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Inflammation-associated changes in DOR expression and function in the mouse colon.

Jesse J DiCello1,2, Ayame Saito1,2, Pradeep Rajasekhar1,2

  • 1Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria , Australia.

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Summary
This summary is machine-generated.

Endogenous opioids activate delta-opioid receptors (DOR) in the colon, inhibiting motility. DOR signaling is enhanced during inflammation, suggesting therapeutic potential for targeting DOR in the gut.

Keywords:
G protein-coupled receptor, intestinal motilityendocytosisenteric nervous systemopioid receptor

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Area of Science:

  • Gastroenterology
  • Neuroscience
  • Pharmacology

Background:

  • Endogenous opioids regulate intestinal function via opioid receptors (ORs) in the enteric nervous system.
  • While mu-OR activation causes adverse effects, delta-opioid receptors (DOR) are a potential target for analgesia.
  • The function and regulation of DOR in the colon remain poorly understood.

Purpose of the Study:

  • To investigate the role and regulation of DOR in mouse colonic motility.
  • To determine if endogenous opioids activate DOR in myenteric neurons.
  • To explore DOR signaling changes during intestinal inflammation.

Main Methods:

  • Administered DOR agonists (DADLE, deltorphin II, SNC80) to mouse colon preparations.
  • Stimulated colons electrically, chemically, and mechanically to evoke endogenous opioid release.
  • Utilized transgenic mice expressing DOR fused to enhanced green fluorescent protein (EGFP) to track receptor internalization.
  • Induced acute colitis using dextran sulfate sodium (DSS).

Main Results:

  • DOR agonists inhibited electrically evoked colonic contractions and induced neurogenic contractions.
  • Colon stimulation led to DOR endocytosis in myenteric neurons but not in circular muscle.
  • DSS-induced colitis showed increased DOR endocytosis and nerve fiber density in the circular muscle.
  • Responsiveness to the DOR agonist SNC80 was enhanced in the inflamed colon.

Conclusions:

  • Endogenous opioids activate DOR in mouse myenteric neurons, regulating colonic motility.
  • Activated DOR undergoes endocytosis, inhibiting neurogenic colonic motility.
  • DOR signaling is potentiated during intestinal inflammation.
  • DOR represents a viable therapeutic target within the enteric nervous system, especially in inflammatory conditions.