Facilitation of neuropathic pain by the NPY Y1 receptor-expressing subpopulation of excitatory interneurons in the dorsal horn

Abstract

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.

Recent advances in our understanding of the organization of dorsal horn neuron populations and their contribution to cutaneous mechanical allodynia

“…2, suggesting that this ablation strategy is likely to have affected a large proportion of superficial DH excitatory interneurons belonging to different functional populations (Gutierrez-Mecinas et al 2019a;Todd 2017). Selective ablation of DH excitatory neurons expressing the NPY receptor NPYY1R, using intrathecal delivery of NPY-saporin, significantly reduces neuropathic static CMA in rats (Nelson et al 2019). Interestingly, such intervention also reduces cold hypersensitivity induced by nerve injury, which is reported by 28% of patients with neuropathic pain (Bouhassira et al 2005).…”

“…Interestingly, such intervention also reduces cold hypersensitivity induced by nerve injury, which is reported by 28% of patients with neuropathic pain (Bouhassira et al 2005). However, it is unclear which of the different types of neurons that have been ablated is responsible for the behavioral effect, as NPYY1R is expressed by numerous excitatory neurons in the superficial DH including SOM + and CR + (but not PKCγ +) neurons (Nelson et al 2019). Similarly, virally mediated ablation of the large population of DH CCK + cells nearly abolishes static CMA after peripheral nerve injury in mice (Liu et al 2018).…”

A spinal neural circuitry for converting touch to itch sensation

“…Nonetheless, caution is warranted while extrapolating the endogenous function of a receptor from behaviors resulting from its pharmacological activation or inhibition, which could trigger a novel signaling pathway that may not occur in vivo 47 . On the other hand, there is substantial evidence that the spinal NPY-NPY receptor system plays a role in inhibition of nociceptive transmission under normal and neuropathic conditions [58][59][60][61][62] . Thus, it is not surprising that an artificial activation of spinal NPY neurons could inhibit somatosensory transmission across modalities.…”

Dorsal Horn PKCγ Interneurons Mediate Mechanical Allodynia through 5-HT2AR-Dependent Structural Reorganization

“…1). The excitatory interneurons expressing neuropeptide Y1 receptors (Y1R), which are involved in both mechanical and thermal allodynia that arises after inflammatory and neuropathic injury, may also be a target of PKC␥ interneurons as Y1Rs do not colocalize with PKC␥ and are found superficial to PKC␥ interneurons (Diaz-delCastillo et al, 2018;Nelson et al, 2019) (Fig. 1).…”