Peripheral α‐helical CRF (9‐41) does not reverse stress‐induced mast cell dependent visceral hypersensitivity in maternally separated rats

Abstract

Water avoidance-stress leads to persistent mast cell dependent visceral hypersensitivity in maternally separated rats, which can be prevented, but not reversed by blockade of peripheral CRF-receptors. We conclude that persistent poststress mast cell activation and subsequent visceral hypersensitivity are not targeted by CRF-receptor antagonists.

The role of mast cells in functional GI disorders

“…In preclinical studies, several types of stresses and stress mediators such as corticotropin releasing hormone (CRF) and related peptides have been shown to modulate ion and water secretion as well as intestinal and colonic paracellular and transcellular permeability, primarily via nerve–MC interactions 36 37. Similarly, stress-induced rectal hyperalgesia could be prevented and reversed by administration of an MC stabiliser 38. Other studies have confirmed and extended this paradigm to the human intestine.…”

Stress and Chronic Pelvic Pain

“…91 Rats that underwent NMS not only displayed a larger VMR immediately following WAS, they also displayed a significantly longer period of WAS-induced hypersensitivity than non-NMS rats. 88,92 Treatment with CRF 1 and/or CRF 2 antagonists, prior to WAS exposure, was shown to reduce colorectal sensitivity in NMS rats. 4,92 This effect was observed both centrally and peripherally, as administration of α-helical CRF [9][10][11][12][13][14], which predominantly blocks CRF 2 and does not cross the bloodbrain barrier, was capable of preventing increased VMR when administered prior to WAS exposure.…”

“…4,92 This effect was observed both centrally and peripherally, as administration of α-helical CRF [9][10][11][12][13][14], which predominantly blocks CRF 2 and does not cross the bloodbrain barrier, was capable of preventing increased VMR when administered prior to WAS exposure. 92 The authors attribute this result to preventing mast cell destabilization following stress exposure, as α-helical CRF [9][10][11][12][13][14] was unable to reverse WAS-induced colorectal hypersensitivity when given after WAS exposure. The efficacy of CRF 1 antagonist to reverse stress-induced colorectal sensitivity in NMS rats has not been appropriately tested, as Schwetz et al 4 treated with CRF 1 antagonist both prior to WAS and 30 min before CRD.…”

Psychological Stress Induces Visceral Analgesic or Hyperalgesic Response in Rodents: A Role of Preconditions

“…The effect of both acute (restraint, WAS) and chronic stress (WAS 4–10 days, maternal separation) related to an increase in colonic permeability can be abolish by pretreatment of rat with the peripheral administration of the nonselective CRF antagonist, astressin or selective CRF 1 antagonists [20]. In a recent study, it has been demonstrated that the mast cell-dependent visceral hypersensitivity observed in maternally separated rats after an acute exposure to a psychological stress can be prevented but not reversed by the peripherally restricted CRF receptor antagonist, α-helical CRF 9–41 [21]. Furthermore, the preventive effect of the CRF receptor antagonist was linked to the stabilization of mast cells and maintenance of the epithelial barrier at the colonic level [21].…”

“…In a recent study, it has been demonstrated that the mast cell-dependent visceral hypersensitivity observed in maternally separated rats after an acute exposure to a psychological stress can be prevented but not reversed by the peripherally restricted CRF receptor antagonist, α-helical CRF 9–41 [21]. Furthermore, the preventive effect of the CRF receptor antagonist was linked to the stabilization of mast cells and maintenance of the epithelial barrier at the colonic level [21]. …”