Sensory plasticity of dorsal horn silent neurons: a critical mechanism for neuropathic pain

Abstract

The spinal cord dorsal horn (DH) integrates and modulates sensory processing but undergoes critical plasticity following nerve injury, leading to pain hypersensitivity. Mechanical allodynia, or touch-evoked pain, is a highly prevalent and debilitating symptom of neuropathic pain. It has been proposed that, after nerve injury, innocuous sensory neurons gain access to nociceptive-specific (NS) circuits in the DH due to altered spinal inhibitory controls, thereby converting touch into pain. It is however unclear how sensory processing is reorganized in these conditions across the different laminae of the DH to generate this symptom. In this study, we developed a novel ex vivo somatosensory preparation to selectively analyze excitatory neuronal activity across all DH laminae simultaneously, following physiological stimulations of the skin. Using two-photon calcium (Ca2+) imaging, we studied the DH activity under physiological conditions, after spinal disinhibition or nerve injury, and generated a computational model to reveal the sensory plasticity of individual DH neurons that leads to neuropathic pain. We demonstrate that spinal disinhibition, whether pharmacologically induced or resulting from nerve injury, converts most DH excitatory neurons into highly polymodal cells. We further show that such disinhibition unmasks an unprecedented number of previously silent neurons in both superficial and deep DH laminae, responding to a wide dynamic range (WDR) of sensory modalities. The computational model pinpoints that neuropathic pain does not result primarily from the transformation of excitatory NS neurons into WDR neurons, but rather from the activation of a previously dormant excitatory circuit. This newly active circuit spans both superficial and deep DH laminae and is predominantly composed of WDR excitatory neurons The identification of this extensive silent neuronal network provides critical insights into DH plasticity mechanisms underlying neuropathic pain, and should guide future therapeutic strategies. HighlightsSensory modalities of dorsal horn neurons are defined by spinal inhibition Neuropathic mechanical allodynia does not result from the transformation of nociceptive specific neurons into wide dynamic range neurons Neuropathic pain is mediated by the activation of a previously silent circuit