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Stress activates pronociceptive endogenous opioid signalling in DRG neurons during chronic colitis
  1. Raquel Guerrero-Alba1,2,
  2. Eduardo E Valdez-Morales1,3,
  3. Nestor N Jimenez-Vargas1,
  4. Cintya Lopez-Lopez1,
  5. Josue Jaramillo-Polanco1,
  6. Takanobu Okamoto1,
  7. Yasmin Nasser1,4,
  8. Nigel W Bunnett5,6,
  9. Alan E Lomax1,
  10. Stephen J Vanner1
  1. 1GI Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada
  2. 2Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, México
  3. 3Departamento de Cirugía, Centro de Ciencias Biomédicas, Universidad Autónoma de Aguascalientes, Cátedras CONACYT, Aguascalientes México
  4. 4Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
  5. 5Monash Institute of Pharmaceutical Sciences and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Australia
  6. 6Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia
  1. Correspondence to Dr Stephen Vanner, GI Diseases Research Unit, Kingston General Hospital, 166 Brock St., Kingston, Ontario, Canada K7L 5G2; vanners{at}


Aims and background Psychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways.

Methods Mouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca2+ imaging techniques.

Results Supernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca2+ responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neurons from an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein βϒ subunits.

Conclusions Stress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.


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