SLMS Academic Careers Office

Grand Challenges

10. Molecular Control of Pain Processing

Supervisor Pair: Stephen Hunt and Suellen Walker 
Potential Student’s Home Department: Cell and Developmental Biology

Pain is a complex medical and social issue with a poorly defined relationship between injury and the subsequent pain state that can evolve. Chronic pain states can emerge but are poorly controlled by current medications: new treatments are urgently needed. Pain signals generated following injury result in substantial changes in the molecular architecture of the central nervous system. Over time, a complex pattern of gene expression evolves, supporting changes in neuronal sensitivity that amplify incoming pain signals. Disruption of these patterns of gene expression may lead to the maintained sensitization that characterizes chronic pain states and emphasizes the need for a detailed understanding of the molecular changes that follow noxious stimulation.

We have shown that the epigenetic regulator, methyl-CpG binding protein 2 (MeCP2) orchestrates the molecular response to noxious stimulation following injury1,2. Mutations in MeCP2 result in the devastating neurodevelopmental disorder called Rett disease: Rett disease patients also exhibit abnormal sensitivity to pain.  In this project we will be investigating the molecular pathways by which MeCP2 regulates pain sensitivity and which may lead to chronic pain states.

One route to regulate network sensitivity is through the MeCP2-regulated transcription factor Npas4. Expression of Npas4 is known to coordinate the redistribution of inhibitory synapses on hippocampal excitatory neurons3 and may serve the same function in the spinal cord where a heterogeneous population of inhibitory neurons controls the flow of nociceptive information through neural circuits.  We will use a variety of approaches to analyse the balance of inhibition and excitation within the dorsal horn4.  The influence of Npas4 and MeCP2 on pain processing will be monitored behaviourally and electrophysiologically using specific gene knockout approaches in mice. Patterns of inhibition will be investigated by confocal analysis of tissue stained with markers that characterize populations of excitatory neurons and transcription factors, such as Npas4, and allow us to map the distribution of inhibitory synapses. Currently available therapies yield limited success in treating persistent pain states.  Understanding how patterns of inhibition are influenced by noxious stimulation is essential if we are to understand why neural circuits fail and generate chronic pain states.

The initial training for the program of research involving mapping of synaptic connection, confocal microscopy and breeding and behavioural analysis of knockout mice will be carried out in the Primary supervisor’s laboratory at CDB/UCL. Prof. Stephen Hunt’s laboratory has an international reputation in the field of molecular neurobiology particularly in pain research. The student will also benefit from close supervision in molecular biological techniques in laboratory of Dr Sandrine Geranton. The secondary supervisor, Dr Suellen Walker will offer training in electrophysiological techniques for measurements of nociceptive threshold. Dr Walker is also involved in clinical research using quantitative sensory testing (QST) and the student will be exposed to clinical aspects of pain research. The added value of the partnership is a multidisciplinary research environment with regular seminars and facilities shared with four independent research groups working in pain research as well as exposure to clinical research and practice.

1. Geranton, S. M., Morenilla-Palao, C., & Hunt, S. P. (2007). A role for transcriptional repressor methyl-CpG-binding protein 2 and plasticity-related gene serum- and glucocorticoid-inducible kinase 1 in the induction of inflammatory pain states. Journal of Neuroscience, 27(23), 6163–6173.

2. Geranton, S. M. (2012). Targeting epigenetic mechanisms for pain relief. Current Opinion in Pharmacology, 12(1), 35–41.

3. Bloodgood, B. L., Sharma, N., Browne, H. A., Trepman, A. Z., & Greenberg, M. E. (2013). The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature, 503(7474), 121–125.

4. Beggs, S., Currie, G., Salter, M. W., Fitzgerald, M., & Walker, S. M. (2012). Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity. Brain : a Journal of Neurology, 135(2), 404–417.