Glycine Receptors in Spinal Nociceptive Control—An Update

Zeilhofer, Hanns Ulrich; Werynska, Karolina; Gingras, Jacinthe; Yévenes, Gonzalo E.

doi:10.3390/biom11060846

Cited by 27 publications

(31 citation statements)

References 73 publications

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“…It was hypothesized that a inhibition of GlyT1 might enhance glycinergic neurotransmission in the dorsal horn of the spinal cord. In this brain region, previous studies demonstrated a loss of synaptic inhibition, and this was suggested to contribute to the chronification of the facilitated pain perception observed in these animal models [ 54 ]. Indeed, GlyT1 active substances (both artificial substrates as well as inhibitors) showed anti-hyperalgesic and antiallodynic potential [ 55 , 56 , 57 , 58 , 59 ].…”

Section: Genetical and Pharmacological Evidence For The Function Of I...mentioning

confidence: 99%

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

Eulenburg

Hülsmann

2022

IJMS

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In addition to being involved in protein biosynthesis and metabolism, the amino acid glycine is the most important inhibitory neurotransmitter in caudal regions of the brain. These functions require a tight regulation of glycine concentration not only in the synaptic cleft, but also in various intracellular and extracellular compartments. This is achieved not only by confining the synthesis and degradation of glycine predominantly to the mitochondria, but also by the action of high-affinity large-capacity glycine transporters that mediate the transport of glycine across the membranes of presynaptic terminals or glial cells surrounding the synapses. Although most cells at glycine-dependent synapses express more than one transporter with high affinity for glycine, their synergistic functional interaction is only poorly understood. In this review, we summarize our current knowledge of the two high-affinity transporters for glycine, the sodium-dependent glycine transporters 1 (GlyT1; SLC6A9) and 2 (GlyT2; SLC6A5) and the alanine–serine–cysteine-1 transporter (Asc-1; SLC7A10).

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Section: Genetical and Pharmacological Evidence For The Function Of I...mentioning

confidence: 99%

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

Eulenburg

Hülsmann

2022

IJMS

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“…Normally, GABAergic neurons in laminae I-III of the spinal cord and in the ventral brainstem exert inhibitory effect on the Aβ-fibers (Agostinelli and Bassuk, 2021). Synaptic inhibition mediated by both glycinergic and GABAergic receptors at the dorsal horn of the spinal cord and in the related brainstem sites is deteriorated by many mechanisms evoked by peripheral inflammation or nerve injury (Agostinelli and Bassuk, 2021;Xing et al, 2021;Zeilhofer et al, 2021). The loss of GABAergic signaling following neuropathy could explain the hyper-stimulation of the Aβ-fibers that accompanies sciatic nerve injury, a process known as central sensitization (Kocot-Kępska et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Potamogeton perfoliatus L. Extract Attenuates Neuroinflammation and Neuropathic Pain in Sciatic Nerve Chronic Constriction Injury-Induced Peripheral Neuropathy in Rats

et al. 2021

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Sciatic nerve injury is often associated with neuropathic pain and neuroinflammation in the central and peripheral nervous systems. In our previous work, Potamogeton perfoliatus L. displayed anti-inflammatory, antipyretic and analgesic properties, predominantly via the inhibition of COX-2 enzyme and attenuation of oxidative stress. Herein, we extended our investigations to study the effects of the plant’s extract on pain-related behaviors, oxidative stress, apoptosis markers, GFAP, CD68 and neuro-inflammation in sciatic nerve chronic constriction injury (CCI) rat model. The levels of the pro-inflammatory marker proteins in sciatic nerve and brainstem were measured with ELISA 14 days after CCI induction. Pretreatment with the extract significantly attenuated mechanical and cold allodynia and heat hyperalgesia with better potential than the reference drug, pregabalin. In addition, CCI lead to the overexpression of prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), tumor necrosis alpha (TNFα), nuclear factor κB (NF-κB), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and NADPH oxidase-1 (NOX-1) and decreased the catalase level in sciatic nerve and brainstem. The observed neuro-inflammatory changes were accompanied with glial cells activation (increased GFAP and CD68 positive cells), apoptosis (increased Bax) and structural changes in both brainstem and sciatic nerve. The studied extract attenuated the CCI-induced neuro-inflammatory changes, oxidative stress, and apoptosis while it induced the expression of Bcl-2 and catalase in a dose dependent manner. It also decreased the brainstem expression of CD68 and GFAP indicating a possible neuroprotection effect. Taking together, P. perfoliatus may be considered as a novel therapy for neuropathic pain patients after performing the required clinical trials.

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“…The evidence discussed above has led to the development of pharmacological tools for the restoration of glycinergic activity. Recent studies have provided robust proof-of-concept that positive allosteric modulators (PAMs) of GlyRs exert anti-nociceptive effects on preclinical models of chronic pain ( Cioffi, 2017 ; Zeilhofer et al, 2018 , 2021 ). Thus, it is likely that the integration of basic research and translational approaches with focus on the glycinergic system may identify novel drugs against chronic pain.…”

Section: Glycinergic Neurotransmission In Chronic Painmentioning

confidence: 99%

“…Increasing evidence points to a critical role of dorsal horn α3-containing GlyRs in chronic inflammatory pain ( Zeilhofer et al, 2021 ; Figure 1C ). Initial electrophysiological studies showed that the activation of EP2 receptors (EP2-R) by prostaglandin E2 (PGE 2 ) decreased Gly-IPSCs in dorsal horn neurons through a PKA-dependent mechanism ( Ahmadi et al, 2002 ).…”

Section: Glycine Receptor Subtypes Involved In Nociception and Chroni...mentioning

confidence: 99%

Glycine Receptor Subtypes and Their Roles in Nociception and Chronic Pain

Martín

Sazo

Utreras

et al. 2022

Front. Mol. Neurosci.

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Disruption of the inhibitory control provided by the glycinergic system is one of the major mechanisms underlying chronic pain. In line with this concept, recent studies have provided robust proof that pharmacological intervention of glycine receptors (GlyRs) restores the inhibitory function and exerts anti-nociceptive effects on preclinical models of chronic pain. A targeted regulation of the glycinergic system requires the identification of the GlyR subtypes involved in chronic pain states. Nevertheless, the roles of individual GlyR subunits in nociception and in chronic pain are yet not well defined. This review aims to provide a systematic outline on the contribution of GlyR subtypes in chronic pain mechanisms, with a particular focus on molecular pathways of spinal glycinergic dis-inhibition mediated by post-translational modifications at the receptor level. The current experimental evidence has shown that phosphorylation of synaptic α1β and α3β GlyRs are involved in processes of spinal glycinergic dis-inhibition triggered by chronic inflammatory pain. On the other hand, the participation of α2-containing GlyRs and of β subunits in pain signaling have been less studied and remain undefined. Although many questions in the field are still unresolved, future progress in GlyR research may soon open new exciting avenues into understanding and controlling chronic pain.

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Glycine Receptors in Spinal Nociceptive Control—An Update

Cited by 27 publications

References 73 publications

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

Potamogeton perfoliatus L. Extract Attenuates Neuroinflammation and Neuropathic Pain in Sciatic Nerve Chronic Constriction Injury-Induced Peripheral Neuropathy in Rats

Glycine Receptor Subtypes and Their Roles in Nociception and Chronic Pain

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