scholarly journals Antiplexin D1 Antibodies Relate to Small Fiber Neuropathy and Induce Neuropathic Pain in Animals

2021 ◽  
Vol 8 (5) ◽  
pp. e1028
Author(s):  
Takayuki Fujii ◽  
Eun-Jae Lee ◽  
Yukino Miyachi ◽  
Ryo Yamasaki ◽  
Young-Min Lim ◽  
...  
Keyword(s):  
Immunofluorescence Assay ◽  
Small Fiber Neuropathy ◽  
Dorsal Root Ganglion Neurons ◽  
Small Fiber ◽  
Extracellular Signal ◽  
Potential Biomarker ◽  
Ganglion Neurons ◽  
Low Prevalence ◽  
Thermal Hypersensitivity

ObjectivesTo assess the prevalence of antiplexin D1 antibodies (plexin D1-immunoglobulin G [IgG]) in small fiber neuropathy (SFN) and the effects of these antibodies in vivo.MethodsWe developed an ELISA for plexin D1-IgG using a recombinant extracellular domain of human plexin D1 containing the major epitope and sera from 58 subjects previously studied with a standard tissue-based indirect immunofluorescence assay (TBA). We screened 63 patients with probable SFN and 55 healthy controls (HCs) for serum plexin D1-IgG using ELISA. The results were confirmed by TBA. IgG from 3 plexin D1-IgG-positive patients, 2 plexin D1-IgG-negative inflammatory disease controls, and 2 HCs was intrathecally injected into mice, which were assessed for mechanical and thermal hypersensitivity 24 and 48 hours after injection.ResultsThe ELISA had 75% sensitivity and 100% specificity using the TBA as a standard, and the coincidence rate of ELISA to TBA was 96.6% (56/58). The frequency of plexin D1-IgG was higher in patients with SFN than in HCs (12.7% [8/63] vs 0.0% [0/55], p = 0.007). Purified IgG from all 3 plexin D1-IgG-positive patients, but not 2 plexin D1-IgG-negative patients, induced significant mechanical and/or thermal hypersensitivity compared with IgG from HCs. In mice injected with plexin D1-IgG-positive but not D1-IgG-negative patient IgG, phosphorylated extracellular signal-regulated protein kinase immunoreactivity, an activation marker, was confined to small dorsal root ganglion neurons and was significantly more abundant than in mice injected with HC IgG.ConclusionsPlexin D1-IgG is pathogenic but with low prevalence and is a potential biomarker for immunotherapy in SFN.

scholarly journals A novel gain-of-function sodium channel β2 subunit mutation in idiopathic small fiber neuropathy

2021 ◽  
Author(s):  
Matthew Alsaloum ◽  
Julie I. R. Labau ◽  
Daniel Sosniak ◽  
Peng Zhao ◽  
Rowida Almomani ◽  
...  
Keyword(s):  
Action Potential ◽  
Sodium Channel ◽  
Small Fiber Neuropathy ◽  
Dorsal Root Ganglion Neurons ◽  
Action Potential Firing ◽  
Gain Of Function ◽  
C Fibers ◽  
Small Fiber ◽  
Potential Firing ◽  
Ganglion Neurons

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Aδ and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several the pore-forming voltage-gated sodium channel α subunits (NaVs) in a subset of patients with SFN, but the auxiliary sodium channel β subunits have been less implicated in the development of the disease. β subunits modulate NaV trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the β2-subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel β subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly-identified Y69H variant of the β2 subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the β2-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of β2 subunits in SFN and strengthens the link between sodium channel β subunits and the development of neuropathic pain in humans.

scholarly journals Temporal mechanically-induced signaling events in bone and dorsal root ganglion neurons after in vivo bone loading

PLoS ONE ◽  
2018 ◽  
Vol 13 (2) ◽  
pp. e0192760
Author(s):  
Jason A. Bleedorn ◽  
Troy A. Hornberger ◽  
Craig A. Goodman ◽  
Zhengling Hao ◽  
Susannah J. Sample ◽  
...  
Keyword(s):  
Dorsal Root Ganglion ◽  
Dorsal Root ◽  
Dorsal Root Ganglion Neurons ◽  
Signaling Events ◽  
Bone Loading ◽  
Ganglion Neurons

scholarly journals Analgesic Effects of Cnidium officinale Extracts on Postoperative, Neuropathic, and Menopausal Pain in Rat Models

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Eun Yeong Lim ◽  
Jae Goo Kim ◽  
Jaekwang Lee ◽  
Changho Lee ◽  
Jaewon Shim ◽  
...  
Keyword(s):  
Ferulic Acid ◽  
Dorsal Root Ganglion Neurons ◽  
Great Efficacy ◽  
Withdrawal Threshold ◽  
Analgesic Effects ◽  
Pain Models ◽  
Cnidium Officinale ◽  
Model Treatment ◽  
Ganglion Neurons

Cnidium officinale, widely cultivated in East Asia, has been reported to exhibit pharmacological efficacy in various disorders. However, little has been reported on its role as a pain killer. In this study, we reveal that the C. officinale extract (COE) has great efficacy as a novel analgesic in various in vivo pain models. Administration of COE attenuated hypersensitivity in all postoperative, neuropathic, and menopausal pain models. Decreased hyperalgesia was confirmed by a mechanical withdrawal threshold assay and ultrasonic vocalization call analysis. In addition, application of COE inhibited the induction of the proinflammatory cytokines and calpain-3 on dorsal root ganglion neurons in a spared nerve injury rat model. Treatment with ferulic acid, which was identified as one of the components of COE by HPLC analysis, alleviated nociceptive behaviors. Our findings suggest that ferulic acid is an active compound from COE, and COE is a potential phytomedical source for pain relief by inhibiting the process of inflammation.

scholarly journals Characterization of Functional Vanilloid Receptors Expressed by Mast Cells

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1332-1340 ◽  
Author(s):  
Tamás Bı́ró ◽  
Marcus Maurer ◽  
Shayan Modarres ◽  
Nancy E. Lewin ◽  
Chaya Brodie ◽  
...  
Keyword(s):  
Mast Cells ◽  
Ruthenium Red ◽  
Dorsal Root Ganglion Neurons ◽  
Interleukin 4 ◽  
Vanilloid Receptors ◽  
45Ca Uptake ◽  
Ganglion Neurons ◽  
Type Receptor

Abstract Capsaicin and its ultrapotent analog resiniferatoxin (RTX) act through specific vanilloid receptors on sensory neurons. The C-type receptor is coupled to 45Ca uptake, whereas the R-type is detectable by [3H]RTX binding. We describe here specific vanilloid responses in murine mast cells (MCs). In the MC lines and in bone marrow-derived mast cells, capsaicin and RTX induced45Ca uptake similarly to that observed for cultured rat dorsal root ganglion neurons (DRGs). This response was antagonized by the antagonists capsazepine and ruthenium red. As in DRGs, pretreatment of MCs with capsaicin or RTX induced desensitization to subsequent stimulation of 45Ca uptake. The potency for desensitization by RTX in the MCs corresponded to that for 45Ca uptake, whereas in DRGs it occurred at significantly lower concentrations corresponding to that for the high-affinity [3H]RTX binding site. Consistent with this difference, in MCs we were unable to detect [3H]RTX binding. Vanilloids were noncytotoxic to the MCs, in contrast to the DRGs. Although vanilloids did not cause degranulation in MCs, in the P815 clone capsaicin evoked selective interleukin-4 release. We conclude that certain MCs possess vanilloid receptors, but only the C-type that functions as a channel. Our finding that MCs can respond directly to capsaicin necessitates a reevaluation of the in vivo pathway of inflammation in response to vanilloids.

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