Renin–angiotensin system in pain: Existing in a double life?

Abstract

Apart from the well-documented role of the renin-angiotensin-aldosterone system (RAAS) in regulating the blood pressure and other related parameters, its role in modulating different physiological/pathological functions, including pain, has also been described. Like its dual role in regulating stress-related anxiety and cognitive functions, its dual role has also been documented in pain modulation in different disease states. Drugs blocking the RAAS activation, viz., renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, AT 1 receptor antagonists and aldosterone antagonists, have been shown to produce beneficial effects in migraine and neuropathic and nociceptive pain. Their beneficial effects have been mainly attributed to inhibition of the inflammatory cascade of reactions by inhibiting the generation of key cytokines, including tumor necrosis factor (TNF)-α. On the contrary, clinical as well as preclinical studies have also shown the paininducing actions of renin-angiotensin system (RAS) blocking drugs. Furthermore, the pain-relieving actions of angiotensin II (AngII) and pain-inducing actions of AT 1 blockers have also been described. The pain-inducing actions of ACE inhibitors have been mainly attributed to interference with metabolism of bradykinin and substance P, while the analgesic actions of AngII have been mainly related to activation of brain localized AT 2 receptors and release of endogenous opioids. The present review describes the dual role of the RAAS in different states of pain.

The cough reflex is upregulated by lisinopril microinjected into the caudal nucleus tractus solitarii of the rabbit

“…This outcome strengthens our interpretation since its involvement in the blockade of AT 1 receptors cannot lead per se to an accumulation of bradykinin and substance P. In addition, the activation of AT 2 receptors by angiotensin II may inhibit ERK1/2 activity (Fischer et al, 1998), an effect that has been proved to downregulate the cough reflex at the level of the caudal NTS (Mutolo et al, 2012). Further, the activation of AT 2 receptors has been suggested to have a role in the release of endogenous opioids (Bali et al, 2014) that are well-known to exert not only analgesic, but also antitussive effects (see e.g. Mutolo et al, 2008).…”

“…Since lisinopril-induced cough potentiation could be linked to an accumulation of bradykinin (Bali et al, 2014;Fox et al, 1996;Moreaux et al, 2001), bilateral microinjections (n = 7) of 0.05 mM bradykinin (30-0 nl; 1.5-2.5 pmol) were performed into the caudal NTS. About 10 min after the microinjections (maximum effect), the cough number increased from 3.13 ± 0.40 to 4.33 ± 0.35 (p < 0.001) during mechanical stimulation and from 3.71 ± 0.42 to 5.86 ± 0.45 (p < 0.001) during chemical stimulation (see also Fig.…”

“…The protussive effects of ACE inhibitors may be related to an action on NTS sensory neurons due to a bradykinin-induced release of substance P. Since both pro-and antinociceptive roles of the RAS have also been described (Bali et al, 2014), we suggest that studies on the involvement of the RAS in pain and cough modulation could lead to novel therapeutic approaches especially for chronic pathological conditions.…”

“…They have been associated with low cough incidence in humans, so that they are usually employed to substitute ACE inhibitors in patients displaying as side effect persistent cough (e.g., Paster et al, 1998;Mutolo et al, 2013 also for further Refs.). The mechanism of ACE inhibitorinduced cough remains unclear, but likely involves mainly the protussive mediators bradykinin and substance P, agents that are degraded by ACE and therefore accumulated in the respiratory system when the enzyme is inhibited (e.g., Bali et al, 2014;Fox et 1996; Moreaux et al, 2001;Tomaki et al, 1996;Mutolo et al, 2010Mutolo et al, , 2013 also for further Refs. ).…”

Effect of 3-substituted 1,4-benzodiazepin-2-ones on bradykinin-induced smooth muscle contraction

“…Bradykinin (BK) is one of the most potent pain-producing agents formed under inflammatory conditions. Multitude of its sensiti zing and excitatory effects on peripheral nociceptors supporting its role as a prototype of peripheral pain mediators have been described [1,2,6,10]. A number of bradykinin effects mediated by products of the arachidonic acidcyclooxygenase cascade testify to the existence of mutual interactions between the pain mediators [12].…”