4 YEAR PhD IN NEUROSCIENCE
Institute of Child Health
Pain continues to be a leading health problem and several recent epidemiological surveys have consistently shown that the overall prevalence of chronic pain in the general populations is around 20%. Careful clinical studies of patients in chronic pain have identified the increased excitability of nociceptive primary sensory neurons as the primary culprit. We therefore examine the receptors and ion channels that control the excitability of these neurons with the aim to identify suitable targets for novel analgesic drugs (http://www.ich.ucl.ac.uk/ich/academicunits/Neural_plasticity/Homepage). Transient receptor potential (TRP) channels, including the prototypical TRPV1 - the receptor that mediates the pungency of capsaicin, the hot ingredient of chili pepper, have emerged as principle transducers that determine the receptive properties of sensory neurons. Moreover, sodium and potassium channels are differentially expressed in sensory neurons signaling pain.
We use a range of techniques to comprehensively analyze the properties of these sensory neurons. We use extracellular recordings in a skin nerve in vitro preparation to investigate the properties of sensory neurons in wild type and mutant mice. Cultured sensory neurons are used for whole cell patch clamp recordings and calcium imaging. These techniques are used in combination with laser micro dissection and quantitative rtPCR to profile the gene expression pattern in distinct neuronal subpopulations. Using psychophysical methods, and evoked potential techniques we also investigate how changes in sensory neuron properties affect the pain perception of humans.
1.) Neurotrophic factors are essential for the survival of sensory neurons during development. Lack of NGF or its cognate high affinity receptor trkA results in the embryonic death of nociceptors and therefore cause congenital insensitivity to pain. Neurotrophins continue to modulate the properties of nociceptors throughout life, but analysis of this has been hampered by the lack of specific pharmacological tools. Using novel knockin mice and treatment with modified kinase blocking molecules a new opportunity has arisen to specifically and reversibly block trk signaling. We will use this approach to determine how signaling through trkA, trkB or trkC modulates the sensitivity of nociceptive and non-nociceptive sensory in the adult.
2.) One of the peculiar properties of nociceptors is their activity dependent change of conduction velocity. We have recently shown that this is caused by periods of prolonged hyperpolarization which in turn strongly reduces the excitability of nociceptors, but not of non-nociceptive afferents to adequate stimuli. The specific and global control of nociceptor excitability makes this hitherto unrecognized principle a novel eminent target for the control of pain at source and we will investigate the mechanisms that underlie this unique feature of nociceptors.
3.) Little is known how the functional properties of sensory neurons emerge during embryogenesis. We have recently shown that TRP channel expression appears in waves from the time the DRG anlagen are formed to early postnatal life. This functional maturation is replicated by neural stem cells which differentiate into sensory neurons. We will examine the factors that control the development of multiple sensory phenotypes, particularly of nociceptors and thermoreceptors.
A. Leffler, B. Mönter, M. Koltzenburg (2006)
The role of TRPV1 and ASIC-subunits in proton sensitivity of subpopulations of primary nociceptive neurons in rats and mice
Neuroscience, 139 (2006) 699-709
C. Munns, M. AlQatari, M.Koltzenburg (2006)
Many cold-sensitive peripheral neurons of the mouse do not express TRPM8 or TRPA1
Cell Calcium, Aug 30; [Epub ahead of print]
S.P. Hunt, M. Koltzenburg (2005)
Neurobiology of Pain
Oxford: Oxford University Press, 1-403
J. Hjerling-Leffler, F. Marmigère, M. Heglind, A. Cederberg, M. Koltzenburg, S. Enerbäck, P. Ernfors (2005)
The boundary cap: a source of neural crest stem cells generating multiple sensory neuron subtypes
Development 132 (2005) 2623-2632
M.J. Caterina, A. Leffler, A.B. Malmberg, W.F. Martin, J. Trafton, K. Petersen-Zeitz, M. Koltzenburg, A.I. Basbaum, D. Julius, (2000)
Impaired nociception and pain perception in mice lacking the capsaicin receptor,
Science, 288 (2000) 306-313.