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.

Shedding Light on the Pharmacological Interactions between μ-Opioid Analgesics and Angiotensin Receptor Modulators: A New Option for Treating Chronic Pain

“…Components of the renin-angiotensin system (RAS) have been previously reviewed or discussed extensively [19,24,[58][59][60][61][62][63][64]. Nevertheless, the main findings are briefly summarized here for an overview.…”

“…There is no clear consensus whether AT2Rs are expressed on sensory neurons creating a direct pharmacological target for analgesia [18,37,38,106,107,110], or the observed beneficial effect is mediated by immune cells infiltrating injured nerves [80,107]. The neuro-immune cross-talk proposed by the latter studies was recently reviewed by Balogh et al [19].…”

“…Accumulating evidence has proven that drugs affecting the renin-angiotensin system can modulate pain transmission [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. Recent studies have also shown that drugs mimic or antagonize angiotensin type 1 and 2 (AT1R and AT2R) receptor-mediated actions do produce a beneficial analgesic effect in rodent models of chronic pain types [17,20,22,28,29,[35][36][37][38].…”

Angiotensin and Endothelin Receptor Structures With Implications for Signaling Regulation and Pharmacological Targeting

“…In the kidney, physiological stimulation of the receptor causes diuresis and natriuresis by decreasing salt and water transport from the tubules to the capillaries, triggering sodium and water excretion ( 34 ). Chronic AT 2 R overexpression has deleterious effects on cardiomyocytes ( 35 ) and AT 2 R activation, as AT 1 R, is involved in neuropathic pain ( 36 , 37 ).…”

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

“…Elevated circulating Ang II in the brain was reported to be associated with the genesis of arterial hypertension [ 8 ], whereas the overactivation of RAAS is crucially involved in the pathogenesis of hypertension and hypertension-related cardiovascular disorders [ 9 ]. Moreover, the beneficial effects of previous studies have shown that RAS blockers can reduce the development of hypertension and its associated neuropathic pain, cognitive impairment and cerebral injury [ 6 , 10 , 11 ]. By understanding role of the neuropeptides, opioids and angiotensin in CV function, we hope to trace the molecular origin of heart failure during the development of hypertension.…”