μ-Opioid Receptor-Mediated AT1R-TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System

Opioids, a kind of peptide hormone involved in the development of hypertension, cause systemic and cerebral inflammation, and affects regions of the brain that are important for blood pressure (BP) control. A cause-and-effect relationship exists between hypertension and inflammation; however, the role of blood pressure in cerebral inflammation is not clear. Evidence showed that AT1R and mu OR heterodimers' formation in the NTS might lead to the progression of hypertension. In this study, we investigated the formation of the mu OR/AT1R heterodimer, determined its correlation with mu ORs level in the NTS, and explored the role of TLR4-dependent inflammation in the development of hypertension. Results showed that Ang II increased superoxide and Iba-1 (microgliosis marker: ionized calcium-binding adaptor molecule (1) levels in the NTS of spontaneously hypertensive rats (SHRs). The AT1R II inhibitor, losartan, significantly decreased BP and abolished superoxide, Iba-1, TLR4 expression induced by Ang II. Furthermore, losartan significantly increased nNsOS(S1416) phosphorylation. Administration of a mu OR agonist or antagonist in the NTS of WKY and SHRs increased endogenous mu-opioids, triggered the formation of mu OR/AT1R heterodimers and the TLR4-dependent inflammatory pathway, and attenuated the effect of depressor nitric oxide (NO). These results imply an important link between neurotoxicity and superoxides wherein abnormal increases in NTS endogenous mu-opioids promote the interaction between Ang II and mu OR, the binding of Ang II to AT1R, and the activation of microglia. In addition, the interaction between Ang II and mu OR enhanced the formation of the AT1R and mu OR heterodimers, and inactivated nNOS-derived NO, leading to the development of progressive hypertension.

Automated summary

Opioids play a role in the development of hypertension by causing inflammation and affecting blood pressure control. The formation of AT1R and mu OR heterodimers may contribute to the progression of hypertension.