Persistent pain is a major public health problem that results in a significant financial burden from reduced productivity and increased health care resource utilization. Our goal is to improve understanding of the development and resolution of pain as it relates to nerve injury induced peripheral neuronal input to the spinal cord, and develop improved understanding of the peripheral neuron's role in the transition from acute to persistent pain. This research will lead to testable therapeutic interventions that may span from drug selectivity to gene therapy. The central hypothesis of this project is that A-high threshold mechanoreceptor (AHTMR) neurons become hyperexcitable in the face of injury and the extent and duration of this excitability play direct roles in persistent pain from nerve injury and the establishment of central sensitization. We base this on observations that 1) AHTMR activity is increased and the mechanical thresholds of phenotypically defined AHTMR neurons are similar to mechanical withdrawal thresholds in freely moving animals, 2) AHTMR neurons become rapidly excitable and remain active weeks after nerve injury, 3) the duration of AHTMR activity appears to determine the persistence of pain behavior after injury. Based on these observations we focus on the role of the AHTMR in driving persistent pain or permitting resolution of pain behaviors through definitive establishment of AHTMR neurons as the foundation of pain behaviors using a combination of in vitro and in vivo electrophysiologic techniques with the aid of novel optically active channels that are selective for AHTMR regulation. The specific aims are: 1. Correlate trajectory of resolution of hypersensitivity of mechanosensitive afferents in a model of slow (partial spinal nerve ligation) recovery to trajectory of resolution of neuropathic pain behavior. AHTMR activity is a component of injury related paw withdrawal and the relationship of hypersensitivity behavior to neuronal hypersensitivity will be investigated and characterized. 2. Characterize afferent neuron activity and selectivity of optically active silencig and excitation. This will establish the bimodal control of the peripheral neuron with optically active molecules and determine afferent subtype selectivity of functional activation. 3. Measure changes in pain behavior by controlled AHTMR activity. A direct link of AHTMR activity and both paw withdrawal hypersensitivity and non-evoked pain behavior will be tested and established.

R01GM104249

2013-07-01

2019-06-30