Chemogenetic inhibition of Grpr- and/or Npff-expressing spinal neurons in mice suppresses chloroquine-evoked itch but not signs of mechanical allodynia in a neuropathic pain model

Pain. 2026 Jun 2. doi: 10.1097/j.pain.0000000000004024. Online ahead of print.

ABSTRACT

Mechanical hypersensitivity following peripheral nerve injury is common and difficult to treat. It has been suggested that this results from activation of a normally silent spinal cord circuit that links low-threshold mechanoreceptive primary afferents to nociceptive projection neurons in lamina I and that this pathway involves a class of excitatory interneurons known as vertical cells. We have recently identified 2 neurochemical types of vertical cells, based on expression of the gastrin-releasing peptide receptor (GRPR) and neuropeptide FF (NPFF). Although little is known about the role of NPFF cells, those that express GRPR are strongly implicated in itch; for example, it has been reported that ablation of GRPR cells suppresses itch but has no effect on pain. In this study, we have used chemogenetics to inhibit each population separately (in GRPRCreERT2 and NPFFCre mice) and both together (in GRPRCreERT2; NPFFCre mice). We found that the itch evoked by intradermal injection of chloroquine in the calf was suppressed in each case, but there was no effect on baseline mechanical sensitivity. In addition, we saw no effect of the chemogenetic inhibition on either mechanical hypersensitivity or on a measure of spontaneous pain in the spared nerve injury model of neuropathic pain. These results indicate that both of these populations of vertical cells are involved in the itch evoked by chloroquine but do not support a role for these cells in neuropathic mechanical hypersensitivity.

PMID:42240073 | DOI:10.1097/j.pain.0000000000004024