Regulation and function of PlexinA2 forward signaling in persistent pain

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Persistent pain is a significant clinical and public health problem. Once established, persistent pain is often refractory to existing treatments and associated with adverse health outcomes. Persistent pain develops following peripheral nerve injury when orphan sprouts form neuromas in denervated tissues which become electrically hyperexcitable and generate spontaneous and evoked ectopic action potentials. These responses may be the result of epigenetic mechanisms. Epigenetic mechanisms are responsible for alterations in cellular phenotype that do not involve changes to the DNA sequence and generally serve as an avenue for environmental factors to influence behavior of the genome. Accordingly, epigenetic mechanisms are well established regulators of a wide variety of physiological and pathological processes. However, epigenetic involvement in persistent pain after peripheral nerve injury remains largely unexplored. The central hypothesis for this COBRE Research Project is that altered epigenetic regulation of the semaphorin-plexin signaling pathway in sensory neurons plays a functional role in axon guidance and promotes persistent pain states. In addition, we hypothesize that changes to the sensory environment during neuronal development may epigenetically prime nociceptors to promote altered nociceptive thresholds later in life. Our study will: 1) provide novel information regarding cell-type specific position and activity of important regulatory elements in peripheral nervous system after nerve injury and in chronic inflammation; 2) determine the effects of semaphorin-plexin family genes on neurite outgrowth, repulsion and pain behaviors; and 3) identify how early life stress may affect the epigenome of sensory neurons and alter gene expression to increase susceptibility to pain-related behaviors in later life. An improved understanding of the regulatory changes in the expression of genes important in neuron regeneration and neuronal hyperexcitability may provide therapeutic targets for novel strategies toward the prevention and treatment of neuropathic pain.