Glycinergic and GABAergic tonic inhibition fine tune inhibitory control in regionally distinct subpopulations of dorsal horn neurons

Abstract

Inhibition mediated by glycine and GABA in the spinal cord dorsal horn is essential for controlling sensitivity to painful stimuli. Loss of inhibition results in hyperalgesia, a sensitized response to a painful stimulus, and allodynia, a pain-like response to an innocuous stimulus like touch. The latter is due, in part, to disinhibition of an excitatory polysynaptic pathway linking low threshold touch input to pain projection neurons. This critical impact of disinhibition raises the issue of what regulates the activity of inhibitory interneurons in the dorsal horn under non-pathological conditions. We have found that inhibitory neurons throughout lamina I-III, identified by the GAD67 promoter-driven EGFP, are tonically inhibited by glycine or GABA in a regionally distinct way that is mirrored by their inhibitory synaptic input. This tonic inhibition strongly modifies action potential firing properties. Surprisingly, we found that inhibitory neurons at the lamina II/III border are under tonic glycinergic control and receive synapses that are predominantly glycinergic. Futhermore, this tonic glycinergic inhibition remains strong as the mice mature postnatally. Interestingly, GlyT1, the glial glycine transporter, regulates the strength of tonic glycinergic inhibition of these glycine-dominant neurons. The more dorsal lamina I and IIo inhibitory neurons are mainly under control by tonic GABA action and receive synapses that are predominantly GABAergic. Our work supports the hypothesis that tonic glycine inhibition controls the inhibitory circuitry deep in lamina II that is likely to be responsible for separating low threshold input from high threshold output neurons of lamina I.

Lamina specific loss of inhibition may lead to distinct neuropathic manifestations: a computational modeling approach

“…Conversely, the P-Neuroid responded to "nonnoxious" stimulation only after reducing by 50% the inhibitory tone provided by the Gly-Neuroid (which represents a glycinergic neuron in lamina III, in agreement with previous studies (Inquimbert et al, 2007;Takazawa and MacDermott, 2010a) (Figure 4d). This result together with the aforementioned increase of the P-Neuroid response to "noxious" stimuli when the inhibitory influence of the Gly-Neuroid was diminished in the same proportion, suggests that inhibitory neurons in lamina III are responsible for keeping the nociceptive pathway separated from the mechanoreceptive pathway.…”

“…These cells are mainly GABA-immunoreactive and many of them exhibit also high levels of glycine-immunoreactivity, thereby suggesting that a significant proportion of inhibitory neurons co-release GABA and glycine. On the other hand, there is evidence demonstrating that inhibition can act in a regionally distinct manner in the spinal cord of some rodents (Takazawa and MacDermott, 2010a), which in turn suggests that regionally specific loss of inhibition (local disinhibition) may lead to different neuropathic manifestations. In order to address this issue, the present study aims: (1) to construct a network-model of the SDH that acknowledges and integrates neuroanatomical information provided by different experimental studies, (2) to evaluate how useful is the Neuroid (Prada et al, 2012) in modeling each neuron included in the model, (3) to analyze the response of the model after simulating regionally specific changes in inhibitory control, and (4) to stimulate further research in this direction.…”

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

“…Inhibitory interneurons of the spinal dorsal horn have been proposed to gate the flow of innocuous and nociceptive sensory information from the periphery to higher brain centers (12), and supportive evidence for this idea is growing (13)(14)(15)(16)(17). Loss of GABAergic/glycinergic inhibition contributes to enhanced transmission of nociceptive signals through the dorsal horn circuit during pain states, resulting in hyperalgesia and allodynia (3,(18)(19)(20).…”

Glycine transport inhibitors for the treatment of pain

“…In interneurones of the spinal cord, both glycine and GABA can be present in the same synaptic vesicles, which is presumably due to the presence of both GlyT2 and a GABA transporter capable of maintaining the intracellular GABA concentration at similar levels as glycine [31,32]. However, segregation of GABAergic and glycinergic neurotransmission in dorsal spinal cord is extensive [11,19,28], with GABAergic synapses dominating in laminae I and IIo, and glycinergic transmission dominating in laminae Iii and III. This selectivity is presumably generated by cell type selective expression of GlyT2, GABA transporters and subsynaptic receptor types [11].…”

“…This is due to a reduction in the activity of the potassium chloride co-transporter (KCC2) [27] that leads to an increase in intracellular chloride, so activation of GABA or glycine receptors causes depolarization and a pronociceptive excitation of these pain transmission neurons. However, GlyT inhibitors would not be expected to strongly exacerbate this pronociceptive adaptation because inhibitory neurotransmission in lamina I of the dorsal horn is predominantly GABAergic [28] and GlyT2 expression is relatively sparse in this region [9][10][11].…”