Dorsal Horn Parvalbumin Neurons Are Gate-Keepers of Touch-Evoked Pain after Nerve Injury

Abstract

SUMMARYNeuropathic pain is a chronic debilitating disease that results from nerve damage, persists long after the injury has subsided, and is characterized by spontaneous pain and mechanical hypersensitivity. Although loss of inhibitory tone in the dorsal horn of the spinal cord is a major contributor to neuropathic pain, the molecular and cellular mechanisms underlying this disinhibition are unclear. Here, we combined pharmacogenetic activation and selective ablation approaches in mice to define the contribution of spinal cord parvalbumin (PV)-expressing inhibitory interneurons in naive and neuropathic pain conditions. Ablating PV neurons in naive mice produce neuropathic pain-like mechanical allodynia via disinhibition of PKCγ excitatory interneurons. Conversely, activating PV neurons in nerve-injured mice alleviates mechanical hypersensitivity. These findings indicate that PV interneurons are modality-specific filters that gate mechanical but not thermal inputs to the dorsal horn and that increasing PV inter-neuron activity can ameliorate the mechanical hypersensitivity that develops following nerve injury.

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

“…PKCγ neurons, enriched in the inner part of layer II, are indeed controlled by a subset of mixed glycine/GABA interneurons containing parvalbumin (PV). Ablation of these neurons produced neuropathic pain-like mechanical allodynia, while activating PV neurons in nerve-injured mice alleviates mechanical hypersensitivity [67]. Consistently, another study performed in Cre-GlyT2 mice, where glycinergic neurons were ablated with exquisite regional precision in the deep dorsal horn layers by using spinal injections of viral particles driving the Cre-dependent expression of a neurotoxin, revealed the critical role of these neurons in processing noxious thermal and mechanical signals [9].…”

“…Regarding the inhibitory mechanisms that regulate nociception and chronic pain states, the initial gate control theory of pain proposed that the activity of these interneurons is controlled by electrical input from low-threshold The scheme is based on [61,62,67,71] mechanosensitive fibers to increase inhibition, and from high-threshold nociceptors to reduce inhibition [63]. Peripheral inflammation or nerve injuries initiate a functional reorganization of the dorsal horn circuitry, which leads to a net reduction in inhibitory tone and increased excitability in ascending pathways [61,64].…”

Peripheral afferents and spinal inhibitory system in dynamic and static mechanical allodynia

“…Targeted manipulations of specific spinal dorsal horn neurons reveal critical roles of phenotypically diverse inhibitory interneurons in the feed-forward suppression of Aβ-input-evoked nociceptive circuit activation [8; 9; 43] where a population of spinal excitatory interneurons transiently expressing vesicular glutamate transporter 3 (VGLUT3) participate in dynamic but not static (punctate) mechanical allodynia, while somatostatin-expressing ones do in both [7]. It would be interesting to examine whether GABAergic and glycinergic inhibition differentially affect responses of these two excitatory neuronal populations to mechanosensory afferent inputs.…”

Making sense out of spinal cord somatosensory development

“…The SOM + population makes up a large proportion (∼59%) of the excitatory interneurons in lamina II (Gutierrez-Mecinas et al, 2016). Those residing at the lamina II/III border overlap with PKCγ neurons, a population also implicated in mechanical allodynia (Malmberg et al, 1997;Petitjean et al, 2015). SOM + neurons in the outer part of lamina II and at the II/III border are not normally activated by Aβ low threshold mechanosensory input (touch) because of a feedforward inhibitory mechanism (discussed below).…”