Delta opioid receptors on nociceptive sensory neurons mediate peripheral endogenous analgesia in colitis.

Background: Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4 T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia.

Methods: The peripheral analgesia associated with the accumulation of CD4 T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Na1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model.

Results: Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa.

Conclusion: The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders.