Angiotensin Type 2 Receptors: Painful, or Not?

Abstract

Pain in response to various types of acute injury can be a protective stimulus to prevent the organism from using the injured part and allow tissue repair and healing. On the other hand, neuropathic pain, defined as ‘pain caused by a lesion or disease of the somatosensory nervous system’, is a debilitating pathology. The TRPA1 neurons in the Dorsal Root Ganglion (DRG) respond to reactive oxygen species (ROS) and induce pain. In acute nerve injury and inflammation, macrophages infiltrating the site of injury undergo an oxidative burst, and generate ROS that promote tissue repair and induce pain via TRPA1. The latter discourages using the injured limb, with a lack of movement helping wound healing. In chronic inflammation caused by diabetes, cancer etc., ROS levels increase systemically and modulate TRPA1 neuronal functions and cause debilitating neuropathic pain. It is important to distinguish between drug targets that elicit protective vs. debilitating pain when developing effective drugs for neuropathic pain. In this context, the connection of the Angiotensin type 2 receptor (AT2R) to neuropathic pain presents an interesting dilemma. Several lines of evidence show that AT2R activation promotes anti-inflammatory and anti-nociceptive signaling, tissue repair, and suppresses ROS in chronic inflammatory models. Conversely, some studies suggest that AT2R antagonists are anti-nociceptive and therefore AT2R is a drug target for neuropathic pain. However, AT2R expression in nociceptive neurons is lacking, indicating that neuronal AT2R is not involved in neuropathic pain. It is also important to consider that Novartis terminated their phase II clinical trial (EMPHENE) to validate that AT2R antagonist EMA401 mitigates post-herpetic neuralgia. This trial, conducted in Australia, United Kingdom, and a number of European and Asian countries in 2019, was discontinued due to pre-clinical drug toxicity data. Moreover, early data from the trial did not show statistically significant positive outcomes. These facts suggest that may AT2R not be the proper drug target for neuropathic pain in humans and its inhibition can be harmful.

Novel Pharmacology Following Heteromerization of the Angiotensin II Type 2 Receptor and the Bradykinin Type 2 Receptor

“…In particular, the coexpression of Ga z and the two receptors in the nervous system is especially interesting, due to the growing appreciation of the functional role of the AT 2 receptor in mediating neurological processes (53,54). Indeed, an AT 2 receptor antagonist progressed to Phase II clinical trials for the treatment of neuropathic pain (54,55), although the trial had to be terminated due to toxicological concerns arising from pre-clinical data that only became available after the start of the trial (56). In addition, it is well established that the B 2 receptor is also involved in the mediation of various types of pain, including neuropathic pain (57), and it is interesting to speculate on a possible involvement of the AT 2 -B 2 heteromer in mediating pain or other neurological processes.…”

Editorial: Termination of pro-inflammatory signaling and its dysregulation in autoimmune diseases

“…Given the detrimental inflammatory events in autoimmune diseases and the limitations of current therapeutic approaches (including non-responders and adverse effects), novel antiinflammatory strategies are desirable (6). For the angiotensin II type 2 receptor (AT 2 R), for instance, a significant antiinflammatory and tissue-protective capacity has been described (7).…”

New Advances on Pathophysiology of Diabetes Neuropathy and Pain Management: Potential Role of Melatonin and DPP-4 Inhibitors

“…The low and moderate levels of ROS and RNS are very useful for fighting against infections and maintaining cellular structural integrity. The in vivo and clinical studies demonstrate a promising relationship between ROS and neurological complications ( Barutta et al, 2011 ; Mihanfar et al, 2021 ; Akbarzadeh, Darband, Sadighparvar, and Majidinia; Pulakat and Sumners, 2020 ; H.; Wu, Wen, Jiang, Liu, & Nie, 2018 ). ROS complications and oxidative stress lead to the development of unhealthy reactions at the cellular and molecular levels, such as DNA damage, lipid peroxidation, protein degradation, and secretion of antioxidant enzymes.…”