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Critical role of capsaicin-sensitive sensory neurons in gender difference in the stress-induced gastric mucosal injury in rats


Recent studies have demonstrated that the outcome of critically ill patients is better in females than in males. Although estrogen has been shown to be critically involved in regulation of immune responses, the detailed mechanism(s) underlying such gender differences has yet to be fully understood. Since proinflammation plays a critical role in the development of the organ dysfunction seen in such critically ill patients, estrogen might show any anti-inflammatory effects to attenuate such inflammatory responses. We previously reported that capsaicin-sensitive sensory neurons (CSSN), nociceptive neurons, play an important role in attenuating inflammatory responses by releasing calcitonin gene-related peptide (CGRP), which promotes the endothelial production of prostacyclin, one of the anti-inflammatory prostaglandins [1]. Since estrogen increases the synthesis of nerve growth factor, which increases the CGRP production, estrogen might attenuate inflammatory responses by promoting CGRP release from CSSN. We examined this possibility in the present study.

Methods and results

Gastric accumulation of neutrophils as well as gastric mucosal injury were significantly less in female rats than in male rats subjected to water-immersion restraint stress (WIRS). Gastric levels of CGRP and 6-keto-PGF1α, a stable metabolite of PGI2, were significantly higher in female rats than those in male rats subjected to WIRS. Administration of capsazepine, a vanilloid receptor-1 antagonist, markedly reduced the gastric levels of CGRP and 6-keto-PGF1α in female rats subjected to WIRS. Both gastric accumulation of neutrophils and gastric mucosal injury in female rats pretreated with capsazepine were comparable with those seen in male rats.


These results suggest that CGRP release from CSSN is more marked in female rats than male rats, contributing to differences in the gastric tissue levels of PGI2 in rats subjected to WIRS. This difference in the regulatory function for inflammatory responses might at least partly explain the gender difference in the development of stress-induced gastric mucosal injury in rats.


  1. Harada N, et al.: Gastroenterology 2001, 120(suppl):A-148.

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Harada, N., Okajima, K. & Uchiba, M. Critical role of capsaicin-sensitive sensory neurons in gender difference in the stress-induced gastric mucosal injury in rats. Crit Care 7, P208 (2003).

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  • Estrogen
  • Nerve Growth Factor
  • PGI2
  • Restraint Stress
  • Nociceptive Neuron