Angiotensin receptors and neuropathic pain

Abstract

Growing evidence implicates the renin-angiotensin system (RAS) in multiple facets of neuropathic pain (NP). This narrative review focuses primarily on the major bioactive RAS peptide, Angiotensin II (Ang II), and its receptors, namely type 1 (AT1R) and type 2 (AT2R). Both receptors are involved in the development of NP and represent potential therapeutic targets. We first discuss the potential role of Ang II receptors in modulation of NP in the central nervous system. Ang II receptor expression is widespread in circuits associated with the perception and modulation of pain, but more studies are required to fully characterize receptor distribution, downstream signaling, and therapeutic potential of targeting the central nervous system RAS in NP. We then describe the peripheral neuronal and nonneuronal distribution of the RAS, and its contribution to NP. Other RAS modulators (such as Ang (1-7)) are briefly reviewed as well. AT1R antagonists are analgesic across different pain models, including NP. Several studies show neuronal protection and outgrowth downstream of AT2R activation, which may lead to the use of AT2R agonists in NP. However, blockade of AT2R results in analgesia. Furthermore, expression of the RAS in the immune system and a growing appreciation of neuroimmune crosstalk in NP add another layer of complexity and therapeutic potential of targeting this pathway. A growing number of human studies also hint at the analgesic potential of targeting Ang II signaling. Altogether, Ang II receptor signaling represents a promising, far-reaching, and novel strategy to treat NP.

Keywords: ACE inhibitor; Angiotensin; Macrophages; Mas receptor; Neuroimmune interactions; Neuropathy; Type 1 angiotensin receptor; Type 2 angiotensin receptor.

Figure 1.

Schematic depicting the renin–angiotensin system with receptors, inhibitory drug molecules, and downstream processes relevant to NP. Historically, the sources of angiotensinogen, renin, and ACE were first identified as the liver, kidney, and lung epithelia, although more recent studies have identified expression of these components in many other cell types, including those in the CNS and peripheral nervous system. Physiological processes of relevance to NP described in this review are listed downstream of their respective receptors. AGT, angiotensinogen; ACE, angiotensin-converting enzyme; Ang, angiotensin; AT1R and AT2R, angiotensin II type 1 and type 2 receptors; AT4R, angiotensin IV-specific receptor; AT7R/Mas receptor, Ang (1-7) receptor; CeA, central nucleus of the amygdala; CNS, central nervous system; PVN, paraventricular nucleus of the hypothalamus.

Figure 2.

Overview of RAS expression in peripheral, central neuronal, and nonneuronal structures related to NP. Structures within the sagittal rodent brain of known relevance to RAS signaling are labeled accordingly. Expression patterns have been reported consistently in the literature, with the possible exception of AT2R in DRG neurons. CeA, central amygdala; CVLM, caudal ventrolateral medulla; DRG, dorsal root ganglion; Hipp, hippocampus; NP, neuropathic pain; RAS, renin–angiotensin system; PVN, paraventricular nucleus; SGC, satellite glial cells.