Mutations affecting glycinergic neurotransmission in hyperekplexia increase pain sensitivity

Vuilleumier, Pascal Henri; Fritsche, R.; Schliessbach, Jürg; Schmitt, Bernhard; Arendt-Nielsen, Lars; Zeilhofer, Hanns Ulrich; Curatolo, Michele

doi:10.1093/brain/awx289

Cited by 25 publications

(16 citation statements)

References 64 publications

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“…3 ). Recent studies on loss-of-function mutations in genes encoding glycine receptors and glycine transporters underline the importance of glycinergic neurotransmission for central pain modulation in humans (Vuilleumier et al 2018 ). Neuronal intracellular [Cl] − concentration influences membrane potential dynamics and neuronal inhibition in spinal neurons (Javdani et al 2015 ).…”

Section: Dorsal Horn and Nociceptionmentioning

confidence: 99%

Substance P and pain chronicity

2018

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Substance P (SP) is a highly conserved member of the tachykinin peptide family that is widely expressed throughout the animal kingdom. The numerous members of the tachykinin peptide family are involved in a multitude of neuronal signaling pathways, mediating sensations and emotional responses (Steinhoff et al. in Physiol Rev 94:265–301, 2014). In contrast to receptors for classical transmitters, such as glutamate (Parsons et al. in Handb Exp Pharmacol 249–303, 2005), only a minority of neurons in certain brain areas express neurokinin receptors (NKRs) (Mantyh in J Clin Psychiatry 63:6–10, 2002). SP is also expressed by a variety of non-neuronal cell types such as microglia, as well as immune cells (Mashaghi et al. in Cell Mol Life Sci 73:4249–4264, 2016). SP is an 11-amino acid neuropeptide that preferentially activates the neurokinin-1 receptor (NK1R). It transmits nociceptive signals via primary afferent fibers to spinal and brainstem second-order neurons (Cao et al. in Nature 392:390–394, 1998). Compounds that inhibit SP’s action are being investigated as potential drugs to relieve pain. More recently, SP and NKR have gained attention for their role in complex psychiatric processes. It is a key goal in the field of pain research to understand mechanisms involved in the transition between acute pain and chronic pain. The influence of emotional and cognitive inputs and feedbacks from different brain areas makes pain not only a perception but an experience (Zieglgänsberger et al. in CNS Spectr 10:298–308, 2005; Trenkwaldner et al. Sleep Med 31:78–85, 2017). This review focuses on functional neuronal plasticity in spinal dorsal horn neurons as a major relay for nociceptive information.

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Section: Dorsal Horn and Nociceptionmentioning

confidence: 99%

Substance P and pain chronicity

2018

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“…the importance of glycine in human pain modulation could be recently confirmed. 38 Neuropathic pain seems to be linked to mechanisms largely independent of the COX-2-PGE 2 -eP2 pathway, as demonstrated in multiple animal models. 39 Methodological restrictions in humans, such as risks associated with repeated dural punctures, difficulty to study inhibitory postsynaptic currents and inflammatory mediators the same way as in animals, as well as ethical considerations, system.…”

Section: Discussionmentioning

confidence: 99%

Current evidence for central analgesic effects of NSAIDs: an overview of the literature

2018

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Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for a variety of painful conditions. Their peripheral anti-inflammatory effect due to inhibition of prostaglandin synthesis is well documented. In the late 1980's, animal data suggested for the first time that NSAIDs might have central effects as well. Since that time, central inflammatory and nociceptive pathways that are potential targets of NSAIDs have been extensively studied in both animal and human models. This review provides an overview of the relevant literature implicated in the central effects of NSAIDs. The role of different enzymes and mediators, as well as the central effects of NSAIDs are discussed. Literature search was performed by PubMed NCBI. A large body of evidence supports the central effects of NSAIDs in animal models of inflammatory pain conditions. Relevant mechanisms that underlie this central action involve spinal upregulation of the enzyme cyclooxygenase, increased spinal prostaglandin E2 production, modulation of inhibitory fast synaptic currents in lamina I and II of the dorsal horn, and glycine-dependent modulation of pain. Results from animal models are not yet sufficiently supported by human studies. This does not necessarily imply that the central effects of NSAIDs are irrelevant to human pain, but rather that methodological and regulatory barriers are the limiting step to translating findings from animal studies to human research protocols.

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“…Our data suggest that propacetamol might have a previously unrecognized GlyRα1-modulating route of action by its metabolite DEG in addition to its known properties like cox inhibition. Since previously published data from patients with loss-of-function mutations of GlyRα1 indicate markedly reduced pain thresholds [36], propacetamol may prove effective in pain modalities that have previously been associated with diminished glycinergic neurotransmission like neuropathic pain. Moreover, DEG might also facilitate glycincergic neurotransmission mediated by other GlyR subtypes like GlyRα3, which has been implicated in the hyperalgesia and allodynia resulting from inflammation [37]; here, it might increase the local glycine concentration by its inhibition of glycine transporter via GlyT1 and GlyT2.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol

et al. 2021

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Treating neuropathic pain remains challenging, and therefore new pharmacological strategies are urgently required. Here, the enhancement of glycinergic neurotransmission by either facilitating glycine receptors (GlyR) or inhibiting glycine transporter (GlyT) function to increase extracellular glycine concentration appears promising. Propacetamol is a N,N-diethylester of acetaminophen, a non-opioid analgesic used to treat mild pain conditions. In vivo, it is hydrolysed into N,N-diethylglycine (DEG) and acetaminophen. DEG has structural similarities to known alternative GlyT1 substrates. In this study, we analyzed possible effects of propacetamol, or its metabolite N,N-diethylglycine (DEG), on GlyRs or GlyTs function by using a two-electrode voltage clamp approach in Xenopus laevis oocytes. Our data demonstrate that, although propacetamol or acetaminophen had no effect on the function of the analysed glycine-responsive proteins, the propacetamol metabolite DEG acted as a low-affine substrate for both GlyT1 (EC50 > 7.6 mM) and GlyT2 (EC50 > 5.2 mM). It also acted as a mild positive allosteric modulator of GlyRα1 function at intermediate concentrations. Taken together, our data show that DEG influences both glycine transporter and receptor function, and therefore could facilitate glycinergic neurotransmission in a multimodal manner.

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Mutations affecting glycinergic neurotransmission in hyperekplexia increase pain sensitivity

Cited by 25 publications

References 64 publications

Substance P and pain chronicity

Substance P and pain chronicity

Current evidence for central analgesic effects of NSAIDs: an overview of the literature

Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol

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