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
pain-inducing 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.