Professor Steve McMahon
Stephen B McMahon, FMedSci, FSB
Stephen McMahon is Sherrington Professor of Physiology at King’s College London, and Director of the London Pain Consortium. He is a neuroscientist who trained with Patrick Wall in the 1980s. He is principally interested in somatosensory systems and actively engaged in work ranging from molecular biology to electrophysiology to human psychophysical studies. He has published more than 250 original research articles, many highly rated (H-index >80) and is co-editor of the Textbook of Pain. His work has been published in leading scientific journals including, Nature, Nature Medicine, Science, Nature Neuroscience, Cell, Neuron and Brain. He is the holder of a Wellcome Trust Senior Investigator Award and a Fellow of the Academy of Medical Sciences
His major interest is in pain mechanisms. He was the principal investigator (PI) on a major grant from the Wellcome Trust in 2002 to establish the London Pain Consortium (LPC), of which he is the Scientific Director. Further funding from the Wellcome Trust, most recently in the form of a 5 year Strategic Award, in May 2008, on which he was again the PI, supports continuing research activity and a 4-year PhD training programme. Total support for the LPC currently exceeds £13m. He is also the academic lead of an EU consortium, Europain, which is a private-public partnership funded under the Innovative Medicines Initiative (IMI) scheme. This brings together a large group of academic scientists working in Europe with a group of pharmaceutical companies with an interest in analgesic drug development. Europain receives €6m support from the EU and €13.5m from industry and is undertaking precompetitive clinical and preclinical research aimed at improving understanding and treatment of chronic pain.
Both of these collaborations (the London Pain Consortium and Europain) involve a series of interlinked and mutually supportive programmes of experimental research, underpinned and supported by a coordinated training and bioinformatics facility. There are considerable synergies between the programmes. About half of the research activity is focused on the study of pain in preclinical models, with the major aims of: identifying novel pain mediators; elucidating the peripheral and central nervous system changes contributing to pain; improving and refining animal models of pain and the measurement of pain in these models. The other half of the research activity explores pain mechanisms in humans, with the major aims of: establishing and validating mechanism-based pain models in human volunteers; finding objective measures of spontaneous pain; collecting detailed phenotypic data on chronic pain patients; and determining psychosocial, genetic and clinical risk factors for development of chronic pain.
Pain, Injury and Repair of the Damaged Nervous System
A recent European survey of more than 45,000 people in 16 countries revealed that almost 1 in 5 of the European population suffers chronic pain – moderate or severe pain persisting for more than 6 months (http://www.painineurope.com). The prevalence of chronic pain increases dramatically with age. It represents a huge pool of human suffering. Our ability to treat these chronic pain conditions is currently limited. A large part of my research aims at understanding the neuronal mechanisms of chronic pain. Some of the most intractable pain states are associated with damage to the nervous system itself. A second major focus of my laboratory is to develop methods to promote repair of such damage.
Nerve growth factor and pain
Nerve Growth Factor is a naturally occurring protein, which, as its name suggests, plays an important role in the development of the nervous system. We have found that in some disease states and after some types of injury, the levels of NGF rise in the affected tissues.
This extra NGF has short-term and long-term actions on the nervous system. First, NGF activates and sensitizes pain-signalling sensory nerves (so-called nociceptors). This results in abnormal sensory nerve traffic, which is perceived as pain. NGF also binds to receptors on sensory nerve terminals, and is transported to the sensory neuron where it increases the expression of many gene products including receptors, ion channels & neurotransmitters. In this way, NGF has a prolonged effect on the way nociceptors respond to and signal information about tissue damage. We have shown that neutralising NGF’s actions may be a novel way treating chronic pain
Brain-derived neurotrophic factor and pain.
We have shown that this protein (BDNF) is manufactured in the cell body of nociceptors acts as a neurotransmitter, conveying messages to neurones in the spinal cord that signal pain-related information. In some chronic injury states, BDNF levels are very markedly increased in sensory nerves,
and in these states BDNF seems to play an even more prominent role as a central signalling molecule of pain. Interestingly, the most important regulator of BDNF levels seems to be NGF. So there is a chain of events involving neurotrophic factors:
1) damage to tissues in the body can lead to increased NGF production; 2) this in turn leads to increased BDNF production in some of the nociceptors; 3) activity in the nociceptors now releases more BDNF into the spinal cord; 4) this carries the message to the brain that tissue damage has occurred.
Spinal cord injury
There are no effective treatments to promote the repair of spinal cord injuries, so sufferers face a lifetime of disability
Many also experience chronic pain. We are currently exploring a number of approaches to repair spinal cord injuries. We have shown, in preclinical models, that one form of spinal injury – avulsion of nerve roots – can be treated with neurotrophic factors. These factors are insufficient to repair injures of the spinal cord itself. An important reason seems to be the inhibitory nature of the glial scar that forms at the site of central nervous system lesions. With Dr Elizabeth Bradbury, we have shown that degrading one component of the glial scar – chondroitin sulphate proteoglycans – enables regeneration of damaged central neurones and restitution of some sensory and motor behaviours.
Epigenetics and pain
We know from the study of twins that our genes play a role in determining our pain thresholds and may predispose us to develop certain chronic pain conditions. There are also many environmental risk factors, such as smoking or obesity. Yet, the mechanisms through which they might exert their influence – often only after many years – are still unknown. One possibility is that epigenetic processes, such as histone modifications or DNA methylation, are involved.
Epigenetics is the study of heritable or stable changes in gene function that do not affect the sequence itself. For instance, histone acetylation will affect the spacing of DNA and help recruit transcription factors, which in turn influences which parts of the sequence are used at any given time.
We have found evidence that this process of acetylation is changed in models of chronic neuropathic pain, and that interfering with this process using drugs (HDAC inhibitors) can reduce pain-like behaviours. We are now exploring this further to examine whether other epigenetic mechanisms are involved and to what extent they might help determine who does or does not develop chronic pain.
Chemokines and pain
Chemokines are small signalling proteins which are known to attract immune cells to sites of inflammation and injury. Chemokines can be secreted by immune cells, glia and neurons. Expression of most chemokines is usually low. However, following injury and inflammation, chemokine signalling is upregulated.
Enhanced chemokine signalling can lead to increased neuronal excitability, and subsequently intensified pain. It is unclear whether chemokines act directly on neurons to induce these effects, or whether they act indirectly via the immune cells they attract to sites of injury.
We have used a translational UVB burn model to show that the chemokine CXCL5 ,derived from infiltrating immune cells, is a key mediator of inflammatory pain in both humans and rats. Our focus now is to explore the relative contributions of neuronal and non-neuronal chemokine signalling in pain.
- Caroline Abel - External Funding Liaison Officer
- Dr Ana Antunes-Martins - Post Doctoral Researcher
- Vivien Cheah - Administrator
- Dr Carla Cox - Post Doctoral Researcher
- Dr Megan Crow - Post Doctoral Researcher
- Dr Franziska Denk - Post Doctoral Researcher
- John Grist - Laboratory Manager
- Holly Hopkins - PhD student
- Jayne Kelleher - PhD student
- Federica LaRusa - PhD student
- Sheridan McMurray - PhD student
- Ifeoma Offiah - PhD student
- Kathryn Paterson - Research Assistant/ Part-time PhD student
- Dr Martin Smith - Post Doctoral Researcher
- Dr Matthew Thakur - Post Doctoral Researcher
- 2010 Restoration of spinal cord injury induced by Neuronal Calcium Sensor 1. Yip PK, Wong L-F, Sears T, Yanez R. McMahon S. Cortical overexpression of neuronal calcium sensor 1 induces functional plasticity in spinal cord following unilateral pyramidal tract injury in rat. PLoS Biology. 2010 Jun 22;8(6):e1000399
- 2007 Demonstration of heritability of pain traits. Norbury TA, MacGregor AJ, Urwin J, Spector TD, McMahon SB. Heritability of responses to painful stimuli in women: a classical twin study. Brain. 2007 Nov;130(Pt 11):3041-9. Epub 2007 Oct 11
- 2006 Demonstration that Retinoic acid receptor β2 can promote CNS repair. Wong LF, Yip PK, Battaglia A, Grist J, Corcoran J, Maden M, Azzouz M, Kingsman SM, Kingsman AJ, Mazarakis ND, McMahon SB. Retinoic acid receptor beta2 promotes functional regeneration of sensory axons in the spinal cord. Nat Neurosci. 2006 Feb;9(2):243-50. Epub 2005 Dec 25
- 2005 Editor of Wall and Melzack’s Textbook of Pain (Elsevier Press, London) McMahon SB., Bennett DHL. & Bevan S (2006). Inflammatory mediators and modulators of pain. In McMahon SB. and Koltzenburg M. (eds) Wall and Melzack’s Textbook of Pain, Churchill Livingstone, London, 5th Edition, publication date August 2006
- 2003 Demonstration that Ephrins modulate spinal nociceptive processing. Battaglia AA, Sehayek K, Grist J, McMahon SB, Gavazzi I. EphB receptors and ephrin-B ligands regulate spinal sensory connectivity and modulate pain processing. Nat Neurosci. 2003 Apr;6(4):339-40
- 2002 Repair of spinal cord injury with chondroitinase treatment.
Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW, McMahon SB. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature. 2002 Apr 11;416(6881):636-40
- 2002 Demonstration of abnormal purinergic functions in patients with idiopathic detrusor instability. O'Reilly BA, Kosaka AH, Chang TK, Ford AP, Popert R, Rymer JM, McMahon SB. A quantitative analysis of purinoceptor expression in human fetal and adult bladders. J Urol. 2001 May;165(5):1730-4
- 2000 Demonstration that GDNF can treat experimental neuropathic pain.
Boucher TJ, Okuse K, Bennett DL, Munson JB, Wood JN, McMahon SB. Potent analgesic effects of GDNF in neuropathic pain states. Science. 2000 Oct 6;290(5489):124-7
- 2000 Identification of ATP acting on P2X3 receptors as peripheral mediator of micturition. Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit WG, Burnstock G, McMahon SB, Ford AP. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature. 2000 Oct 26;407(6807):1011-5
- 2000 First report of growth across dorsal root entry zone in adult animals (trophic factor induced) Ramer MS, Priestley JV, McMahon SB. Functional regeneration of sensory axons into the adult spinal cord. Nature. 2000 Jan 20;403(6767):312-6
- 1999 Identification of BDNF as an important spinal pain modulator.
Thompson SWN., Bennett DLH., Kerr BJ., Bradbury EJ. & McMahon SB. (1999). BDNF is an endogenous modulator of nociceptive responses in the spinal cord. Proceedings of the National Academy of Sciences. USA. 96(14):7714-7718
- 1998 Influential review of nociceptor function. Snider WD, McMahon SB.Tackling pain at the source: new ideas about nociceptors. Neuron. 1998 Apr;20(4):629-32. Review
- 1995 Demonstration that NGF is an important pain mediator.
McMahon SB, Bennett DL, Priestley JV, Shelton DL. The biological effects of endogenous nerve growth factor on adult sensory neurons revealed by a trkA-IgG fusion molecule. Nat Med. 1995 Aug;1(8):774-80
- 1994 Characterisation of role of NGF with null mutant mice.
Crowley C, Spencer SD, Nishimura MC, Chen KS, Pitts-Meek S, Armanini MP, Ling LH, McMahon SB, Shelton DL, Levinson AD, et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell. 1994 Mar 25;76(6):1001-11
- 1994 First mapping on neurotrophin receptors by adult sensory neurones. McMahon SB, Armanini MP, Ling LH, Phillips HS. Expression and co-expression of Trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets. Neuron. 1994 May;12(5):1161-71
- 1994 Role of activity-dependent mechanisms in generation of spinal cord somatotopically. Lewin GR, Mckintosh E, McMahon SB. NMDA receptors and activity-dependent tuning of the receptive fields of spinal cord neurons. Nature. 1994 Jun 9;369(6480):482-5
- 1993 Role of neurotrophins as motoneuron survival factors. Henderson CE, Camu W, Mettling C, Gouin A, Poulsen K, Karihaloo M, Rullamas J, Evans T, McMahon SB, Armanini MP, et al. Neurotrophins promote motor neuron survival and are present in embryonic limb bud. Nature. 1993 May 20;363(6426):266-70
- 1989 Demonstration that peripheral target fields regulate spinal reflex organisation. McMahon SB, Wall PD. Changes in spinal cord reflexes after cross-anastomosis of cutaneous and muscle nerves in the adult rat. Nature. 1989 Nov 16;342(6247):272-4. Erratum in: Nature 1989 Dec 21-28;342(6252):958
- 1987 Spinal cord plasticity driven by noxious stimulation. Cook AJ, Woolf CJ, Wall PD, McMahon SB. Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input. Nature. 1987 Jan 8-14;325(7000):151-3
- 1983 Description of a novel spinal pathway important in pain processing. McMahon SB, Wall PD. A system of rat spinal cord lamina 1 cells projecting through the contralateral dorsolateral funiculus. J Comp Neurol. 1983 Feb 20;214(2):217-23