The neurotensin receptor 1 agonist PD149163 alleviates visceral hypersensitivity and colonic hyperpermeability in rat irritable bowel syndrome model.

Background: An impaired intestinal barrier with the activation of corticotropin-releasing factor (CRF), Toll-like receptor 4 (TLR4), and proinflammatory cytokine signaling, resulting in visceral hypersensitivity, is a crucial aspect of irritable bowel syndrome (IBS). The gut exhibits abundant expression of neurotensin; however, its role in the pathophysiology of IBS remains uncertain. This study aimed to clarify the effects of PD149163, a specific agonist for neurotensin receptor 1 (NTR1), on visceral sensation and gut barrier in rat IBS models.

Methods: The visceral pain threshold in response to colonic balloon distention was electrophysiologically determined by monitoring abdominal muscle contractions, while colonic permeability was measured by quantifying absorbed Evans blue in colonic tissue in vivo in adult male Sprague-Dawley rats. We employed the rat IBS models, i.e., lipopolysaccharide (LPS)- and CRF-induced visceral hypersensitivity and colonic hyperpermeability, and explored the effects of PD149163.

Key results: Intraperitoneal PD149163 (160, 240, 320 μg kg^-1) prevented LPS (1 mg kg^-1, subcutaneously)-induced visceral hypersensitivity and colonic hyperpermeability dose-dependently. It also prevented the gastrointestinal changes induced by CRF (50 μg kg^-1, intraperitoneally). Peripheral atropine, bicuculline (a GABA_A receptor antagonist), sulpiride (a dopamine D₂ receptor antagonist), astressin₂-B (a CRF receptor subtype 2 [CRF₂] antagonist), and intracisternal SB-334867 (an orexin 1 receptor antagonist) reversed these effects of PD149163 in the LPS model.

Conclusions and inferences: PD149163 demonstrated an improvement in visceral hypersensitivity and colonic hyperpermeability in rat IBS models through the dopamine D₂, GABA_A, orexin, CRF₂, and cholinergic pathways. Activation of NTR1 may modulate these gastrointestinal changes, helping to alleviate IBS symptoms.