Abstract
BackgroundInflammatory 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.MethodsThe 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 Nav1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model.ResultsEndogenous 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.ConclusionThe 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.
Highlights
Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4+ T lymphocytes in mice
To identify receptor(s) responsible for the opioid-induced analgesia at the later phase of the dextran sulfate sodium (DSS)-induced colitis, we used conditional knockout mice in which the enkephalin opioid receptors mu (MOR) or delta (DOR) are deleted in Nav1.8-expressing nociceptive neurons. cKO mice in which μ-Opioid receptor (MOR) (Oprm1) or δ-Opioid receptor (DOR) (Oprd1) genes are deleted in nociceptors were generated by crossing Oprm1fl/fl or Oprd1fl/fl mice with mice that express Cre recombinase in Nav1.8-expressing neurons [16, 48]
As genetic background may impact pain assays, the cKO MOR or cKO DOR were compared to their respective Cre-negative MOR flox or DOR flox littermates with the same genetic background
Summary
Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4+ T lymphocytes in mice. Methods: The peripheral analgesia associated with the accumulation of CD4+ T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice deleted for either of the two opioid recep‐ tors for enkephalins (i.e., μ (MOR) and δ (DOR) receptors) in Nav1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model. We compared the visceral sensitivity of mice with opioid receptor-deficient nociceptors to that of control opioid receptor floxed mice in the dextran sulfate sodium (DSS)-induced colitis model in which T lymphocyte accumulation induces analgesia [5, 9, 10, 23, 46]
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