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Neuropeptidergic Inhibition of Pain Transmission

Nelson, Tyler Scott (2023) Neuropeptidergic Inhibition of Pain Transmission. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Nelson, Tyler Scotttsn11@pitt.edutsn110000-0002-6675-4820
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSeal, Rebecca
Committee MemberAlbers, Kathryn
Committee MemberHoward-Quijano,
Committee MemberKoerber, H
Committee MemberZeilhofer, Hanns
Thesis AdvisorTaylor, Bradley
Date: 15 September 2023
Date Type: Publication
Defense Date: 11 August 2022
Approval Date: 15 September 2023
Submission Date: 26 September 2022
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 280
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Neuropeptides, Neuropathic Pain, NPY, Neuropeptide Y, Spinal Cord, Dorsal Horn, Synergy, Pain, Gastrin Releasing Peptide, Y1 Receptor, Spared Nerve Injury, Allodynia
Date Deposited: 15 Sep 2023 14:23
Last Modified: 15 Sep 2023 14:23


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