4 YEAR PhD IN NEUROSCIENCE
Department of Cell and Developmental Biology
The molucular neurobiology of pain and affective disorders
1) The Neurobiology of Substance P
Using molecular techniques that 'knockout' the substance P receptor gene we showed that the idea that substance P was causal in acute pain perception was almost certainly incorrect. Instead of released substance P being a 'pain signal' within the nervous system, we have shown that substance P is an important component of a defensive system brought into play following the appearance of danger in the environment. This system is predominantly motivational and is central to the development of many affective and addictive disorders as well as modifying the response to pain. We have therefore examined a number of neurobiological sequelae of affective disorders including neurogenesis in the hippocampus, activity of the stress pathways and the behavioural response to addictive drugs. More recently we have begun to look at the role of genetic background in the expression of particular behaviours such as sensitization to opiates and response to novelty and found a strong effect of genotype. The project will be to look at the relationship between dopaminergic and noradrenergic neurons and substance P using confocal microscopy and neuronal tracing techniques and by quantifying neurogenesis. Many affective disorders such as depression are thought to be, in part, a disruption of monoaminergic transmission. It is therefore essential to know where NK1 receptors are located and thus to understand how substance P modulates monoamines and behaviour.
2) Molecular changes in the spinal cord and sensory neurons induced by painful stimulation.
There are two aspects to this work. First, we have identified a series of molecular changes that are essential to maintaining chronic pain states in the dorsal horn of the spinal cord. We will continue to explore these changes and their relationship to synaptic plasticity. It seems very likely from preliminary work that the types of molecular change seen in the spinal cord mirror those seen in the hippocampus following long-term potentiation (LTP) and also that are disrupted in particular types of human mental retardation such as Rett syndrome. Second, we are looking at the potential for sensory fibres that respond to noxious stimulation, to synthesize proteins at their axon terminals within the skin and other tissues. Local translation has previously been identified in axons of Aplysia and in hippocampal dendrites where it is required for maintenance of LTP. Our research suggests that local translation of protein and other biochemical mechanisms such as ubiquitination are essential processes regulating sensory neuron sensitivity. To examine molecular changes and their influence on pain processing we will use a variety of molecular, behavioural and biochemical approaches coupled with visualization of different molecules using confocal microscopy and in situ hybridization. A key question will be to identify mRNA that is transported from the sensory neuron cell body to its endings in the skin.
Rygh LJ, Suzuki R, Rahman W, Wong Y, Vonsy JL, Sandhu H, Webber M, Hunt S, Dickenson AH. (2006)
Local and descending circuits regulate long-term potentiation and zif268 expression in spinal neurons.
European J Neuroscience 24:761-72
Gadd C A, Murtra P, De Felipe C & Hunt SP. (2003)
Neurokinin-1 receptor expressing neuron in the amygdala modulate morphine reward and anxiety behaviors in the mouse
. Neuroscience 23:8271-8280
Morcuende S, Gadd CA, Peters M, Moss A, Harris EA, Sheasby A, Fisher AS, De Felipe C, Mantyh PW, Rupniak NMJ, Giese KP and Hunt SP. (2003)
Increased neurogenesis and BDNF in NK1 gene knockout mice.
European J Neuroscience 18:1-9
Suzuki R, Morcuende S, Webber M, Hunt SP, Dickenson A.H. (2002)
Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways.
Nat Neurosci. 5:1319-26.
Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP. (2002)
Molecular mechanisms of cancer pain.
Nat Rev Cancer 3:201-9
Murtra, P, Sheasby, A.M., Hunt, S.P. and De Felipe, C.D (2000)
Rewarding effects of opiates are absent in mice lacking the receptor for Substance P.
Nature 405, 180-183
De Felipe, C., Herrero, J.E., O'Brien, J. A., Palmer, J.A., Doyle, C.A., Smith, A.J.H., Laird, J.M.A., Belmonte, C., Cervero, F. and Hunt, S.P (1998)
Altered nociception, analgesia, and aggression in mice lacking the substance P receptor.