Dissection of the Organizational Differences Between Paw and Trunk Pain Circuits

University Of Pennsylvania, Philadelphia PA

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Abstract

? DESCRIPTION (provided by applicant): Chronic pain is a costly and complex human health problem. While many chronic pain conditions are region specific (chronic back pain, for instance), we currently know very little about regional differences in pain circuit organization. I was recently discovered that the human fingertips have the best acuity (i.e. can detect fine spatial detail) for pain stimuli compared to other body regions. However, the human fingertips have a lower density of nociceptive fibers compared to other skin areas, raising the question of how a skin area with a low innervation density displays high sensory acuity. My lab recently generated a new inducible Cre mouse line (MrgDCreERT2) that allows for genetic tracing of individual non-peptidergic nociceptors. While paw skin and trunk skin nociceptors have similar peripheral receptive field sizes, after sparse nociceptor labeling, I found that their spinal cord projections display a different morphology (paw nociceptors have rounded central terminals while trunk nociceptors have long and thin central terminals). This finding suggests that nociceptors innervating the hand form different neural circuits from those innervating the proximal limb/trunk skin. I propose to determine if, and how, pain circuits representing the paw and trunk of mice are differently organized. While my preliminary experiments suggest that spinal cord terminal morphologies (round and long) are segregated based on body position (paw-vs.-trunk), these experiments have not excluded the possibility that these morphologies instead belong to different functional subtypes. In Aim 1, I will further test the hypothesis that paw and trunk nociceptors have different morphologies by performing higher density nociceptor labeling to determine if these terminal types remain segregated. Further, to exclude the possibility that these terminal morphologies belong to functionally distinct subpopulations, I will test if a major distinguisher of non-peptidergic nociceptor subtypes (sensitivity to itch-causing beta-alanine) correlates with terminal morphology by combining genetic tracing with calcium imaging. In Aim 2, I will test the hypothesis that paw and trunk nociceptor circuits have different rates of overlap between neighboring nociceptor skin and/or spinal cord terminals. I will use a combination of genetic and viral vector tools to label neighboring nociceptors with different fluorescent proteins. I will then measure overlap rates between neighboring nociceptor terminals and compare these rates between paw and trunk circuits. In summary, these experiments will be the first to elucidate key circuit differences between paw and trunk nociceptors and could provide a likely mechanism to explain the high spatial acuity of the fingertips for pain.