The peripheral mechanisms of inflammatory itch and pain will be studied in a mouse model of allergic contact dermatitis (ACD) in humans. ACD is a Type IV delayed hypersensitivity reaction initiated by T lymphocytes specific for an allergen. ACD is a significant clinical problem and a major occupational disease affecting millions of people worldwide each year and seriously impacting their quality of life. Despite extensive biological studies of the inflammatory mechanisms causing ACD, there have been few if any studies of the peripheral sensory neurons and their abnormal hyperexcitability and ongoing activity that contribute to the itch and pain of ACD. Preliminary electrophsiological recordings from candidate pruriceptive mechanosensitive neurons in the mouse reveal membrane hyperexcitability (dissociated neurons in vitro) and spontaneous activity (in vivo) after experimentally produced ACD. We will test the hypothesis that this hyperexcitability renders neurons more responsive to endogenous chemicals such as the chemokines that orchestrate the elicitation of ACD. We will use transgenic fluorescent markers combined with recordings of electrophysiological or activated calcium responses, to identify and characterize, both in vivo and in vitro, specific subtypes of pruriceptive/nociceptive cutaneous peripheral sensory neurons. We will determine the ionic mechanisms contributing to the hyperexcitability and test the increased efficacy of certain chemokines to directly excite neurons after ACD. We will also test the efficacy of chemokine receptor antagonists in reducing both the in-vivo neuronal hyperexcitability and the spontaneous itch and nociceptive behavior that accompany ACD. The outcomes will generate new peripheral neuronal targets, and new ion channels and receptors to target for the treatment of inflammatory itch and pain.
Although allergic contact dermatitis (ACD) is a significant clinical problem affecting millions of people worldwide, there are few if any studies of the neuronal basis for the pain and itch associated with the disease. Using a translational mouse model of ACD in humans, we will identify and characterize itch- and pain mediating peripheral sensory neurons that become hyperexcitable after ACD. We will determine the ionic mechanisms of this hyperexcitability, test for the capacity of certain chemotactic chemokines, known to orchestrate the inflammation of ACD, to also directly excite sensory neurons. We will also test the efficacy of chemokine receptor antagonists in reducing the neuronal hyperexcitability and the spontaneous itch and nociceptive behavior that accompany ACD. The outcomes will generate new peripheral neuronal targets, and new ion channels and receptors to target, for the treatment of inflammatory itch and pain.
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