Drug Repurposing to Target Neuroinflammation and Sensory Neuron-Dependent Pain

Sisignano, Marco; Gribbon, Philip; Geißlinger, Gerd

doi:10.1007/s40265-022-01689-0

Cited by 14 publications

(11 citation statements)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, profiling of the endogenous opioid analgesic system could be next addressed in Scn9a R 185 H mice. Another component of neuropathic pain lies in neuroinflammation ( Sommer et al, 2018 ; Sisignano et al, 2022 ). The impact of Scn9a R 185 H mutation on neuroinflammation or on a broader scale may be further explored by omics approaches.…”

Section: Discussionmentioning

confidence: 99%

The Human SCN9AR185H Point Mutation Induces Pain Hypersensitivity and Spontaneous Pain in Mice

Xue

Kremer

Moreno

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

The voltage-gated sodium channel Nav1.7 is encoded by SCN9A gene and plays a critical role in pain sensitivity. Several SCN9A gain-of-function (GOF) mutations have been found in patients with small fiber neuropathy (SFN) having chronic pain, including the R185H mutation. However, for most of these variants, their involvement in pain phenotype still needs to be experimentally elucidated. In order to delineate the impact of R185H mutation on pain sensitivity, we have established the Scn9aR185H mutant mouse model using the CRISPR/Cas9 technology. The Scn9aR185H mutant mice show no cellular alteration in the dorsal root ganglia (DRG) containing cell bodies of sensory neurons and no alteration of growth or global health state. Heterozygous and homozygous animals of both sexes were investigated for pain sensitivity. The mutant mice were more sensitive than the wild-type mice in the tail flick and hot plate tests, acetone, and von Frey tests for sensitivity to heat, cold, and touch, respectively, although with sexual dimorphic effects. The newly developed bioinformatic pipeline, Gdaphen is based on general linear model (GLM) and random forest (RF) classifiers as well as a multifactor analysis of mixed data and shows the qualitative and quantitative variables contributing the most to the pain phenotype. Using Gdaphen, tail flick, Hargreaves, hot plate, acetone, cold plate, and von Frey tests, sex and genotype were found to be contributing most to the pain phenotype. Importantly, the mutant animals displayed spontaneous pain as assessed in the conditioned place preference (CPP) assay. Altogether, our results indicate that Scn9aR185H mice show a pain phenotype, suggesting that the SCN9AR185H mutation identified in patients with SFN having chronic pain contributes to their symptoms. Therefore, we provide genetic evidence for the fact that this mutation in Nav1.7 channel plays an important role in nociception and in the pain experienced by patients with SFN who have this mutation. These findings should aid in exploring further pain treatments based on the Nav1.7 channel.

show abstract

Section: Discussionmentioning

confidence: 99%

The Human SCN9AR185H Point Mutation Induces Pain Hypersensitivity and Spontaneous Pain in Mice

Xue

Kremer

Moreno

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Neuropathic pain affects around 10 percent of the general population and is induced by lesions and diseases of the somatosensory system, infections, or toxic substances [2]. However, the available therapies are very scarce because of their low efficacy and severe adverse effects [32]. Based on these circumstances, there is a high medical need for novel, safe, effective treatment approaches for neuropathic pain [32].…”

Section: Discussionmentioning

confidence: 99%

“…However, the available therapies are very scarce because of their low efficacy and severe adverse effects [32]. Based on these circumstances, there is a high medical need for novel, safe, effective treatment approaches for neuropathic pain [32]. Nevertheless, the development of many therapy strategies failed, having faced the challenge that neuropathic pain is a multifunctional event mediated by various mediators with pleiotropic effects.…”

Section: Discussionmentioning

confidence: 99%

The FKBP51 Inhibitor SAFit2 Restores the Pain-Relieving C16 Dihydroceramide after Nerve Injury

Wedel

Hahnefeld

Alnouri

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

Neuropathic pain is a pathological pain state with a broad symptom scope that affects patients after nerve injuries, but it can also arise after infections or exposure to toxic substances. Current treatment possibilities are still limited because of the low efficacy and severe adverse effects of available therapeutics, highlighting an emerging need for novel analgesics and for a detailed understanding of the pathophysiological alterations in the onset and maintenance of neuropathic pain. Here, we show that the novel and highly specific FKBP51 inhibitor SAFit2 restores lipid signaling and metabolism in nervous tissue after nerve injury. More specifically, we identify that SAFit2 restores the levels of the C16 dihydroceramide, which significantly reduces the sensitization of the pain-mediating TRPV1 channel and subsequently the secretion of the pro-inflammatory neuropeptide CGRP in primary sensory neurons. Furthermore, we show that the C16 dihydroceramide is capable of reducing acute thermal hypersensitivity in a capsaicin mouse model. In conclusion, we report for the first time the C16 dihydroceramide as a novel and crucial lipid mediator in the context of neuropathic pain as it has analgesic properties, contributing to the pain-relieving properties of SAFit2.

show abstract

“…Several lines of evidence suggest analgesic effects of the thirdgeneration parenteral cephalosporin antibiotic ceftriaxone in preclinical pain models. The assumed mechanism of action is enhancement of the glutamate reuptake by upregulation of the glutamate transporter GLT-1 in the spinal cord and elsewhere (Sisignano et al, 2022). GLT-1 is a sodium-dependent transporter that plays a key role in glutamate homeostasis by removing excess Frontiers in Cell and Developmental Biology frontiersin.org glutamate in the central nervous system (Peterson and Binder, 2019).…”

Section: Ceftriaxonementioning

confidence: 99%

Neuropathic pain: Mechanisms and therapeutic strategies

Petroianu

Aloum

Adem

2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The physiopathology and neurotransmission of pain are of an owe inspiring complexity. Our ability to satisfactorily suppress neuropathic or other forms of chronic pain is limited. The number of pharmacodynamically distinct and clinically available medications is low and the successes achieved modest. Pain Medicine practitioners are confronted with the ethical dichotomy imposed by Hippocrates: On one hand the mandate of primum non nocere, on the other hand, the promise of heavenly joys if successful divinum est opus sedare dolorem. We briefly summarize the concepts associated with nociceptive pain from nociceptive input (afferents from periphery), modulatory output [descending noradrenergic (NE) and serotoninergic (5-HT) fibers] to local control. The local control is comprised of the “inflammatory soup” at the site of pain origin and synaptic relay stations, with an ATP-rich environment promoting inflammation and nociception while an adenosine-rich environment having the opposite effect. Subsequently, we address the transition from nociceptor pain to neuropathic pain (independent of nociceptor activation) and the process of sensitization and pain chronification (transient pain progressing into persistent pain). Having sketched a model of pain perception and processing we attempt to identify the sites and modes of action of clinically available drugs used in chronic pain treatment, focusing on adjuvant (co-analgesic) medication.

show abstract

Drug Repurposing to Target Neuroinflammation and Sensory Neuron-Dependent Pain

Cited by 14 publications

References 117 publications

The Human SCN9AR185H Point Mutation Induces Pain Hypersensitivity and Spontaneous Pain in Mice

The Human SCN9AR185H Point Mutation Induces Pain Hypersensitivity and Spontaneous Pain in Mice

The FKBP51 Inhibitor SAFit2 Restores the Pain-Relieving C16 Dihydroceramide after Nerve Injury

Neuropathic pain: Mechanisms and therapeutic strategies

Contact Info

Product

Resources

About