P2X3 receptors and sensitization of autonomic reflexes

A great deal of basic and applied physiology and pharmacology in sensory and autonomic neuroscience has teased apart mechanisms that drive normal perception of mechanical, thermal and chemical signals and convey them to CNS, the distinction of fiber types and receptors and channels that mediate them, and how they may become dysfunctional or maladaptive in disease. Likewise, regulation of efferent autonomic traffic to control organ reflexes has been well studied. In both afferent and efferent limbs, a wide array of potential therapeutic mechanisms has surfaced, some of which have progressed into clinic, if not full regrastration. One conversation that has been less well progressed relates to how the afferent limb and its sensitization shapes the efferent outputs, and where modulation may offer new therapeutic avenues, especially for poorly addressed and common signs and symptoms of disease. Therapeutics for CV disease (HF, hypertension), respiratory disease (asthma, COPD), urological disease (OAB), GI disease (IBS), and inter alia, have largely focused on the efferent control of effector cells to modulate movement, contraction and secretion; medicinal needs remain with limits to efficacy, AEs and treatment resistance being common. We now must turn, in the quest for improved therapeutics, to understand how sensation from these organs becomes maladapted and sensitized in disease, and what opportunities may arise for improved therapeutics given the abundance of targets, many pharmacologically untapped, on the afferent side. One might look at the treatment resistant hypertension and the emerging benefit of renal denervation; or urinary bladder overactivity / neurogenic bladder and the emergence of neuromodulation, capsaicin instillation or botox injections to attenuate sensitized reflexes, as examples of merely the start of such progress. This review examines this topic more deeply, as applies to four major organ systems all sharing a great need from unsatisfied patients.