Repeated water avoidance stress induces visceral hypersensitivity: Role of interleukin‐1, interleukin‐6, and peripheral corticotropin‐releasing factor

Abstract

Repeated WAS for three consecutive days induced visceral allodynia, which was mediated through mast cells, IL-1, and IL-6 pathways. Inhibition of peripheral CRF signaling prevented but did not reverse this response, suggesting that peripheral CRF may be an essential trigger but may not contribute to the maintenance of repeated WAS-induced visceral allodynia.

Losartan improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome

“…As described before, LPS‐, repeated WAS‐, or CRF‐induced visceral allodynia and colonic hyperpermeability are considered to well simulate the pathophysiology of IBS, and we have previously demonstrated that CRF, TLR4, and proinflammatory cytokine signaling mediated these visceral changes …”

“…At the same time, NO inhibits the expression of proinflammatory cytokine genes in various immune cells and suppresses IL‐1β release from macrophages . Incidentally, the chemical mediators including cytokines released by degranulation of mast cells are known to contribute to stress‐induced visceral hypersensitivity and gut hyperpermeability, and NO inhibits the degranulation to improve gut permeability . Thus, losartan may inhibit proinflammatory cytokine signaling by facilitating NO production to improve visceral changes.…”

“…Next, the effects of losartan on repeated WAS model (1 hour daily for 3 consecutive days) were explored (Figure C). This model was shown to successfully and reproducibly induce visceral allodynia and colonic hyperpermeability in rats . The basal threshold was measured, and the vehicle or losartan was injected.…”

“…We have recently shown that LPS injection or repeated water avoidance stress (WAS) induced visceral allodynia and colonic hyperpermeability in rats (animal IBS models), and these changes were mediated via peripheral CRF, toll‐like receptor 4 (TLR4), and proinflammatory cytokine system . Moreover, peripheral injection of CRF mimicked these visceral changes via the TLR4 and cytokine‐dependent pathways .…”

Early‐life adversity, epigenetics, and visceral hypersensitivity

“…20 Previous studies have demonstrated that stress increased CRF expression both in the brain and the intestine, 25,26 and CRF receptor antagonism both in the brain and in the periphery reversed visceral hypersensitivity induced by stress. 13,27 Another study examining the role of DNA methylation in visceral hypersensitivity showed that chronic water avoidance stress induced DNA methylation of the GR promoter and reduced its mRNA and protein expression in the dorsal root ganglia neurons innervating the pelvic viscera. 19 Chronic water avoidance stress also induced DNA methylation of the antinociceptive cannabinoid receptor 1 promoter and downregulated its expression, which may contribute to stress-induced visceral pain.…”