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Visceral Neurophysiology Laboratory

pain, enteric nervous system, nociceptors, colon, peristalsis...

A micrograph displaying immuno-reactive neurons to calcitonin gene-related peptide (red), and nitric oxide synthase (green) within the myenteric plexus of the mouse colon


Research Summary

Pain is an essential component of life. It is a protective sensation that informs us to avoid harmful situations and tissue damage. Noxious stimuli are vital to tell us when a particular movement or task is putting too much strain (or potential damage) on our bodies. Nociceptors are sensory receptors whose transduction sites respond to potentially damaging (painful) stimuli by sending action potentials to the spinal cord and brain. This process is referred to as nociception.

In skin, there is an extensive knowledge about the different types of sensory nerve endings and which specific types of sensory endings respond to which particular stimuli. This is not the case for internal organs. In fact, very little is known about the different types of sensory endings that innervate any of the internal organs in mammals (such as the GI-tract) and even less is known about how disease states, such as inflammatory bowel disease, cause these nerve endings to become hyperexcitable, leading to increased pain sensations. This is problematic if we are to develop analgesics that selectively target pain fibres to improve quality of life, because it is important to know how and where the nerve endings that detect painful stimuli exist in the peripheral organ. Our striking lack of understanding about which sensory nerves detect pain from any internal organ has largely arisen because of the lack of techniques available to visualize only the nerve endings that detect pain.

Research Projects

In 2015, we commenced an exciting collaboration with Dr Hongzhen Hu at Washington University, in St. Louis, Mo. USA. This project has been the first to demonstrate that fluorescent light can be used to activate specific populations of enteric neurons that underlie propulsive contractions of the gastrointestinal tract. This very exciting technique will involve implanting wireless light emitting diodes (LEDs) into mammals, for the wireless control of gastrointestinal motility.

We have recently developed a new technique, whereby it is possible for the first time, to identify the different types of spinal afferent nerve endings that innervate internal organs. This is of supreme interest to us, because the identity, location, neurochemistry and morphology of the nerve endings that detect pain from internal organs, such as the GI-tract, has been a major unanswered question. The major aims of this project are to identify the sites of innervation of the pain fibres throughout the gastrointestinal tract, bladder and uterus and how these nerve endings are activated with the use of calcium imaging.

We have made a recent breakthrough regarding serotonin (5-HT) in the gut wall. It has long been thought that since antagonists of 5-HT receptors block peristalsis that 5-HT must be an important transmitter underlying the generation of peristalsis. We found recently that total depletion (confirmed with mass spectrometry) of endogenous 5-HT did not block peristalsis. In fact it has very minor effects on peristalsis. Also, we found antagonists of 5-HT receptors still blocked peristalsis every when there was no detectable 5-HT in the gut wall. endogenous 5-HT was not a major player in gut motility.

The aims of this project are to characterize the mechanisms by which the nerve endings of spinal afferents transduce nociceptive stimuli into action potentials in the gastrointestinal tract. We use a novel imaging technique, which allows us to visualize activity directly within the spinal afferent endings that detect noxious the major ionic mechanisms underlying their activation.

Recording dynamic changes in intracellular calcium from the nerve endings of CGRP expressing sensory fibres in transgenic CGRP alpha reporter mice
We have generated and published development of a novel transgenic mouse that expressed the red fluorescent protein (mCherry) driven by the CGRP alpha promoter. This allows us for the first time to visualise and then record in live tissue from the nerve endings of nociceptive fibres that express the CGRP alpha gene. This is a major new step forward in recording from spinal afferent nerve endings in visceral organs.

Our laboratory was the first to isolate and record from the isolated whole human colon see (Dinning et al. 2016). This new technique is very exciting because for the first time, we record from the conscious human patient characterize the specific patterns of motor activity that exist in isolated human colon and how these patterns differ in disease states such as ulcerative colitis and Crohn’s disease.

The gut wall contains a complete network of intrinsic nerves capable of propelling contents along the bowel, without any requirement of nerves originating in the brain or spinal cord. Work in our laboratory aims to understand how intrinsic nerves in the gut wall are activated to cause the contents within the bowel to be propelled from one region to another. Our current research projects, broadly address two fundamental area of interest:
1. mechanisms of activation of spinal afferent pain pathways following colo-rectal distension and in response to intestinal inflammation, and
2. the intrinsic neuronal mechanisms underlying colonic propulsion.

Our broad underlying goal is to determine the mechanisms of activation of intrinsic neural networks, underlying complex propulsive motor patterns in the large intestine (such as the migrating motor complex) and how these neural networks become dysfunctional in a variety of complex disease states. We use a variety of novel techniques, including in vivo and in vitro imaging of intracellular calcium, video imaging and spatio-temporal mapping of the colonic wall movements and EMG recordings from mutant mice that lack visceral pain detection.

The aims of this project are to determine how the loss of intrinsic neurons with age leads to impaired colonic motility and the onset of chronic constipation. We have a colony of spontaneous mutant mice that lack a specific gene responsible for development.

Selected Publications

Costa M, Wiklendt L, Keightley L, Brookes SJH, Dinning PG, Spencer NJ (2017) New insights into neurogenic cyclic motor activity in the isolated guinea-pig colon. Neurogastroenterol Motil. [Epub ahead of print]


Hibberd TJ, Costa M, Travis L, Brookes SJH, Wattchow DA, Feng J, Hu H, Spencer NJ (2017) Neurogenic and myogenic patterns of electrical activity in isolated intact mouse colon. Neurogastroenterol Motil. [Epub ahead of print]


Martin AM, Young RL, Leong L, Rogers GB, Spencer NJ, Jessup CF, Keating DJ (2017) The diverse metabolic roles of peripheral serotonin. Endocrinology. [Epub ahead of print]


Nicholas S, Yuan SY, Brookes SJ, Spencer NJ, Zagorodnyuk VP (2017) Hydrogen peroxide preferentially activates capsaicin-sensitive high threshold afferents via TRPA1 channels in the guinea pig bladder. Br J Pharmacol, 174(2):126-138


Martin AM, Lumsden AL, Young RL, Jessup CF, Spencer NJ, Keating DJ (2017) The nutrient-sensing repertoires of mouse enterochromaffin cells differ between duodenum and colon. Neurogastroenterol Motil, 29(6)


Martin AM, Lumsden AL, Young RL, Jessup CF, Spencer NJ, Keating DJ (2017) Regional differences in nutrient-induced secretion of gut serotonin. Physiol Rep, 5(6):e13199


Sorensen J, Wiklendt L, Hibberd T, Costa M, Spencer NJ (2017) Techniques to identify and temporally correlate calcium transients between multiple regions of interest in vertebrate neural circuits. J Neurophysiol, 117(3):885-902


Spencer NJ (2016) Motility patterns in mouse colon: gastrointestinal dysfunction induced by anticancer chemotherapy. Neurogastroenterol Motil, 28(12):1759-1764


Spencer NJ, Keating DJ (2016) Is There a Role for Endogenous 5-HT in Gastrointestinal Motility? How Recent Studies Have Changed Our Understanding. Adv Exp Med Biol, 891:113-22


Spencer NJ, Zagorodnyuk V, Brookes SJ, Hibberd T (2016) Spinal afferent nerve endings in visceral organs: recent advances. Am J Physiol Gastrointest Liver Physiol, 311:G1056-G1063


Spencer NJ, Sorensen J, Travis L, Wiklendt L, Costa M, Hibberd T (2016) Imaging activation of peptidergic spinal afferent varicosities within visceral organs using novel CGRPα-mCherry reporter mice. Am J Physiol Gastrointest Liver Physiol, 311(5):G880-G894


Spencer NJ, Dinning PG, Brookes SJH and Costa M (2016) Insights into the mechanisms underlying colonic motor patterns. J Physiol (Lond), 594(15):4099-4116


Spencer NJ, Kyloh M, Beckett EA, Brookes S, Hibberd T (2016) Different types of spinal afferent nerve endings in stomach and esophagus identified by anterograde tracing from dorsal root ganglia. J Comp Neurol, 524(15):3064-3083


Hibberd TJ, Kestell GR, Kyloh MA, Brookes SJH Wattchow DA & Spencer NJ (2016) Identification of different functional types of spinal afferent neurons innervating the mouse large intestine using a novel CGRPα transgenic reporter mouse. Am J Physiol Gastrointest Liver Physiol, 310(8):G561-73


Dinning PG, Sia TC, Kumar R, Mohd Rosli R, Kyloh M, Wattchow DA, Wiklendt L, Brookes SJ, Costa M, Spencer NJ (2016) High-resolution colonic motility recordings in vivo compared with ex vivo recordings after colectomy, in patients with slow transit constipation. Neurogastroenterol Motil, 28(12):1824-1835


Arkwright JW, Underhill ID, Dodds KD, Brookes SJ, Costa M, Spencer NJ, Dinning PG (2016) A composite fibre optic catheter for monitoring peristaltic transit of intra-luminal content. J Biomedical Optics, 9(3):305-10


Brookes S, Chen N, Humenick A, Spencer NJ, Costa M (2016) Extrinsic Sensory Innervation of the Gut: Structure and Function. Adv Exp Med Biol, 891:63-9


Dalziel JE, Young W, Bercik P, Spencer NJ, Ryan LJ, Dunstan KE, Lloyd-West CM, Gopal PK, Haggarty NW, Roy NC (2016) Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility. Neurogastro-enterol Motil, 28(8):1241-51


Spencer NJ (2015) Constitutively active 5-HT Receptors: An Explanation of How 5-HT Antagonists Inhibit Gut Motility in Species Where 5-HT is Not an Enteric Neurotransmitter? Frontiers in Cellular Neuroscience, 9:487


Sharrad DF, Hibberd TJ, Kyloh M, Brookes SJ and Spencer NJ (2015) Quantitative immunohistochemical co-localization of TRPV1 and CGRP in varicose axons of the murine oesophagus, stomach and colorectum. Neuroscience Letters, 599:164-171


Kuizenga MH, Sia TC, Dodds KN, Wiklendt LS, Arkwright JW, Thomas AC, et al. (2015) Neurally mediated propagating discrete clustered contractions superimposed on myogenic ripples in ex vivo segments of human ileum. American Journal of Physiology-Gastrointestinal and Liver Physiology, 308(1):G1-G11


Barnes KJ, Spencer NJ (2015) Can colonic migrating motor complexes occur in mice lacking the endothelin-3 gene? Clinical and experimental pharmacology & physiology, 42(5):485-95


Humenick A, Chen BN, Wiklendt L, Spencer NJ, Zagorodnyuk VP, Dinning PG, Costa M, Brookes S (2015) Activation of intestinal spinal afferent endings by changes in intra-mesenteric arterial pressure. Journal of Physiology, 593(16):3693-709


Zelkas L, Raghupathi R, Lumsden AL, Martin AM, Sun E, Spencer NJ, Young RL, Keating DJ (2015) Serotonin-secreting enteroendocrine cells respond via diverse mechanisms to acute and chronic changes in glucose availability. Nutrition & Metabolism (London), 12:55


Costa M, Wiklendt L, Simpson P, Spencer NJ, Brookes SJ, Dinning PG (2015) Neuromechanical factors involved in the formation and propulsion of fecal pellets in the guinea-pig colon. Neurogastroenterology & Motility, 27(10):1466-77


Spencer NJ, Sia TC, Brookes SJ, Costa M, Keating DJ (2015) Rebuttal from Nick Spencer, Tiong Cheng Sia, Simon Brookes, Marcello Costa and Damien Keating. Journal of Physiology, 593(15):3235


Spencer NJ, Sia TC, Brookes SJ, Costa M, Keating DJ (2015) CrossTalk opposing view: 5-HT is not necessary for peristalsis. Journal of Physiology, 593(15):3229-31


Humenick A, Chen BN, Wiklendt L, Spencer NJ, Zagorodnyuk VP, Dinning PG, Costa M, Brookes SJ (2015) Activation of intestinal spinal afferent endings by changes in intra-mesenteric arterial pressure. Journal of Physiology, 593(16):3693-709


Kyloh M & Spencer NJ (2014) A novel anterograde neuronal tracing technique to selectively label spinal afferent nerve endings that encode noxious and innocuous stimuli in visceral organs. Neurogastroenterology & Motility, 26(3):440-4


Dalziel J, Spencer N, Dunstan K, Lynch A, Haggarty N, Gopal P, Roy NC (2014) An in vitro rat model of colonic motility to determine the effect of b-casomorphin-5 on propagating contractions. Food and Function, 5(11):2768-2774


Herweijer G, Kyloh M, Beckett E, Dodds K and Spencer N (2014) Characterization of primary afferent spinal innervation of mouse uterus. Frontiers in Neuroscience, 8(202):1-6


Barnes K, Beckett E, Brookes S, Sia T and Spencer N (2014) Control of intrinsic pacemaker frequency and velocity of colonic migrating motor complexes in mouse. Frontiers in Neuroscience, 8(96):1-8


Carbone SE, Wattchow DA, Spencer NJ, Hibberd TJ and Brookes SJ (2014) Damage from dissection is associated with reduced neuro-musclar transmission and gap junction coupling between circular muscle cells of guinea pig ileum, in vitro. Frontiers in Psychology, 5(319)


Spencer N, Kyloh M and Duffield M (2014) Identification of different types of spinal afferent nerve endings that encode noxious and innocuous stimuli in the large intestine using a novel anterograde tracing technique. PLoS One, 9(11): e112466


Dinning PG, Wiklendt LS, Omari TI, Arkwright JW, Spencer NJ, Brookes SJ, et al (2014. Neural mechanisms of peristalsis in the isolated rabbit distal colon: A neuromechanical loop hypothesis. Frontiers in Neuroscience, 8(75)


Hibberd T, Spencer N, Zagorodnyuk V, Chen B and Brookes S (2014) Targeted electrophysiological analysis of viscerofugal neurons in the myenteric plexus of guinea-pig colon. Neuroscience, 275:272-284



  • Nick Spencer, PhD

  • Tim Hibberd, PhD

  • David Wattchow, MBBS, PhD, FRACS

Support Staff

  • Melinda Kyloh, Research Assistant

  • Lee Travis, Research Assistant

  • Lauren Keightley, Research Assistant


  • Raghu Kumar, PhD Student

  • Alyce Martin, PhD Student (co-supervised with Damien Keating, Molecular & Cellular Physiology Lab)

  • Emily Sun, PhD Student

  • Reizal Mohdrosli, PhD Student

    Dr David Smolilo, PhD Student

    Alice Short, Honours Student

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