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Molecular and genetic studies of pain and itch

  • Author(s): Dembo, Todd Michael
  • Advisor(s): Julius, David
  • et al.
Abstract

Chronic pain and itch pose ever present, steadily growing burdens to human health. Still, we have limited understanding of the mechanisms that underlie their development and persistence. Furthermore, treatments for these conditions tend to be palliative, rather than curative, leading to mixed patient outcomes. With this in mind, we used next generation sequencing to assemble a transcriptional profile of the molecular changes in skin and sensory neurons that associate with a unique, stochastic mouse model of atopic dermatitis. This model combines the genetic sensitization of a PAR2 overexpression animal with environmental challenge by house dust mite allergens. To our knowledge, this is the first profiling effort that broadened its focus beyond the skin to look at the important, itch-facilitating contribution of sensory neurons. An interesting feature of this PAR2 model is that, by virtue of its stochasticity, it may allow for the independent identification of both protective and deleterious changes. These datasets will serve as useful resources for clinicians and researchers interested in the pathogenesis and prevention of atopic dermatitis.

Among the many genetic changes detected in our analysis was brain-derived neurotrophic factor (BDNF), which is expressed by sensory neurons and has been repeatedly implicated in different pain and itch conditions. Thus, in a parallel series of studies, we investigated the neuronal expression pattern and behavioral contributions of primary afferent-derived BDNF. Contrary to previous reports, we found that BDNF expression within dorsal root ganglia predominates in large-diameter, myelinated neurons. Furthermore, we found little evidence that BDNF contributes significantly to acute or chronic pain, with one notable exception observed in the formalin test of inflammatory pain. The selective deletion of BDNF from primary sensory neurons markedly reduced nocifensive behaviors during the second phase of the formalin test, which is thought to model tissue injury-induced post-operative pain. Surprisingly, this difference was sexually dimorphic, and only occurred in male mice. However, based on its expression pattern within sensory ganglia and its minimal apparent contribution to pain or itch, we suggest that, in the future, primary afferent-derived BDNF should be studied in the context of low-threshold mechanotransduction.

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