Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp
Tyler S. Nelson, … , Andrew J. Todd, Bradley K. Taylor
Tyler S. Nelson, … , Andrew J. Todd, Bradley K. Taylor
Published October 12, 2023
Citation Information: JCI Insight. 2023;8(22):e169554. https://doi.org/10.1172/jci.insight.169554.
View: Text | PDF
Research Article Neuroscience

Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp

Abstract

Neuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are heterogenous in composition in terms of morphology, neurophysiological characteristics, and gene expression, we hypothesized that a more precisely defined subpopulation mediates neuropathic hypersensitivity. Using fluorescence in situ hybridization, we found that Y1-INs segregate into 3 largely nonoverlapping subpopulations defined by the coexpression of Npy1r with gastrin-releasing peptide (Grp/Npy1r), neuropeptide FF (Npff/Npy1r), and cholecystokinin (Cck/Npy1r) in the superficial DH of mice, nonhuman primates, and humans. Next, we analyzed the functional significance of Grp/Npy1r, Npff/Npy1r, and Cck/Npy1r INs to neuropathic pain using a mouse model of peripheral nerve injury. We found that chemogenetic inhibition of Npff/Npy1r-INs did not change the behavioral signs of neuropathic pain. Further, inhibition of Y1-INs with an intrathecal Y1 agonist, [Leu31, Pro34]-NPY, reduced neuropathic hypersensitivity in mice with conditional deletion of Npy1r from CCK-INs and NPFF-INs but not from GRP-INs. We conclude that Grp/Npy1r-INs are conserved in higher order mammalian species and represent a promising and precise pharmacotherapeutic target for the treatment of neuropathic pain.

Authors

Tyler S. Nelson, Heather N. Allen, Paramita Basu, Pranav Prasoon, Eileen Nguyen, Cynthia M. Arokiaraj, Diogo F.S. Santos, Rebecca P. Seal, Sarah E. Ross, Andrew J. Todd, Bradley K. Taylor

×

Figure 7

Schematized model for NPY Y1 agonists to inhibit Grp/Npy1r-INs and dampen neuropathic pain, silencing a key component of the ascending circuit in the dorsal horn that mediates mechanical allodynia.

Options: View larger image (or click on image) Download as PowerPoint
Schematized model for NPY Y1 agonists to inhibit Grp/Npy1r-INs and dampe...
In the context of nerve injury, aberrant hyperexcitation of Npy1r/Grp-INs may drive allodynia. Exogenous administration of NPY or Y1 agonist binding to the Gi-coupled NPY Y1 receptor on Npy1r/Grp-INs results in cellular inhibition and the abolishment of peripheral nerve injury–induced mechanical allodynia. We posit that NPY Y1 agonists act by inhibiting a key neuron population implicated in the transduction of mechanical allodynia. Briefly, non-noxious mechanical stimuli activate Aß/Aδ myelinated afferents (shown in red) that project into the deeper laminae of the dorsal horn and synapse onto interneurons marked by the expression of CCK (purple) and PKCγ (yellow). Normally, feed-forward inhibition prevents the activation of these interneurons, and as a result light touch is perceived as nonpainful. For example, inhibitory NPY interneurons (light gray) may “gate” Npy1r/Grp-INs to prevent these neurons from being activated and driving pain-like behaviors. However, in the context of neuropathic pain, feed-forward inhibition is lost, and innocuous light touch inputs activate a theorized dorsally directed microcircuit to allow innocuous mechanical sensory information to be perceived as painful. In this theorized circuit, activated CCK and PKCγ interneurons excite transient central cells (theorized here as Npy1r/Grp-INs), which in turn synapse onto GRPR-INs (vertical cells), which then activate ascending projection neurons (PNs) that travel via the spinothalamic and spinoparabrachial tracts to be processed via higher order pain centers, such as the lateral parabrachial nucleus. Image is updated from our circuit diagrams previously published under CC BY license (24, 26).