Endogenous neuropeptide Y (NPY) exerts long-lasting spinal inhibitory control of neuropathic pain, but its mechanism of action is complicated by the expression of its receptors at multiple sites in the dorsal horn: NPY Y1 receptors (Y1Rs) on post-synaptic neurons and both Y1Rs and Y2Rs at the central terminals of primary afferents. We found that Y1R-expressing spinal neurons contain multiple markers of excitatory but not inhibitory interneurons in the rat superficial dorsal horn. To test the relevance of this spinal population to the development and/or maintenance of acute and neuropathic pain, we selectively ablated Y1R-expressing interneurons with intrathecal administration of an NPY-conjugated saporin ribosomal neurotoxin that spares the central terminals of primary afferents. NPY-saporin decreased spinal Y1R immunoreactivity but did not change the primary afferent terminal markers isolectin B4 or calcitonin-gene-related peptide immunoreactivity. In the spared nerve injury (SNI) model of neuropathic pain, NPY-saporin decreased mechanical and cold hypersensitivity, but disrupted neither normal mechanical or thermal thresholds, motor coordination, nor locomotor activity. We conclude that Y1R-expressing excitatory dorsal horn interneurons facilitate neuropathic pain hypersensitivity. Furthermore, this neuronal population remains sensitive to intrathecal NPY after nerve injury. This neuroanatomical and behavioral characterization of Y1R-expressing excitatory interneurons provides compelling evidence for the development of spinally-directed Y1R agonists to reduce chronic neuropathic pain.
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Grants R01NS45954 and R01DA37621 to BKT, and Swedish RC (04-2887) to TH, Soma Bose for her help with the CGRP, IB4, Y1R, and NK1 staining, and Dr. Janice Urban (Rosalind Franklin University) for her gift of Y1 receptor antibody.
The datasets generated during and/or analyzed during the current study will be made available from the corresponding author on request.
Nelson, Tyler S.; Fu, Weisi; Donahue, Renee R.; Corder, Gregory F.; Hökfelt, Tomas; Wiley, Ronald G.; and Taylor, Bradley K., "Facilitation of Neuropathic Pain by the NPY Y1 Receptor-Expressing Subpopulation of Excitatory Interneurons in the Dorsal Horn" (2019). Physiology Faculty Publications. 147.