Mas Receptor as a Target for Neuropathic Pain Management: Insights into Angiotensin-(1-7) Signaling and Therapeutic Opportunities

Abstract

Mas is a G protein-coupled receptor (GPCR) that binds to Angiotensin (1-7) and it is evaluated as an important element of non classical Renin Angiotensin System. While the RAS axis has been considered as pro-inflammatory and pro-nociceptive by leveraging the Angiotensin II and AT1 receptor, the Angiotensin (1-7) /Mas axis offers anti-inflammatory, vessels dilating, and neuroprotective functions. It is produced by two mechanisms first, Angiotensin (1-7) is obtained from Angiotensin II via the mechanism of angiotensin converting enzyme 2 (ACE2) and also by the binding of the formed Ang-(1-7) to its receptor, Mas receptor, it activates several signaling pathways such as PI3K/Akt, ERK1/2 and nitric oxide (NO). These pathways together prevent neuronal death, decrease oxidative stress and inhibit the nuclear factor-kappa B (NF-κB), and reduces the expression of various cytokines like TNF-α, IL-1β and IL-6. With regard to neuropathic pain, the Mas receptor contributes to regulation of glial-neuronal crosstalk and negative regulation of microglial and astrocytic activity and neuroimmune balance. Experimental studies have shown that the use of Mas receptor by Angiotensin (1-7) or synthetic activators attenuates mechanical alodynia and thermal hypoesthesia, proving that the Marques and colleagues’ hypothesis has possible therapeutic applications. Also, the Mas receptor has functional cross-talk with other pain-modulatory systems, including the endogenous opioid and endocannabinoid systems, contributing to the enhancer of this sort of analgesia. Thus, the novel Angiotensin (1-7)/Mas receptor pathway can be considered as the novel promising candidate for the use of new non-opioid analgesic for the treatment of neuropathic pain. Further research in Mas receptor agonists, peptide analogs, and targeted drug delivery system shows that there is potential to practical application of these discoveries.