The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders

Abstract

A sensory role for ATP was proposed long before general acceptance of its extracellular role. ATP activates and sensitizes signal transmission at multiple sites along the sensory axis, across multiple synapses. P2X and P2Y receptors mediate ATP modulation of sensory pathways and participate in dysregulation, where ATP action directly on primary afferent neurons (PANs), linking receptive field to CNS, has received much attention. Many PANs, especially C-fibers, are activated by ATP, via P2X3-containing trimers. P2X3 knock-out mice and knock-down in rats led to reduced nocifensive activity and visceral reflexes, suggesting that antagonism may offer benefit in sensory disorders. Recently, drug-like P2X3 antagonists, active in a many inflammatory and visceral pain models, have emerged. Significantly, these compounds have no overt CNS action and are inactive versus acute nociception. Selectively targeting ATP sensitization of PANs may lead to therapies that block inappropriate chronic signals at their source, decreasing drivers of peripheral and central wind-up, yet leaving defensive nociceptive and brain functions unperturbed. This article reviews this evidence, focusing on how ATP sensitization of PANs in visceral "hollow" organs primes them to chronic discomfort, irritation and pain (symptoms) as well as exacerbated autonomic reflexes (signs), and how the use of isolated organ-nerve preparations has revealed this mechanism. Urinary and airways systems share many features: dependence on continuous afferent traffic to brainstem centers to coordinate efferent autonomic outflow; loss of descending inhibitory influence in functional and sensory disorders; dependence on ATP in mediating sensory responses to diverse mechanical and chemical stimuli; a mechanistically overlapping array of existing medicines for pathological conditions. These similarities may also play out in terms of future treatment of signs and symptoms, in the potential for benefit of P2X3 antagonists.

Keywords: AF-219; P2X3; afferent sensitization; airways hyperreactivity; cough; urinary symptoms; visceral disorders.

Figure 1

ATP is released in heightened amounts in a variety of somatic and visceral tissue systems and may cause hyperexcitability (“sensitization”) of PANs. Depending on the nature of the affected tissue, the elevated afferent discharge drives the increased perception of irritative symptoms (hyperesthesia) as well as lowering the threshold for activation of autonomic reflexes. These elevated reflexes (hyperreflexia) in turn give rise to many of the signs of chronic disorders, which can usually be easily observed or measured, if not perceived by the patient.

Figure 2

Normal physiological sensory perception and reflexes are important defensive mechanisms, under conditions of acute stress or physical threat, when a high stimulus intensity (blue sigmoid) represents potential harm. During chronic dysregulation, afferent functions experience sensitization, wherein normally low threshold or sub-threshold stimulus intensities, posing little or no threat, now induce unpleasant sensations and inappropriate autonomic responses. Many mechanisms have been proposed to contribute to such sensitization, but the key priming autacoid remains elusive, though it could turn out to be ATP in some visceral systems such as LUT and airways.

Figure 3

Morphology and wiring of LUT and airways. The urinary tract and airways walls show a similar overall morphology, despite quite distinct structural differentiation in the epithelial layer. In both systems, ATP (shown as blue triangles) is present in large extracellular concentrations, released by various cells including epithelia, fibroblasts and smooth muscles, and can activate C-fiber afferent and promote sensitization. Release of ATP is augmented in conditions of stress, injury, inflammation and infection.

Figure 4

The reflex bladder. In the neonate, C-fibers carry bladder filling signals to activate spinal segmental reflexes that regulate involuntary excitatory responses. Overlaying and—in a healthy person—overriding this reflex bladder is a voluntary control system, that is laid down during the early post-natal years. Here, Aδ fibers play a dominant role, impacting with second order neurons that send signals up to the brain. In neurogenic-bladder patients (typified following spinal injury), a rapid deterioration of this descending inhibitory control occurs, ”unmasking” the C-fiber reflex beneath. The more gradual emergence of this reflex, due to idiopathic loss of descending C-fiber inhibition, may account for the development of many LUT symptoms (as conceived by WC de Groat).