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Stucky Lab identifies a new, non-opioid based target for treating chronic pain: TRPC5 (Science Translational Magazine)

  

Touch and Pain: Transduction mechanisms under normal and disease states

Chronic pain affects approximately 100 million adults in the United States, costing around $635 billion and many patients are sub-optimally treated as a result of limited understanding of the mechanistic causes of the chronic pain. The Stucky Lab has made key contributions to the pain field’s understanding of how ion channels on pain-sensing neurons contribute to pain and touch sensation. We are known for the unique “skin-nerve” recording technique whereby sensory afferent responses from rodents are measured in their native skin environment. We were the first lab to demonstrate that the Transient Receptor Potential Ankyrin 1 (TRPA1) channel is essential for detection of painful mechanical stimuli in normal, non-injured skin by using parallel genetic deletion and pharmacological inhibition of the TRPA1 channel. This work was published in the Journal of Neuroscience and Molecular Pain in 2009. Since that time, numerous publications have emerged that further build upon this work, including a widely-cited manuscript demonstrating that TRPA1 is responsible for the mechanical sensitization of pain receptors after tissue inflammation (Lennertz et al., 2012, PLoS ONE), and therefore, can serve as a target for inhibiting pain in many common inflammatory disorders.

An exciting current direction in our lab is identifying the mechanisms underlying the role of chronic pain in damaged skin, by examining the bidirectional signaling between keratinocytes and sensory neurons in normal and tissue-injured skin. While sensory neurons have long been known to mediate touch and pain transduction, epidermal keratinocytes are the initial “first responders” to tactile stimuli. We are dissecting the cellular mechanisms by which keratinocytes communicate with sensory nerve terminals, and conversely, the mechanisms by which sensory neurons communicate and sensitize keratinocytes during tissue injury. We are using multiple complementary pharmacological and cutting edge site-selective genetic approaches, such as optogenetic silencing, CRISPR/Cas9 gene editing and “cell sniffer” assays to interrogate the mechanistic direction and molecules underlying keratinocyte to sensory neuron signaling in vivo.

Another major area of focus is on translational models of chronic pain including inflammation, nerve injury and diseases associated with devastating pain, particularly in areas of unmet medical need. For example, patients with sickle cell disease have severe pain during red cell sickling crises and develop chronic underlying pain; effective treatments for this pain are lacking. We have made key discoveries in mechanisms that underlie the severe pain in sickle cell disease by performing parallel studies in mouse models of sickle cell disease and concomitantly measuring pain in patients with sickle cell disease (Hillery et al., 2011, Blood; Brandow et al., 2013, American Journal of Hematology; Zappia et al., 2014, Pain). Sickle cell disease is of particular interest because 1) it has aspects of chronic as well as acute pain, 2) the pain develops naturally as part of the underlying disease and therefore, may serve as a model for other naturally-occurring types of chronic pain in humans, and 3) parallel studies in the animal models and in patients with sickle cell disease can be conducted by the same laboratory.

Support for these projects
R01 NS40538; R01 NS070711; R21 NS095627-01; Advancing a Healthier Wisconsin