| First Author | Cao B | Year | 2022 |
| Journal | Neuron | PubMed ID | 36223767 |
| Mgi Jnum | J:330718 | Mgi Id | MGI:7384155 |
| Doi | 10.1016/j.neuron.2022.09.027 | Citation | Cao B, et al. (2022) Spinal cord retinoic acid receptor signaling gates mechanical hypersensitivity in neuropathic pain. Neuron |
| abstractText | Central sensitization caused by spinal disinhibition is a key mechanism of mechanical allodynia in neuropathic pain. However, the molecular mechanisms underlying spinal disinhibition after nerve injury remain unclear. Here, we show in mice that spared nerve injury (SNI), which induces mechanical hypersensitivity and neuropathic pain, triggers homeostatic reduction of inhibitory outputs from dorsal horn parvalbumin-positive (PV+) interneurons onto both primary afferent terminals and excitatory interneurons. The reduction in inhibitory outputs drives hyperactivation of the spinal cord nociceptive pathway, causing mechanical hypersensitivity. We identified the retinoic acid receptor RARalpha, a central regulator of homeostatic plasticity, as the key molecular mediator for this synaptic disinhibition. Deletion of RARalpha in spinal PV+ neurons or application of an RARalpha antagonist in the spinal cord prevented the development of SNI-induced mechanical hypersensitivity. Our results identify RARalpha as a crucial molecular effector for neuropathic pain and a potential target for its treatment. |
