TRP Channels in Visceral Pain

Abstract

Visceral pain is both different and similar to somatic pain - different in being poorly localized and usually referred elsewhere to the body wall, but similar in many of the molecular mechanisms it employs (like TRP channels) and the specialization of afferent endings to detect painful stimuli. TRPV1 is sensitive to low pH. pH is lowest in gastric juice, which may cause severe pain when exposed to the oesophageal mucosa, and probably works via TRPV1. TRPV1 is found in afferent fibres throughout the viscera, and the TRPV1 agonist capsaicin can recapitulate symptoms experienced in disease. TRPV1 is also involved in normal mechanosensory function in the gut. Roles for TRPV4 and TRPA1 have also been described in visceral afferents, and TRPV4 is highly enriched in them, where it plays a major role in both mechanonociception and chemonociception. It may provide a visceral-specific nociceptor target for drug development. TRPA1 is also involved in mechano-and chemosensory function, but not as selectively as TRPV4. TRPA1 is colocalized with TRPV1 in visceral afferents, where they influence each other's function. Another modulator of TRPV1 is the cool/mint receptor TRPM8, which, when activated can abrogate responses mediated via TRPV1, suggesting that TRPM8 agonists may provide analgesia via this pathway. In all, the viscera are rich in TRP channel targets on nociceptive neurones which we hope will provide opportunities for therapeutic analgesia.

Transient receptor potential (TRP) channels: a clinical perspective

“…Of note, methylglyoxal (an endogenous carbonyl compound that is produced in large amounts during hyperglycemic conditions) activates human TRPA1 (Ohkawara et al ., ). Furthermore, TRPA1 has been implicated in migraine (Edelmayer et al ., ), dental pain (Haas et al ., ), chemotherapy‐induced neuropathic pain (Nassini et al ., ) and colicky pain of GI origin (Blackshaw et al ., ).…”

“…TRP channels are widely expressed in the digestive tract, with important roles in taste, visceral sensation, GI motility, as well as absorptive and secretory functions (see Boesmans et al ., ; Holzer, ; Blackshaw et al ., ). Changes in TRP channel expression have been detected in a variety of GI ailments as exemplified by increased TRPV1 expression in both GERD (Matthews et al ., ; Bhat and Bielefeldt, ) and irritable bowel syndrome (Akbar et al ., ; Keszthelyi et al ., ).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…There is good evidence that TRP channels are involved in both of these processes (Fig. 25;see Holzer, 2004;Blackshaw et al, 2010Blackshaw et al, , 2013Holzer, 2011a,b).…”

“…TRPA1 also has an influence on gastrointestinal motility (reviewed in Blackshaw et al, 2010Blackshaw et al, , 2013. TRPA1 agonists delay in vivo gastric emptying through serotonergic pathways.…”

Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists

“…Indeed, several pharmaceutical companies have launched drug discovery programs aimed at the design and synthesis of potent and selective small molecule TRPA1 inhibitors as potential analgesic and anti-inflammatory agents [22,[28][29]. In preclinical future science group Patent Review Preti, Saponaro & Szallasi models, TRPA1 antagonists showed promise in diabetic neuropathy [22], dental pain [30], chemotherapy-mediated neuropathic pain [31] and colicky pain [32]. In addition, several lines of evidence implicates TRPA1 in the pathomechanism of migraine.…”