Acute stress induces visceral hypersensitivity via glucocorticoid receptor–mediated membrane insertion of TRPM8: Involvement of a non‐receptor tyrosine kinase Pyk2

Abstract

Background Psychological stress is an important factor for the development and recurrence of irritable bowel syndrome (IBS). The mechanisms underlying stress‐induced visceral hypersensitivity (VH), a key pathophysiological component in IBS, are still incompletely understood. We aimed to test whether transient receptor potential melastatin 8 (TRPM8) participates in acute stress–induced VH. Methods Rats were subjected to 1‐hour water avoidance stress (WAS). Visceral sensitivity was measured with visceromotor response to colorectal distension. Western blot and immunofluorescence were applied to evaluate the expression of GR and TRPM8 and activation of PKA, Akt, and PKC pathways. Results WAS‐caused VH depended on glucocorticoid receptors (GRs) and TRPM8 channels. In a dorsal root ganglion (DRG)–derived cell line, corticosterone rapidly (within 30 minutes) induced membrane expression of TRPM8. This effect was inhibited by GR antagonism and was mimicked by membrane‐impermeable corticosterone. PKA, PI3K/Akt, and PKC pathways, which lied downstream of GR and acted in parallel to promote membrane expression of TRPM8, contributed to WAS‐induced VH. The non‐receptor tyrosine kinase Pyk2, which may serve as a convergence point for PKA, PI3K/Akt, and PKC pathways, facilitated membrane insertion of TRPM8 via tyrosine‐phosphorylating TRPM8 in L6‐S2 DRGs and participated in WAS‐induced VH. Conclusions Collectively, acute stress–induced VH could involve membrane‐bound GR‐dependent enhancement of TRPM8 function in nociceptive DRG neurons. Mechanistically, Pyk2 could act as a key mediator that coordinates multiple protein kinase signaling and triggers phosphorylation and membrane insertion of TRPM8.

ZBTB20 mediates stress‐induced visceral hypersensitivity via activating the NF‐κB/transient receptor potential channel pathway

“…[35][36][37] They are also implicated in the induction of VH by stress. 11,14,15 Notably, we found in this study that these channels all contributed to stresscaused VH. Chronic WAS-caused increased expression of TRPV1, TRPA1, and TRPM8 in nociceptive DRGs of rats.…”

Expression of TRP Channels in Colonic Mucosa of IBS-D Patients and Its Correlation with the Severity of the Disease

“…Our previous study has found the role of TRPM8 in visceral hypersensitivity [ 15 ]. The immunostaining of TRPM8, however, showed no difference between IBS-D and HC ( p > 0.05, Figures 4(a) and 4(b) ).…”

“…TRPM2 and TRPM8 were the relatively less-studied TRP channels. We have previously found that either altered distribution or expression of TRPM8 in sensory neurons under different circumstances contributed to visceral hypersensitivity [ 15 ]. For TRPM2, its expression was enhanced in the distal colon of a TNBS-colitis rat model and administration of TRPM2 antagonist or TRPM2 deficiency-attenuated visceromotor response to colorectal distension [ 14 ].…”

“…Unfortunately, clinical studies concerning TRPA1 still lack. It is the same case with TRPV4 [ 12 , 13 ], TRPM2 [ 14 ], and TRPM8 [ 15 , 16 ], as lots of preclinical studies indicated their involvement in visceral nociception.…”

The impact of acute and chronic stress on gastrointestinal physiology and function: a microbiota–gut–brain axis perspective

“…A more recent study using 1 h of water‐avoidance stress in rats showed a similar increase in visceral hypersensitivity. This study linked the increased pain response of the animals to increased TRPM8 channel expression in nociceptive DRG neurons which was facilitated by the non‐genomic effects of membrane‐bound glucocorticoid receptors (Luo et al., 2020). Longer stressor durations have been investigated in the model of single prolonged stress for post‐traumatic stress disorders, in which animals are exposed to 2 h of restraint stress, 20 min of forced swimming and subsequent anaesthesia, which is followed by a single electric foot shock after the animal wakes up (Chen, Chen et al., 2022; He et al., 2013; He, Lang et al., 2017).…”