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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2017)

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.

    Cover page: Molecular and genetic studies of pain and itch
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2021)
    Pruritus is a common symptom of inflammatory skin conditions, including atopic dermatitis (AD). Although primary sensory neurons that transmit pruritic signals are well-cataloged, little is known about the neuronal alterations that occur as a result of skin disruption in AD. To address this question, we examined the molecular and behavioral consequences of challenging Grhl3PAR2/+ mice, which overexpress PAR2 in suprabasal keratinocytes, with serial topical application of the environmental allergen house dust mite (HDM). We monitored behavior and used RNA sequencing, qPCR, and in situ hybridization to evaluate gene expression in trigeminal ganglia (TG), before and after HDM. We found that neither Grhl3PAR2/+ nor wild-type (WT) mice exhibited spontaneous scratching, and pruritogen-induced acute scratching did not differ. In contrast, HDM exacerbated scratching in Grhl3PAR2/+ mice. Despite the absence of scratching in untreated Grhl3PAR2/+ mice, several TG genes in these mice were up-regulated compared to WT. HDM treatment of the Grhl3PAR2/+ mice enhanced up-regulation of this set of genes and induced additional genes, many within the subset of TG neurons that express TRPV1. The same set of genes was up-regulated in HDM-treated Grhl3PAR2/+ mice that did not scratch, but at lesser magnitude. Finally, we recorded comparable transcriptional changes in IL31Tg mice, demonstrating that a common genetic program is induced in two AD models. Taken together, we conclude that transcriptional changes that occur in primary sensory neurons in dermatitis-susceptible animals underlie a genetic priming that not only sensitizes the animal to chronic allergens but also contributes to pruritus in atopic skin disease.
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2018)
      BDNF is a critical contributor to neuronal growth, development, learning, and memory. Although extensively studied in the brain, BDNF is also expressed by primary afferent sensory neurons in the peripheral nervous system. Unfortunately, anatomical and functional studies of primary afferent-derived BDNF have been limited by the availability of appropriate molecular tools. Here, we used targeted, inducible molecular approaches to characterize the expression pattern of primary afferent BDNF and the extent to which it contributes to a variety of pain and itch behaviors. Using a BDNF-LacZ reporter mouse, we found that BDNF is expressed primarily by myelinated primary afferents and has limited overlap with the major peptidergic and non-peptidergic subclasses of nociceptors and pruritoceptors. We also observed extensive neuronal, but not glial, expression in the spinal cord dorsal horn. In addition, because BDNF null mice are not viable and even Cre-mediated deletion of BDNF from sensory neurons could have developmental consequences, here we deleted BDNF selectively from sensory neurons, in the adult, using an advillin-Cre-ER line crossed to floxed BDNF mice. We found that BDNF deletion in the adult altered few itch or acute and chronic pain behaviors, beyond sexually dimorphic phenotypes in the tail immersion, histamine, and formalin tests. Based on the anatomical distribution of sensory neuron-derived BDNF and its limited contribution to pain and itch processing, we suggest that future studies of primary afferent-derived BDNF should examine behaviors evoked by activation of myelinated primary afferents.
        Cover page: Primary Afferent-Derived BDNF Contributes Minimally to the Processing of Pain and Itch.
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