Neurochemicals in the peripheral nervous system: functions in health and disease
Our studies are mainly concerned with the physiological and pathological roles of neurochemicals in human gut and bladder. Confocal immunohistochemistry is used to map peptides and their receptors, which are characterized using molecular techniques and pharmacological techniques such as radioligand binding, transmitter release and smooth muscle contraction.
Current Projects
Current Projects
Neurochemicals and Receptors in Inflammatory Bowel Disease and Slow Transit Constipation
In this NHMRC-funded study, Lu Liu, Fei Shang and Irit Markusare using a number of techniques to investigate the location, functions and receptors for several neurochemicals, in the human lower gastrointestinal tract. The tachykinin peptides substance P and neurokinin A are both potent in contracting strips of isolated colon muscle, but the contractility is attenuated in diverticular disease and ulcerative colitis. Acetylcholine, acting via several different subtypes of muscarinic receptors, is the major excitatory transmitter in the gut. Continuing studies are being carried out in colon specimens with diverticular disease, Crohn’s disease, ulcerative colitis and chronic constipation, in comparison with age- and region-matched specimens of “normal” colon. Strikingly, certain disease groups have shown very marked differences in response to neurokinin A and changes in affinity of its receptors have been seen in ulcerative colitis. Changes in expression of tachykinin related genes occur in several of the disorders. Recently we have found alterations in expression of connexin (gap junction) proteins and cannabinoid receptors in the mucosal tissue of colonic specimens of slow transit constipation.
 | Immuno-double labelling showing the distribution of Substance P (green) and VIP (red) in human colon myenteric ganglia |
Hemokinin-1 (HK-1), a novel tachykinin, can bind to the same receptor as substance P (SP) and has been shown to elicit similar biological effects. Unlike SP, HK-1 originates from non-neuronal cells. It is hypothesized that some inflammatory actions in the gastrointestinal tract previously attributed to SP may be HK-1 mediated. The aim of Lisa Dai’s study is to measure HK-1 induced changes in prostaglandin E2 (PGE2) production and in PGE2 related enzymes cyclooxygenase (COX) in normal human colon.
Neurochemicals in Human Bladder: Relevance to Incontinence Disorders
Incontinence, although a “taboo subject”, is a debilitating chronic disease responsible for loss of social dignity with major socio-economic costs. Approximately 17% of the population over 40 suffers from this distressing disorder. There is increasing evidence that factors released from the urothelium play an important role in direct signalling to afferent nerves, myofibroblasts and the detrusor muscle. We hypothesise that these processes are altered in different bladder disorders, leading to symptoms of urgency, frequency, painful urge to empty the bladder, and/or urge incontinence. Our study is identifying how muscarinic, vanilloid, purinergic and tachykinin receptor subtypes differ between normal, overactive and painful bladder, thus opening up new directions in the search for effective therapy of these common but often neglected conditions. Kylie Mansfield’s recent work has shown that muscarinic receptors abound in the urothelium (the lining of the bladder) - a tissue thought until recently to be merely an inert barrier. Prajni Sadananda has shown that this layer has contractile properties, and releases the signalling molecule ATP in response to acid and capsaicin, via acid sensitive ion channels (ASICs) and TRPV1.
Bladder Dysfunction in Spinal Cord Injury (SCI) and Multiple Sclerosis (MS)
Bladder and urethral dysfunction is almost universally prevalent in people with disorders of the central nervous system. Modern treatment of neuropathic bladder dysfunction in SCI focuses on lowering intravesical pressures with antimuscarinic drugs to protect renal function, but these drugs have major side effects and don’t work in all patients who therefore are at risk of leakage and kidney damage. Together with A/Prof Richard Millard from POWH, we are investigating receptor changes in biopsy specimens from the bladders of patients with traumatic spinal cord injury, and with multiple sclerosis. We hope to come up with novel and more effective treatments, without side-effects, based on changes in nerve receptors and signalling , for which patients would not require surgical intervention and hospitalisation.
Honours Projects for 2010
Project 1: Cannabinoids produce their biochemical and pharmacological effects by interacting with CB1 and CB2 cannabinoid receptors, both of which belong to G-protein coupled receptor superfamily. CB1 receptors are primarily located in the CNS, but also in peripheral tissues including the enteric nervous system where CB1 receptors regulate intestinal motility and secretion. Our recent studies have shown that CB1 receptors may be implicated in the pathophysiology of slow transit constipation (STC), a severe colonic motility disorder of unknown aetiology predominantly affecting young women. This project will characterise and localise CB1 receptors in human colonic smooth muscle and mucosa of STC in comparison with normal tissue, in order to gain insight into the relationship between the endocannabinoid system and the pathophysiology of STC. Please contact
lu.liu@unsw.edu.au
Project 2: Novel tachykinins in human intestinal function and inflammation. Tachykinins released from enteric nerve system regulate gastrointestinal (GI) motility, secretion, and immune function. The newly discovered tachykinins, hemokinin and endokinins from non-neuronal sources provide a new mechanism in the regulation of intestinal inflammation. In this project, we will characterize and localize novel tachykinin in human colon and investigate their impact on intestinal inflammation. Please contact
lu.liu@unsw.edu.au
Project 3: Role of acid sensing ion channels (ASICs) in the bladder urothelium. Please contact
e.burcher@unsw.edu.au
Skills learnt: Isolated organ pharmacology, radioligand binding, real time PCR, immunohistochemistry, confocal microscopy, and ELISA.
Postdoctoral Position Available
Experienced postdoctoral researcher required to take day-to-day responsibility for an NHMRC-funded project regarding neurochemicals in human and animal bladder. Some liaison will be required with research and hospital staff located in other institutions. Please contact
e.burcher@unsw.edu.au
Researchers
Members of the Group
Prof Elizabeth Burcher, NHMRC Principal Research Fellow
Dr Lu Liu, Senior Lecturer
Dr Kylie Mansfield, Senior Lecturer
Dr Fei Shang, Research Assistant
Irit Markus, Research Assistant
Prajni Sadananda, Postrgraduate Student
Lisa Dai, Postgraduate Student
Other Collaborators
A/Prof Kate Moore, Dr Ying Cheng, Pelvic Floor Unit, St George Hospital, Sydney
A/Prof Denis King, Dr David Lubowski, St George Hospital, Sydney
A/Profs Richard Millard, Robert Farnsworth, Prince of Wales Hospital, Sydney
Dr Ken Vaux, Adventist Hospital, Sydney
Dr Bridget Southwell, Murdoch Children's Research Inst, Melbourne
Some Recent Publications
Burcher, E., Zeng, X.-P., Strigas, J., Shang, F., Millard, R.J. & Moore, K.H. (2000) Autoradiographic localization of tachykinin and calcitonin gene-related peptide receptors in adult urinary bladder. J. Urol. 163: 331-337.
Lee, C.M., Kumar, R., Lubowski, D.Z. & Burcher, E. (2002) Neuropeptides and nerve growth in inflammatory bowel diseases: A quantitative immunohistochemical study. Dig. Dis. Sci. 47, 495-502.
Liu, L., Shang, F., Markus, I. & Burcher, E. (2002) Role of substance P in the human colon: alterations in disease. J. Pharmacol. Exp. Ther. 302, 627-635.
Warner, F.W., Shang, F., Millard, R.J. & Burcher, E. (2002) Enhancement of neurokinin A-induced smooth muscle contraction in human urinary bladder by mucosal removal and phosphoramidon: relationship to peptidase inhibition. Eur. J. Pharmacol. 438, 171-177.
Liu, L., Markus, I., Vandenberg, R.J., Neilan, B.A., Murray, M. & Burcher, E. (2004) Molecular identification and characterization of three isoforms of tachykinin NK1-like receptors in the cane toad, Bufo marinus. Am. J. Physiol. Reg. Int. Comp. 287, R575-585.
Mansfield, K.J., Liu, L., Mitchelson, F.J., Moore, K.H., Millard, R.J. & Burcher, E. (2005) Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: Changes in ageing. Br. J. Pharmacol. 144, 1089−1099.
Liu, L., Mansfield, K.J., Kristiana, I., Vaux, K.J., Millard, R.J. & Burcher, E. (2007) The molecular basis of urgency: Regional difference of vanilloid receptor expression in the human urinary bladder. Neurology & Urodynamics 26, 433-438.
Burcher E, Shang F, Warner FJ, Du Q, Lubowski DZ, King DW, Liu L (2008) Tachykinin NK2 receptor and functional mechanisms in human colon: changes with indomethacin and in diverticular disease and ulcerative colitis. J. Pharmacol. Exp. Ther. 324, 170-178.
Sadananda, P., Chess-Williams, R., Burcher, E. (2008) Contractile properties of the pig bladder mucosa in response to neurokinin A: a role for myofibroblasts? Br J Pharmacol 153, 1465-1473.
Mansfield, K.J., Chandran, J.J., Vaux, K.J., Millard, R.J., Christopoulos, A., Mitchelson, F.J., Burcher, E. (2009) Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa. J. Pharmacol. Exp. Ther. 328, 893-899.