Clinically peripheral nerve injury and regeneration is a common occurrence. Normal regeneration results in faulty localization of stimuli, increased two point discrimination thresholds and general hypersensitivity, ranging from relativity innocuous hyperesthesia often described as unusual or vivid sensations to allodynia or causalgia which are debilitating painful sensations often elicited by innocuous cutaneous stimuli. Although most of these symptoms show improvement with time others, most notably the pain syndromes, can last for years and greatly affect an individual's quality of life. Our major goal in this proposal is to understand the cellular processes that underlie plasticity in sensory neurons following peripheral nerve injury. Specifically, we will look at the effects of target-derived trophic factor signaling induced plasticity of primary sensory neurons re-innervating the skin. We have now shown that many types of regenerated cutaneous afferent fibers show increased sensitivity following regeneration. In another series of studies we examined the effects of overexpression of trophic factors in the skin. Depending on the factor expressed we found that different types of cutaneous sensory neurons were sensitized to mechanical and thermal stimuli. In addition we found that there was an increase in specific combinations of receptors/channels that are believed to be involved in the transduction of peripheral stimuli by sensory neurons (e.g. TRP and ASIC channels). Finally, we found that the expression of these same trophic factors and receptors/channels is increased in the DRG and skin respectively following nerve injury. We hypothesize that the increase in trophic signaling results in the increased expression of several TRP and ASIC channels in regenerating cutaneous fibers resulting in an increased sensitivity to peripheral stimuli. Here we propose to use a novel in vivo siRNA procedure which allows us to knock down the expression of individual receptors/channels specifically in the regenerating cutaneous fibers and an ex vivo recording preparation to directly test this hypothesis. Evaluation of our hypotheses and the determination of the specific signaling events receptors/channels responsible for sensitization of these fibers will provide new insights to these processes and more importantly could provide potential targets for the development of pharmaceutical therapies. These new therapies could provide for improved functional recovery following regeneration as well as alleviation of the adverse symptoms and potential chronic pain syndromes.
Peripheral nerve injury and subsequent regeneration often leads to a variety of sensory deficits including chronic pain syndromes. In this application we are proposing to determine specific cellular and molecular changes in sensory neurons that could lead to these symptoms. Determination of these mechanisms could provide targets for new pharmaceutical therapies that could provide for improved functional recovery following regeneration as well as alleviation of the adverse syndromes.
|Jankowski, Michael P; Lawson, Jeffrey J; McIlwrath, Sabrina L et al. (2009) Sensitization of cutaneous nociceptors after nerve transection and regeneration: possible role of target-derived neurotrophic factor signaling. J Neurosci 29:1636-47|
|Jankowski, Michael P; McIlwrath, Sabrina L; Jing, Xiaotang et al. (2009) Sox11 transcription factor modulates peripheral nerve regeneration in adult mice. Brain Res 1256:43-54|
|Rau, Kristofer K; McIlwrath, Sabrina L; Wang, Hong et al. (2009) Mrgprd enhances excitability in specific populations of cutaneous murine polymodal nociceptors. J Neurosci 29:8612-9|
|Woodbury, C Jeffery; Kullmann, Florenta A; McIlwrath, Sabrina L et al. (2008) Identity of myelinated cutaneous sensory neurons projecting to nocireceptive laminae following nerve injury in adult mice. J Comp Neurol 508:500-9|
|Malin, Sacha A; Davis, Brian M; Koerber, H Richard et al. (2008) Thermal nociception and TRPV1 function are attenuated in mice lacking the nucleotide receptor P2Y2. Pain 138:484-96|
|Elitt, Christopher M; Malin, Sacha A; Koerber, H Richard et al. (2008) Overexpression of artemin in the tongue increases expression of TRPV1 and TRPA1 in trigeminal afferents and causes oral sensitivity to capsaicin and mustard oil. Brain Res 1230:80-90|
|Lawson, Jeffrey J; McIlwrath, Sabrina L; Woodbury, C Jeffery et al. (2008) TRPV1 unlike TRPV2 is restricted to a subset of mechanically insensitive cutaneous nociceptors responding to heat. J Pain 9:298-308|
|Woodbury, C Jeffery; Koerber, H Richard (2007) Central and peripheral anatomy of slowly adapting type I low-threshold mechanoreceptors innervating trunk skin of neonatal mice. J Comp Neurol 505:547-61|
|Koerber, H Richard; Mirnics, Karoly; Lawson, Jeffrey J (2006) Synaptic plasticity in the adult spinal dorsal horn: the appearance of new functional connections following peripheral nerve regeneration. Exp Neurol 200:468-79|
|Albers, Kathryn M; Woodbury, C Jeffrey; Ritter, Amy M et al. (2006) Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors. J Neurosci 26:2981-90|
Showing the most recent 10 out of 24 publications