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Visceral Pain Research (VIPER) Group

pain, nociceptors, colon, bladder, analgesia...

Visceral Pain Research Group 2016, based at SAHMRI
and part of the Infection and Immunity theme

 

Research Summary

Chronic pathological pain arising from our internal (visceral) organs is a colossal global problem, affecting millions of patients with Irritable Bowel Syndrome, Inflammatory Bowel Disease and overactive bladder. Our group investigates the underlying causes of chronic visceral pain, and the development of new treatments. Using state of the art molecular, anatomical and functional approaches allows us to study mechanisms from the single cell through to in vivo and clinical studies.

These multi-faceted research programs have translated to high-impact publications in journal such as Nature, Nature Communications, Nature Reviews Gastroenterology and Hepatology, Gastroenterology, Gut, Pain and The Journal of Neuroscience.

Our group is funded by the National Health and Medical Research Council of Australia (NHMRC), The Australian Research Council (ARC), and research collaborations with numerous international industry partners, including Takeda Pharmaceuticals and Ironwood Pharmaceuticals.

As an indication of clinical translation our group, in collaboration with Ironwood Pharmaceuticals, identified the mechanism of pain relief of a new drug, linaclotide, in treating patients with Irritable Bowel Syndrome with Constipation (IBS-C). Linaclotide, a guanylate cyclase-C (GC-C) agonist is effective in relieving abdominal pain associated with IBS-C and is available and registered for use by IBS-C patients in the USA and Europe.

Research Projects

We have established several novel methods for determining the different functional afferent classes innervating the gut and bladder, the mechanotransduction channels underlying their function, the interaction of these channels with inflammatory mediators, and how this changes during acute and chronic pain.

We are investigating whether mediators and receptors normally associated with itch also apply to the viscera. These projects involve collaborations with Prof Nigel Bunnett (Columbia University), Prof Lin Chang (UCLA) and Dr Daniel Poole (Monash University).

We are interested in the contribution of NaV channels to chronic visceral pain. We recently showed that NaV1.1 contributes to mechanical pain associated with a model of Irritable Bowel Syndrome. These projects involve collaborations with Prof David Julius (UCSF), Prof Glenn King (UQ), Prof Richard Lewis (UQ) and Dr Irina Vetter (UQ).

Alterations in spinal cord processing of visceral afferent signalling during chronic pain
Information on how the spinal cord integrates sensory information from the viscera is lacking. We are investigating how these mechanisms are altered during chronic pain and how they contribute to sensory symptoms.

We are interested in the venom peptides produced by marine animals and how they can be used to investigate and potentially treat chronic pain. We recently showed that Vc1.1, derived from marine cone snail Conus victoriae, has anti-nociceptive actions in models of IBS and in human sensory neurons. These projects involve collaborations with Prof David Adams (Illawarra Health and Medical Research Institute), Prof David Craik (UQ) and Dr Richard Clark (UQ).

We are interested in the oxytocinergic system and its regulation of the viscera. We recently showed that oxytocin analogues inhibit colonic nociceptors during chronic visceral pain, but not in healthy states. These projects involve collaborations with Prof Paul Alewood (UQ) and Dr Markus Muttenthaler (UQ).

We are investigating how infection or inflammation of one organ can profoundly affect the function of adjacent organs and how this results in co-morbidities during chronic visceral pain. We are investigating novel approaches to treat the underlying cause and the associated co-morbidities.

We have implemented optogenetic techniques that will allow us to trigger or inhibit nociceptive signalling from various regions of the viscera. Aspects of these projects involve a collaboration with Prof Nick Spencer (Flinders Uni).

Selected Publications

Castro J, Harrington AM, Garcia-Caraballo S, Maddern J, Grundy L, Zhang J, Page G, Miller P, Craik D, Adams DJ, Brierley SM (2017). α-conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors. Gut, pii: gutjnl-2015-310971. doi: 10.1136/gutjnl-2015-310971 (Epub ahead of print). (Impact factor 14.66)

 

Osteen JD, Herzig V, Gilchrist J, Emrick JJ, Zhang C, Wang X, Castro J, Garcia-Caraballo S, Grundy L, Rychkov GY, Weyer AD, Dekan Z, Undheim EAB, Alewood P, Stucky CL, Brierley S.M, Basbaum AI, Bosmans F, King GF, Julius D (2016). Subtype-selective spider toxins implicate Nav1.1 voltage-gated sodium channels in mechanical pain. Nature, 534(7608):494-9. (Impact factor 41.456)

 

Carstens BD, Berecki G, Daniel JT, Lee HS, Jackson KAV, Tae H-S, Sadegh M, Castro J, O’Donnell T, Deiteren A, Brierley SM, Craik DJ, Adams DJ, Clark RJ (2016). Structure-Activity Studies of Cysteine-Rich α-Conotoxins Targeting the GABAB Receptor Reveal a Minimal Functional Motif. Angew Chem Int Ed Engl., 55(15):4692-6. (Impact factor 11.26)

 

Brust A, Croker DE, Colless B, Ragnarsson-McGrath L, Andersson A, Palant E, Jain K, Garcia-Caraballo S, Castro J, Brierley SM, Alewood PF, Lewis RJ (2016). Conopeptide-derived κ-opioid agonists: design of potent, selective and metabolic stable dynorphine mimetics with anti-nociceptive properties. Journal of Medicinal Chemistry, 59(6):2381-95. (Impact factor 5.447)

 

Dantas de Araujo A, Mehdi Mobli M, Castro J, Harrington AM, Vetter I, Dekan Z, Muttenthaler M, Wan JJ, Lewis RJ, King GF, Brierley SM & Alewood PF (2014). Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain. Nature Communications, 5:3165. (Impact factor 10.015)

 

Brierley SM and DR Linden (2014). Neuroplasticity and dysfunction after gastrointestinal inflammation. Nature Reviews Gastroenterology and Hepatology, 11(10):611-27. (Impact factor: 10.25)

 

Hughes PA, Castro J, Harrington AM, Issacs NJ, Moretta M, Hick GA, Urso D and Brierley SM (2013). Increased kappa-opioid receptor expression and function during chronic visceral hypersensitivity. Gut, 63(7):1199-200. (Impact factor 10.73)

 

Castro J, Harrington AM, Hughes PA, Martin CM, Ge P, Shea CM, Jin H, Jacobson S, Hannig G, Mann E, Cohen MB, MacDougall JE, Lavins BJ, Kurtz CB, Silos-Santiago I, Johnston JM, Currie MG, and Brierley SM (2013). Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic GMP. Gastroenterology, 145(6):1334-46. (Impact factor 12.81)

 

Hughes PA, Harrington AM, Castro J, Liebregts T, Adam B, Grasby DJ, Issacs NJ, Maldeniya L, Martin CM, Persson J, Andrews JM, Holtmann GJ, Blackshaw LA and Brierley SM (2013). Sensory neuro-immune interactions differ between IBS subtypes. Gut, 62(10):1456-65. (Impact factor 10.73)

 


Investigators

  • Stuart M. Brierley, PhD

  • Joel Castro, PhD

  • Andrea Harrington, PhD

  • Luke Grundy, PhD

  • Sonia Garcia Caraballo, PhD

  • Annemie Deiteren, PhD, MD

    Amanda Lumsden, PhD

    Gudrun Schober, PhD

Support Staff

    Tracey O'Donnell, Research Assistant

  • Jessica Maddern, Research Assistant

  • Jessi Moore, Research Assistant

Students

  • Andelain Erickson, PhD Student

    Ashlee Caldwell, PhD Student

    Stefanie Doms, Visiting Masters Student, Leuven, Belgium


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