Effects of γ-Aminobutyric Acid and Glutamate Signalings from Primary Sensory Neurons to Gate the Spinal Transmission of Mechanical Pain in Mice.

Abstract

The majority of dorsal root ganglion neurons are excitatory glutamatergic neurons. Recent studies suggest that a subset of dorsal root ganglion neurons are able to synthesize γ-aminobutyric acid (GABA) and are immunoreactive to vesicular GABA transporter (Vgat) that packages GABA into the synaptic vesicles critical for inhibitory neurotransmission. The current study aimed to investigate the spinal circuits innervated by these Vgat + primary sensory neurons and interrogate the role of Vgat + primary sensory neurons in nociceptive modification. The authors used viral tracings, immunohistochemistry, patch clamp electrophysiologic recordings, optogenetics, chemogenetics, and behavioral assays in male Vgat-Cre mice to dissect the anatomical connectivity and function of Vgat + primary sensory neurons. The data showed that the central terminals of Vgat + primary sensory neurons made inhibitory connections with spinal cord somatostatin-positive excitatory interneurons and meanwhile formed glutamatergic connections with local GABAergic interneurons driving feedforward inhibition. The functional dichotomy of Vgat + primary sensory neurons constituted an inhibitory spinal circuit that prevented aversive and pain-like responses of mice to innocuous or noxious mechanical stimuli. After peripheral nerve injury, the reduction of inhibitory drive from Vgat + primary sensory neurons to spinal somatostatin-positive interneurons correlated with mechanical nociceptive sensitization. Optogenetic or chemogenetic stimulation of Vgat + primary sensory neurons effectively alleviated the nerve injury-induced hypersensitivity to mechanical stimulation. The data suggested that the Vgat + primary sensory neurons innervating a discrete spinal microcircuit were ideally suited to suppress the mechanical pain transmission.