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Increased κ-opioid receptor expression and function during chronic visceral hypersensitivity
  1. Patrick A Hughes1,2,
  2. Joel Castro1,2,
  3. Andrea M Harrington1,2,
  4. Nicole Isaacs1,
  5. Melissa Moretta1,
  6. Gareth A Hicks3,
  7. David M Urso3,
  8. Stuart M Brierley1,2,4
  1. 1Nerve-Gut Research Laboratory, Discipline of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia
  2. 2Department of Gastroenterology and Hepatology, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia, Australia
  3. 3Tioga Pharmaceuticals Inc., San Diego, California, USA
  4. 4Discipline of Physiology, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia
  1. Correspondence to Dr Stuart M Brierley, Nerve-Gut Research Laboratory, Level 1 Hanson Institute, Frome Road, Adelaide, South Australia 5000, Australia; stuart.brierley{at}adelaide.edu.au

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In a recent article in Gut, Hughes et al1 identified distinct patterns of immune dysfunction in IBS patients compared with healthy subjects. In particular, they showed that peripheral blood mononuclear cell (PBMC) supernatants from healthy subjects inhibited colonic afferents in a μ-opioid receptor (MOR)-mediated manner. These findings correlated with β-endorphin from T lymphocytes providing an important MOR-mediated antinociceptive influence in the healthy gut.2 Intriguingly, these inhibitory effects were lost with PBMC supernatants from constipation-predominant IBS patients suggesting a loss of MOR-mediated inhibition, coupled with increased excitatory mediators (TNF-α, IL-1β, IL-6), contributes to abdominal pain.1

We evaluated if this alteration was MOR specific or whether it extended to other members of the opioid receptor family. As clinical studies have shown varying outcomes on visceral pain perception with κ-opioid receptor (KOR) agonists,35 we postulated KOR expression and function are altered during visceral hypersensitivity. Therefore, we determined if the peripherally restricted selective KOR agonist, asimadoline, was able to modify colonic nociceptor function in health and during inflammatory and postinflammatory chronic visceral mechanical hypersensitivity (CVH).6

We performed in vitro afferent recordings from mouse splanchnic high-threshold nociceptors, which respond to focal compression and noxious stretch/distension.1 ,6 …

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Footnotes

  • Contributors PAH, GAH, DMU and SMB conceived the study. PAH, AMH, GAH and SMB designed the experiments. PAH, JC, AMH, NI, MM and SMB conducted and analysed the experiments. SMB wrote the paper and all authors helped with critical revision of the manuscript for important intellectual content.

  • Funding This work was funded by Tioga Pharmaceuticals Inc. PAH is an NHMRC Australian Biomedical Fellow. AMH is an Australian Research Council Discovery Early Career Research Fellow. SMB is an NHMRC R D Wright Biomedical Fellow.

  • Competing interests SMB and PAH received funding from Tioga Pharmaceuticals Inc. to conduct the study. GAH and DMU are employees of Tioga Pharmaceuticals Inc. JC, AMH, NI and MM have nothing to declare.

  • Ethics approval Experiments were approved by the Animal Ethics Committees of the Institute of Veterinary and Medical Science/SA Pathology and the University of Adelaide.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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