Optogenetic inhibition of spinal inhibitory neurons facilitates mechanical responses of spinal wide dynamic range neurons and causes mechanical hypersensitivity

Abstract

Inhibitory interneurons in the spinal dorsal horn (DH) play a major role in regulating innocuous and noxious information. Reduction in inhibitory synaptic transmission is thought to contribute to the development of touch-evoked pain (allodynia), a common symptom of neuropathic pain. However, it is not fully understood how inhibitory neurons in the DH regulate sensory responses in surrounding neurons and modulate sensory transmission. In this study, we established a novel experimental method to analyze temporal activity of DH neurons during the optogenetically induced disinhibition state by combining extracellular recording and optogenetics. We investigated how specific and temporally restricted dysfunction of DH inhibitory neurons affected spinal neuronal activities evoked by cutaneous mechanical stimulation. In behavioral experiments, the specific and temporally restricted spinal optogenetic suppression of DH inhibitory neurons induced mechanical hypersensitivity. Furthermore, this manipulation enhanced the mechanical responses of wide dynamic range (WDR) neurons, which are important for pain transmission, in response to brush and von Frey stimulation but not in response to nociceptive pinch stimulation. In addition, we examined whether a neuropathic pain medication, mirogabalin, suppressed these optogenetically induced abnormal pain responses. We found that mirogabalin treatment attenuated the abnormal firing responses of WDR neurons and mechanical hypersensitivity. These results suggest that temporally restricted and specific reduction of spinal inhibitory neuronal activity facilitates the mechanical responses of WDR neurons, resulting in neuropathic-like mechanical allodynia which can be suppressed by mirogabalin. Our optogenetic methods could be useful for developing novel therapeutics for neuropathic pain.

Keywords: Inhibitory interneurons; Mechanical hypersensitivity; Optogenetics; Pain; Somatosensory system; Wide dynamic range neuron.