Analysis of ascending spinal pain circuits

Project Summary/Abstract Peripheral pain signals are conveyed to the brain by spinal cord projection neurons. There has been a significant emphasis on one projection neuron population that expresses TACR1, Substance P receptor, in transmitting pain signals to the brain. However, every strategy targeting these spinal cord neurons or the receptor itself using selective, potent antagonists has failed to treat pain in human patients, suggesting that there might be additional, independent ascending channels that also transmit pain signals to the brain. Previously, we identified a novel subset of spinal projection neurons that express another neuropeptide receptor, GPR83. We demonstrated that both TACR1- and GPR83-expressing spinal projection neurons can convey noxious signals to the brain to underlie the affective aspect of pain sensation while differentially responding to innocuous thermal and tactile stimuli. Interestingly, our preliminary data suggest that these newly identified GPR83-expressing neurons are conserved in humans, and Gpr83 is expressed in the human spinal cord dorsal horn more abundantly than Tacr1. Our proposed research will explore an exciting idea that GPR83- expressing spinal projection neurons and the GPR83-mediated neuropeptide signaling pathway can be potential therapeutic targets for treating chronic pain. In particular, we will test the functional redundancy between the two spinal output pain circuits that may ensure animals detect and react to harmful pain signals. In Aim 1, we will first determine the combinatorial, pathophysiological role of these two main subtypes of spinal projection neurons (TACR1- and GPR83-expressing) in chronic pain states by examining changes in intrinsic physiological properties and stimulus-evoked firing activities. We will also test their contribution to chronic pain behaviors by examining the behavioral outcomes of silencing these two pathways simultaneously. In Aim 2, we will determine the role of TACR1 and GPR83 and their neuropeptide ligands in chronic pain by conducting proof-of-principle experiments where we will assess chronic pain behaviors following the knockout of these receptor genes or their ligand genes simultaneously. We will also determine the physiological and circuit mechanisms underlying the TACR1 and GPR83-mediated modulation of chronic pain. Our study will provide insights into the molecular, cellular, and circuit mechanisms underlying the increased nociception in chronic pain states and potentially reveal novel therapeutic targets for treating chronic pain.