Endogenous regulation of visceral pain via production of opioids by colitogenic CD4(+) T cells in mice.
OBJECTIVE
A dysregulated response of CD4(+) T cells against the microbiota contributes to the development of inflammatory bowel disease. Effector CD4(+) T cells, generated in response to microbe-derived antigens, can reduce somatic inflammatory pain through the local release of opioids. We investigated whether colitogenic CD4(+) T cells that accumulate in the inflamed colon also produce opioids and are able to counteract inflammation-induced visceral pain in mice.


METHODS
Colitis was induced via transfer of naive CD4(+)CD45RB(high) T cells to immune-deficient mice or by administration of dextran sulfate sodium. Mice without colitis were used as controls. Samples of colon tissue were collected, and production of opioids by immune cells from inflamed intestine was assessed by quantitative polymerase chain reaction and cytofluorometry analyses. The role of intestinal opioid tone in inflammation-induced visceral hypersensitivity was assessed by colorectal distention.


RESULTS
In mice with T cell- or dextran sulfate sodium-induced colitis, colitogenic CD4(+) T cells (T-helper 1 and Th17 cells) accumulated in the inflamed intestine and expressed a high level of endogenous opioids. In contrast, macrophages and epithelial cells did not express opioids; opioid synthesis in the myenteric plexus was not altered on induction of inflammation. In mice with colitis, the local release of opioids by colitogenic CD4(+) T cells led to significant reduction of inflammation-associated visceral hypersensitivity.


CONCLUSIONS
In mice, colitogenic Th1 and Th17 cells promote intestinal inflammation and colonic tissue damage but have simultaneous opioid-mediated analgesic activity, thereby reducing abdominal pain.
INSERM Unité 1043, Toulouse, France; CNRS, U5282, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse UPS, Toulouse, France.
Jérôme
J
Boué
INSERM Unité 1043, Toulouse, France; CNRS, U5282, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse UPS, Toulouse, France.
Lilian
L
Basso
INSERM Unité 1043, Toulouse, France; CNRS, U5282, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse UPS, Toulouse, France.
Nicolas
N
Cenac
INSERM Unité 1043, Toulouse, France; CNRS, U5282, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse UPS, Toulouse, France.
Catherine
C
Blanpied
INSERM Unité 913, Nantes, France; Institut des Maladies de l'Appareil Digestif, Université de Nantes, Nantes, France.
Malvyne
M
Rolli-Derkinderen
INSERM Unité 913, Nantes, France; Institut des Maladies de l'Appareil Digestif, Université de Nantes, Nantes, France.
Michel
M
Neunlist
INSERM Unité 1043, Toulouse, France; CNRS, U5282, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse UPS, Toulouse, France; Department of Pharmacology and Physiology, University of Calgary, Calgary, Alberta, Canada.
Nathalie
N
Vergnolle
INSERM Unité 1043, Toulouse, France; CNRS, U5282, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse UPS, Toulouse, France. Electronic address: gilles.dietrich@inserm.fr.
Gilles
G
Dietrich
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000294:innervation / Q000473:pathology; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D018928:Immunity, Mucosal; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009197:Myenteric Plexus / Q000276:immunology* / Q000502:physiology; D018847:Opioid Peptides / Q000276:immunology* / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D059265:Visceral Pain / Q000276:immunology*
D018847:Opioid Peptides; D016264:Dextran Sulfate
4′,6-diamidino-2-phenylindole; CBA; Cytometric Bead Array; DAPI; DSS; FCS; HPRT; IBD; IFN; IL; Ig; Mouse Model; Mucosal Immunity; OVA; PBS; PDYN; PENK; POMC; T-helper; Th; UC; Visceral Sensitivity; dextran sulfate sodium; fetal calf serum; hypoxanthine phosphoribosyltransferase; immunoglobulin; inflammatory bowel disease; interferon; interleukin; mAb; mRNA; messenger RNA; monoclonal antibody; ovalbumin; phosphate-buffered saline; prodynorphin; proenkephalin; proopiomelanocortin