Trypsin triggers a contraction-then-relaxation response in esophageal circular muscle through a pathway involving TRPV1 receptors and substance P peptide signaling via neurokinin receptors.
Biphasic response in circular muscle onlyTrypsin caused contraction at 100 nM and relaxation at 1 μM exclusively in circular smooth muscle, mediated entirely through substance P and neurokinin receptors NK1/NK2.
What the researchers found
Trypsin induced a concentration-dependent biphasic response (contraction at 100 nM, relaxation at 1 μM) exclusively in esophageal circular smooth muscle, not longitudinal muscle. The response was mediated through a PAR2 → TRPV1 → substance P signaling pathway in sensory neurons, with substance P acting via neurokinin receptors NK1 and NK2.
Gap junctions between smooth muscle cells were essential for the response — gap junction uncouplers (carbenoxolone and octanol) abolished the trypsin-induced contractions entirely. The PAR2-activating peptide SLIGKV-NH2 produced only contraction (monophasic), suggesting the relaxation component involves additional mechanisms at higher trypsin concentrations.
Why it matters
Gastroesophageal reflux disease (GERD) is extremely common, and cases that don't respond to standard acid-suppressing treatment may involve duodenal reflux containing trypsin. Understanding how trypsin disrupts esophageal muscle function through neuropeptide signaling could lead to new therapeutic approaches for refractory GERD targeting the PAR2-substance P pathway rather than acid production alone.
How the study worked
Researchers performed organ bath experiments on isolated circular and longitudinal smooth muscle strips from porcine esophageal body. They applied trypsin at various concentrations and measured contractile responses, then used selective receptor antagonists and channel blockers to dissect the signaling pathway. Tetrodotoxin was used to assess neural involvement, gap junction uncouplers to test intercellular communication, and specific NK1, NK2, and NK3 antagonists to identify the relevant neurokinin receptors.
What this study cannot tell us
This study used porcine esophageal tissue, which may differ from human esophageal physiology. The experiments were conducted on isolated muscle strips in an organ bath, which removes the influence of intact neural circuits and blood supply present in vivo. Additionally, the study focused on acute responses and does not address chronic effects of trypsin exposure relevant to ongoing GERD.
How to read the evidence
This is a preclinical in vitro study using isolated animal tissue. While the pharmacological methodology is rigorous, the findings are mechanistic and have not been validated in human tissue or clinical settings.
When this study was published
Published in 2017, this study is moderately dated but addresses fundamental physiology that remains relevant. More recent work may have expanded on these findings regarding tachykinin signaling in GERD.
The bigger picture
This study adds to growing evidence that neuropeptides like substance P play important roles in gastrointestinal motility disorders. The PAR2-TRPV1-tachykinin axis is increasingly recognized as a key pathway in visceral hypersensitivity and inflammatory gut conditions. Understanding this signaling cascade in the esophagus could inform development of peptide-based or peptide-targeted therapies for motility disorders.
Questions still open
- Could NK1/NK2 receptor antagonists serve as a novel treatment for refractory GERD caused by duodenal reflux?
- Does chronic trypsin exposure alter substance P signaling or neurokinin receptor expression in the esophagus?
- How does this trypsin-substance P pathway interact with acid-mediated damage in combined reflux?
Common questions
What is substance P and what role does it play in the esophagus?
How could this research help people with acid reflux that doesn't respond to standard treatment?
Read the original research
Trypsin induces biphasic muscle contraction and relaxation via transient receptor potential vanilloid 1 and neurokinin receptors 1/2 in porcine esophageal body.
European journal of pharmacology, 797, 65-74
Citation
Xiaopeng, Bai; Tanaka, Yoshimasa; Ihara, Eikichi; Hirano, Katsuya; Nakano, Kayoko; Hirano, Mayumi; Oda, Yoshinao; Nakamura, Kazuhiko. (2017). Trypsin induces biphasic muscle contraction and relaxation via transient receptor potential vanilloid 1 and neurokinin receptors 1/2 in porcine esophageal body.. European journal of pharmacology, 797, 65-74. https://doi.org/10.1016/j.ejphar.2017.01.004