Identification of Spinal Circuits Transmitting and Gating Mechanical Pain

Abstract

SUMMARY Pain processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aβ mechanoreceptors, with Aβ inputs gated through feed-forward activation of spinal inhibitory neurons (IN). Here we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) represent T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent IN-type neurons, which are necessary to gate Aβ fibers from activating SOM+ neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aβ mechanoreceptors, together with spinal SOM+ excitatory and Dyn+ inhibitory neurons form a microcircuit that transmits and gates mechanical pain.

Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain

“…Most of these responses were also blocked by strychnine (data not shown). To determine the molecular identity of ChR2 negative responsive cells, we focused on PKCγ+ excitatory interneurons that transmit Aβ/Aδ touch information to projection neurons (Lu et al, 2013) and SST+ excitatory interneurons that mainly mediate C fiber mechanical pain sensation (Duan et al, 2014). ChR2+ neurites surround PKCγ+ and SST+ neurons ( Figures 5I-J), suggesting that early RET+ dDH neurons might directly synapse onto these excitatory interneurons.…”

“…For example, Aβ touch fibers were found to have polysynaptic excitatory connections onto superficial DH projection neurons, which are normally under strong inhibition (Bardoni et al, 2013;Torsney and MacDermott, 2006). In addition, a series of recent studies characterized the circuitry and function of several molecularly defined populations of DH interneurons in mediating and modulating touch and pain sensation, including PKCγ+, RORα+, VGLUT3+, and somatostatin (SST)+ excitatory interneurons, and dynorphin (Dyn) +, parvalbumin (PV)+, TRPV1+, and GLYT2+ inhibitory interneurons (Bourane, 2015;Duan et al, 2014;Foster et al, 2015;Kim et al, 2012;Lu et al, 2013;Peirs et al, 2015;Petitjean et al, 2015). Nevertheless, the neural circuits underlying one key prediction of the GCT, activation of nociceptive C fibers will dis-inhibit "gating" neurons (open the "gate"), remain unclear.…”

Recent Progress in Understanding the Mechanisms of Pain and Itch: the Second Special Issue

“…In the last 5 years, the field has seen tremendous progress in the molecular and functional characterization of primary sensory neurons [6,7], neurocircuits of pain and itch [8][9][10], immune and glial modulation of pain and itch [11][12][13][14][15], molecular mechanisms of pain [16,17], and identification of brain signatures of pain [18]. Thus, it is timely to highlight the recent progress in a second special issue.…”

Multimodal Frequency Treatment for Facial Pain Caused by Chronic Rhinosinusitis: A Pilot Study

“…The analgesic effect of vibration is likely due to both afferent and cortical processes [64,67,69]. Combining vibratory stimulation with either electrical or thermal stimulation increases the analgesia effect, probably due to the activation and recruitment of multiple types of receptors [30,31,57].…”

“…Vibratory analgesia is based on the observation that stimulation of afferent nerves with mechanical vibration reduces perceived pain [67,68]. The analgesic effect of vibration is likely due to both afferent and cortical processes [64,67,69].…”