Inhibition Mediated by Glycinergic and GABAergic Receptors on Excitatory Neurons in Mouse Superficial Dorsal Horn Is Location-Specific but Modified by Inflammation

Abstract

The superficial dorsal horn is the synaptic termination site for many peripheral sensory fibers of the somatosensory system. A wide range of sensory modalities are represented by these fibers, including pain, itch, and temperature. Because the involvement of local inhibition in the dorsal horn, specifically that mediated by the inhibitory amino acids GABA and glycine, is so important in signal processing, we investigated regional inhibitory control of excitatory interneurons under control conditions and peripheral inflammation-induced mechanical allodynia. We found that excitatory interneurons and projection neurons in lamina I and IIo are dominantly inhibited by GABA while those in lamina IIi and III are dominantly inhibited by glycine. This was true of identified neuronal subpopulations: neurokinin 1 receptor-expressing (NK1Rϩ) neurons in lamina I were GABA-dominant while protein kinase C gamma-expressing (PKC␥ϩ) neurons at the lamina IIi-III border were glycine-dominant. We found this pattern of synaptic inhibition to be consistent with the distribution of GABAergic and glycinergic neurons identified by immunohistochemistry. Following complete Freund's adjuvant injection into mouse hindpaw, the frequency of spontaneous excitatory synaptic activity increased and inhibitory synaptic activity decreased. Surprisingly, these changes were accompanied by an increase in GABA dominance in lamina IIi. Because this shift in inhibitory dominance was not accompanied by a change in the number of inhibitory synapses or the overall postsynaptic expression of glycine receptor ␣1 subunits, we propose that the dominance shift is due to glycine receptor modulation and the depressed function of glycine receptors is partially compensated by GABAergic inhibition.

Altered Cervical Spinal Cord Resting‐State Activity in Fibromyalgia

“…The complex mechanisms of local spinal cord modulatory circuits are still being elucidated; however, a shift from inhibition to excitation within the spinal cord dorsal horn could underlie allodynia, as demonstrated during peripheral inflammation . Such a shift of reduced central inhibition and increased excitation could, in turn, result in increased transmission of nociceptive signals via spinothalamic projection neurons and/or decreased transmission of non‐nociceptive signals.…”

“…Although individual differences in greater ventral and lesser dorsal mean ALFF were not correlated among patients, the inverse correlation of ventral and dorsal mean ALFF across patient and control groups suggests that these results may represent an imbalance between pain and sensory processes in fibromyalgia. The complex mechanisms of local spinal cord modulatory circuits are still being elucidated; however, a shift from inhibition to excitation within the spinal cord dorsal horn could underlie allodynia, as demonstrated during peripheral inflammation (40). Such a shift of reduced central inhibition and increased excitation could, in turn, result in increased transmission of nociceptive signals via spinothalamic projection neurons and/or decreased transmission of non-nociceptive signals.…”

Transgenic Cross-Referencing of Inhibitory and Excitatory Interneuron Populations to Dissect Neuronal Heterogeneity in the Dorsal Horn

“…Recent models of spinal sensory processing have provided a framework for understanding how interneurons contribute to spinal processing mechanisms. Specifically, they have highlighted the important interplay between inhibitory gating mechanisms (Bourane et al, 2015;Foster et al, 2015;Petitjean et al, 2015;François et al, 2017;Sun et al, 2017;Boyle et al, 2019) and polysynaptic excitatory pathways (Torsney and MacDermott, 2006;Takazawa and MacDermott, 2010;Peirs et al, 2015;Takazawa et al, 2017) for normal sensory experience. As these models have developed, so too has the need to differentiate subpopulations of interneurons with unique features and connections that can fulfill specific roles in spinal sensory circuits.…”

Heterogeneous Signaling at GABA and Glycine Co-releasing Terminals

“…As previously discussed, changes to GABA (Mathews and Diamond, 2003 ; Wang et al, 2013 ) and glycine supply/resupply (Rousseau et al, 2008 ; Apostolides and Trussell, 2013 ; Ishibashi et al, 2013 ) can strongly shift the GABA/glycine balance and alterations in IPSC characteristics can be observed within minutes. Indeed, metabolic alteration such as these have been implicated in disease states including chronic pain (Coull et al, 2003 ; Imlach et al, 2016 ; Takazawa et al, 2017 ) and amyotrophic lateral sclerosis (Medelin et al, 2016 ).…”