The therapeutic potential of renin angiotensin aldosterone system (RAAS) in chronic pain: from preclinical studies to clinical trials

ABSTRACT

The prevalence rate of chronic pain is 15% to 25% in adults while the therapeutic arsenal is still insufficient, especially in relieving neuropathic pain. Peripheral pain transmission is conducted by the small Aδ and C sensory nerve fibres. They express elements from the renin-angiotensin-aldosterone system (RAAS), a well-known blood pressure regulator. Recently, studies have demonstrated the role of angiotensin II, its derivatives and aldosterone in the modulation of pain perception, by interacting with receptors expressed by sensory nerve fibres or through the central nervous system. Here, we assess the effects of RAAS modulators in the conduction of pain with molecular, preclinical and clinical approaches, in normal or pathological conditions. Currently, some clinical studies have been carried out on the pain-relieving effect of RAAS modulators and suggest their potential in the management of chronic, inflammatory or neuropathic pain.

KEYWORDS:

• Pain
• renin-angiotensin-aldosterone system

Acknowledgements

The authors would like to thank Mr Paco Derouault, Univ. Limoges, Myelin maintenance and peripheral neuropathies, EA 6309, F-87000 Limoges, France, for a contribution to Figure 1. The authors would also like to thank Atenao for English assistance.

Financial and competing interests disclosure

C Demiot has received a grant from the University of Limoges. F Bessaguet has received a grant from the ministry of higher education and research. L Magy has received a grant from the University Hospital of Limoges. A Desmoulière has received a grant from the University of Limoges. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The prevalence of chronic pain in adults is estimated at 15–25% and the discovery of new therapies would be welcome. Emerging studies have demonstrated the role of RAAS in the modulation of pain perception and RAAS modulators could be new therapeutics in order to improve the treatment of neuropathic, inflammatory, or cancer-related pain.

• Most of RAAS components are expressed in the sensory nervous system: angiotensinogen, angiotensin I and II, renin, ACE, angiotensin II receptors (AT1, AT2), angiotensin 1–7 receptors (Mas), and AR. The stimulation or blocking in the sensory neurons of AT1, AT2, and Mas or the blocking of ARs as well as renin and ACE inhibition modulate the transmission of pain messages.

• Renin inhibition reduces the synthesis of TNF-α, thereby decreasing the activation of its specific receptor ‘TNFR1’ and inducing thermal and mechanical analgesia in neuropathic pain condition.

• The molecular pain modulation mechanism of the ACE inhibition could be the increase in the expression of SP and BK, inducing sometimes hyperalgesia by stimulation of their G-protein-coupled receptors – respectively NK1 receptor and B2 receptor. Hypoalgesic behaviors have been associated with various forms of hypertension and a significant reduction of hypoalgesic behavior was reported with ACEI treatments in rodents and humans.

• The molecular pain modulation effect of AT1 stimulation by angiotensin II in the central nervous system is the activation of the MAP kinase by phosphorylation of p38 responsible for hyperalgesia. The modulation of pain sensitivity by AR blockers is variable. ARBs could have an analgesic effect in central and a hyperalgesic effect in peripheral nervous system. It has been demonstrated that AT1 blockade attenuates neuropathic pain behavior in rodents, which may possibly be attributed to its anti-inflammatory properties by decreasing TNF-α level.

• Stimulation of the AT2 receptor activates Gs protein that stimulates the cAMP-dependent pathway by activating adenylyl cyclase, and finally activates the PKA. The PKA can then phosphorylate a calcium channel involved in the perception of pain stimuli, named TRPV1 and induces hyperalgesia. AT2 receptor blockers have beneficial effect in neuropathic or inflammatory pain conditions and begin to be confirmed in human.

• Activation of the Mas receptor inhibits spinal c-fos expression in inflammatory and neuropathic pain conditions. Mas receptor stimulation also inhibits calcium channels in DRGs, resulting in a decrease in neural activity associated with analgesia in rodents.

• AR stimulation is pro-inflammatory. So, AR blockers are efficient on inflammatory pain or on inflammatory status of chronic pain in rodents, and the efficiency on inflammatory pain (pain due to arthritis) begins to be confirmed in human. It is attributed to inhibition of cascade of inflammatory reactions (TNF-α principally).