Neuropeptidergic Inhibition of Pain Transmission

In the following dissertation, I present data implicating glutamatergic dorsal horn interneurons expressing the inhibitory G protein-coupled neuropeptide Y Y1 receptor (Y1-INs) in the development and maintenance of neuropathic pain. Neuropathic pain is a debilitating form of chronic pain that arises from a lesion or disease affecting the somatosensory system. Many symptoms of neuropathic pain are hypothesized to result from a loss of spinal cord dorsal horn inhibition and/or a gain in dorsal horn excitation that allow innocuous peripheral inputs to be perceived as painful. Thus, promising future pharmacological agents may dampen maladaptive spinal excitatory signaling. One promising therapeutic candidate is neuropeptide Y (NPY) which exhibits long-lasting inhibitory control of spinal nociceptive transmission after injury, primarily through NPY-Y1 receptor signaling. However, NPY Y1 receptors are found on Y1-INs, and NPY Y1 and Y2 receptors are expressed on the central terminals of primary afferent neurons arising from the dorsal root ganglion. This dual expression complicates the interpretation of the specific site of anti-nociceptive action for NPY. Thus, a major goal of this thesis was to clarify the specific site(s) of intrathecal NPY that mediate anti-hyperalgesia in rodent models of neuropathic pain. In this dissertation I detail an extensive pre-clinical research history supporting spinally-directed NPY Y1 agonists as a promising therapeutic for chronic pain. I demonstrate that Y1-INs are both necessary and sufficient for the behavioral signs of neuropathic pain. Additionally, I use single cell RNA-sequencing data in combination with fluorescence in situ hybridization to segregate Y1-INs into three distinct dorsal horn interneuron subpopulations and I demonstrate the conservation of these subpopulations across the murine, rhesus macaque, and human spinal cord dorsal horns. I also utilize genetic tools in combination with in vivo behavior to show that the Grp/Npy1r-expressing subpopulation specifically is necessary for the manifestation of neuropathic pain. Finally, I present how endogenous spinal NPY Y1 receptor signaling can synergistically work with mu opiate receptor signaling to maintain postoperative pain in remission. Together, these observations increase our understanding of how nerve injury increases the excitability of Y1-INs and provide rationale for targeting spinal Y1-INs as a novel approach to treat neuropathic pain