclear. In vitro, µ receptors heterodimerize with α2A -adrenoceptors. We hypothesized that α2A -adrenoceptor agonists would lose their depressor effects when their receptors heterodimerize in the NTS with µ receptors. EXPERIMENTAL APPROACH: We microinjected µ-opioid agonists and antagonists into the NTS of rats and measured changes in BP. Formation of µ receptor/α2A -adrenoceptor heterodimers was assessed with immunofluorescence and co-immunoprecipitation methods, along with proximity ligation assays. KEY RESULTS: Immunofluorescence staining revealed colocalization of α2A -adrenoceptors and µ receptors in NTS neurons. Co-immunoprecipitation revealed interactions between α2A -adrenoceptors and µ receptors. In situ proximity ligation assays confirmed the presence of µ receptor/α2A -adrenoceptor heterodimers in the NTS. Higher levels of endogenous endomorphin-1 and µ receptor/α2A -adrenoceptor heterodimers were found in the NTS of hypertensive rats, than in normotensive rats. Microinjection of the µ receptor agonist [D-Ala(2) , MePhe(4) , Gly(5) -ol]-enkephalin (DAMGO), but not that of the α2A -adrenoceptor agonist guanfacine, into the NTS of normotensive rats increased µ receptor/α2A -adrenoceptor heterodimer formation and BP elevation. The NO-dependent BP-lowering effect of α2A -adrenoceptor agonists was blunted following increased formation of µ receptor/α2A -adrenoceptor heterodimers in the NTS of hypertensive rats and DAMGO-treated normotensive rats. CONCLUSIONS AND IMPLICATIONS: Increases in endogenous µ receptor agonists in the NTS induced µ receptor/α2A -adrenoceptor heterodimer formation and reduced the NO-dependent depressor effect of α2A -adrenoceptor agonists. This process could contribute to the pathogenesis of hypertension.