P2X3-Containing Receptors as Targets for the Treatment of Chronic Pain

Abstract

Current therapies for the treatment of chronic pain provide inadequate relief for millions of suffering patients, demonstrating the need for better therapies that will treat pain effectively and improve the quality of patient's lives. Better understanding of the mechanisms that mediate chronic pain is critical for developing drugs with improved clinical outcomes. Adenosine triphosphate (ATP) is a key modulator in nociceptive pathways. Release of ATP from injured tissue or sympathetic efferents has sensitizing effects on sensory neurons in the periphery, and presynaptic vesicular release of ATP from the central terminals can increase glutamate release thereby potentiating downstream central sensitization mechanisms, a condition thought to underlie many chronic pain conditions. The purinergic receptors on sensory nerves primarily responsible for ATP signaling are P2X3 and P2X2/3. Selective knockdown experiments, or inhibition with small molecules, demonstrate P2X3-containing receptors are key targets to modulate nociceptive signals. Preclinical studies have identified that P2X3-containing receptors are critical for sensory transduction for bladder function, and clinical studies have shown promise in treatment for bladder pain and pain associated with osteoarthritis. Further clinical characterization of antagonists to P2X3-containing receptors may lead to improved therapies in the treatment of chronic pain.

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

“…neuropathic/inflammatory pain or neurodegenerative illnesses). Although a P2XRbased widely used drug is still missing in our therapeutic repertoire, the pharmaceutical industry is working intensively in this field and there is strong hope of achieving a major breakthrough in the near future (Cully, 2020, Krajewski, 2020.…”

Current standard of care in treatment of bladder pain syndrome/interstitial cystitis

“…After the 4 weeks of treatment, gefapixant-treated patients had a decrease in pain ( p = 0.019) as well as an improvement in urinary urgency and in both Patient’s and Clinician’s Global Impression of Change compared with placebo ( p = 0.038). 61 , 62…”

Intracolonic Mustard Oil Induces Visceral Pain in Mice by TRPA1-Dependent and -Independent Mechanisms: Role of Tissue Injury and P2X Receptors

“…Thus far, none of them have been reported to induce side effects, but definitive data on their efficacy and safety are not yet publicly available ( Souza Monteiro de Araujo et al, 2020 ). In addition, P2X3 antagonists are undergoing clinical trials, with promising results for osteoarthritic pain and with a good safety profile, since only taste disturbances (hypogeusia or dysgeusia) have been reported to be frequent after treatment ( Krajewski, 2020 ). Although both TRPA1 and P2X have been suggested as promising pharmacological targets to treat visceral pain (e.g., Lapointe and Altier, 2011 ; Burnstock, 2017 ), our findings show that when visceral pain is caused by tissue injury, pain relief by P2X antagonism appears to be much more effective than TRPA1 inhibition.…”