Role of voltage-gated sodium channels in axonal signal propagation of trigeminal ganglion neurons after infraorbital nerve entrapment

Mulpuri, Yatendra; Yamamoto, Toru; Nishimura, Ichiro; Spigelman, Igor

doi:10.1016/j.ynpai.2022.100084

Cited by 8 publications

(8 citation statements)

References 68 publications

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“…It is important to note that axons contain the necessary secretory machinery, such as protein components of the signal recognition particle, endoplasmic reticulum, and Golgi apparatus, to traffic axonally translated voltage-gated sodium channels to the plasma membrane of axons. 71,118,128,129,180 Consistent with these data are the observations that nerve entrapment 137 and constriction injury 146 result in changes in the sensitivity of action potential propagation in the infraorbital nerve to Na v subtype-selective blockers. Importantly, the local pharmacological block of Na v 1.1 at the site of the constriction injury of the infraorbital nerve attenuated injury-induced mechanical hypersensitivity, suggesting that these axonally translated proteins not only are functional but also may serve as therapeutic targets for the treatment of pain.…”

Section: Pain Effector Molecules In Local Translationmentioning

confidence: 53%

“…For example, after infraorbital nerve entrapment (IoNE), an animal model of trigeminal neuralgia, there is a significant increase in Na v 1.3, Na v 1.7, and Na v 1.8 mRNA in the infraorbital nerve of the IoNE group as compared to the sham group. 137 Conversely, in the trigeminal ganglion (TG) of IoNE animals, there was a reduction in Na v 1.1, Na v 1.6, and Na v 1.8 mRNA. The fact that the pattern of changes in local Na v subunit translation may be injury specific is suggested by our recent observation that Na v 1.1, but not Na v 1.3, Na v 1.7, or Na v 1.8, is increased in the infraorbital nerve after chronic constriction injury.…”

Section: Pain Effector Molecules In Local Translationmentioning

confidence: 99%

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Local translation in primary afferents and its contribution to pain

Gale

Gedeon

Donnelly

et al. 2022

Pain

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Chronic pain remains a significant problem due to its prevalence, impact, and limited therapeutic options. Progress in addressing chronic pain is dependent on a better understanding of underlying mechanisms. Although the available evidence suggests that changes within the central nervous system contribute to the initiation and maintenance of chronic pain, it also suggests that the primary afferent plays a critical role in all phases of the manifestation of chronic pain in most of those who suffer. Most notable among the changes in primary afferents is an increase in excitability or sensitization. A number of mechanisms have been identified that contribute to primary afferent sensitization with evidence for both increases in pronociceptive signaling molecules, such as voltage-gated sodium channels, and decreases in antinociceptive signaling molecules, such as voltage-dependent or calcium-dependent potassium channels. Furthermore, these changes in signaling molecules seem to reflect changes in gene expression as well as posttranslational processing. A mechanism of sensitization that has received far less attention, however, is the local or axonal translation of these signaling molecules. A growing body of evidence indicates that this process not only is dynamically regulated but also contributes to the initiation and maintenance of chronic pain. Here, we review the biology of local translation in primary afferents and its relevance to pain pathobiology.

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Section: Pain Effector Molecules In Local Translationmentioning

confidence: 53%

Section: Pain Effector Molecules In Local Translationmentioning

confidence: 99%

Local translation in primary afferents and its contribution to pain

Gale

Gedeon

Donnelly

et al. 2022

Pain

View full text Add to dashboard Cite

show abstract

“…This increase was observed along with an increase in A-fiber and C-fiber axonal signal transmission, which was subsequently reduced after TTX treatment. 60 By contrast, another study reported a minor, although statistically insignificant, increase of Na V 1.7 protein levels in the TG, 14 days postinfrastructure orbital nerve chronic constriction injury (ION-CCI), when compared with the sham group. 46 Yet another study noted that Na V 1.7 mRNA and protein levels were diminished 12 days after ION-CCI surgery.…”

Section: Discussionmentioning

confidence: 95%

“…The decrease in pinprick score was observed as early as 30 minutes postadministration (194: 1. 60 8D). These findings indicate that compound 194 effectively reduces acute nociception in male and female rats with ION-CCI. )…”

Section: Effects Of Intranasal Administration Of Compound 194 On Pinp...mentioning

confidence: 99%

Intranasal CRMP2-Ubc9 inhibitor regulates NaV1.7 to alleviate trigeminal neuropathic pain

Loya-Lopez,

Allen,

Duran

et al. 2023

Pain

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Dysregulation of voltage-gated sodium NaV1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/NaV1.7 interaction and increased functional activity of NaV1.7. Targeting this feed-forward regulation, we developed compound 194, which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We further demonstrated that 194 effectively reduces the functional activity of NaV1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and neuropathic pain. Here, we used a comprehensive array of approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, and behavioral analyses, to assess the functional implications of NaV1.7 regulation by CRMP2 in trigeminal ganglia (TG) neurons. We confirmed the expression of Scn9a, Dpysl2, and UBE2I within TG neurons. Furthermore, we found an interaction between CRMP2 and NaV1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation with compound 194 uncoupled the CRMP2/NaV1.7 interaction, impeded NaV1.7 diffusion on the plasma membrane, and subsequently diminished NaV1.7 activity. Compound 194 also led to a reduction in TG neuron excitability. Finally, when intranasally administered to rats with chronic constriction injury of the infraorbital nerve, 194 significantly decreased nociceptive behaviors. Collectively, our findings underscore the critical role of CRMP2 in regulating NaV1.7 within TG neurons, emphasizing the importance of this indirect modulation in trigeminal neuropathic pain.

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“…The dorsal root ganglia (DRGs) consist of the cell bodies of primary sensory neurons [ 7 ]. The voltage-gated sodium channels (VGSCs) of the DRGs underlie the transduction and propagation of nociceptive signals [ 8 ]. Several studies have shown that changes in VGSCs in DRG neurons have a decisive effect on the excitability of DRG neurons, resulting in chronic pain sensations, including neuropathic pain and inflammatory pain [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of Nav1.6 Mediated by the p38 MAPK Pathway in the Dorsal Root Ganglia Contributes to Cancer-Induced Bone Pain in Rats

Lin

Chen

et al. 2022

Cells

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Cancer-induced bone pain (CIBP) occurs frequently among advanced cancer patients. Voltage-gated sodium channels (VGSCs) have been associated with chronic pain, but how VGSCs function in CIBP is poorly understood. Here, we aimed to investigate the specific role of VGSCs in the dorsal root ganglia (DRGs) in CIBP. A CIBP rat model was generated by the intratibial inoculation of MRMT-1 breast carcinoma cells. Transcriptome sequencing was conducted to assess the gene expression profiles. The expression levels of key genes and differentiated genes related to activated pathways were measured by Western blotting and qPCR. We implanted a catheter intrathecally for the administration of lentivirus and drugs. Then, the changes in the mechanical withdrawal threshold (MWT) were measured. We identified 149 differentially expressed mRNAs (DEmRNAs) in the DRGs of CIBP model rats. The expression of Nav1.6, which was among these DEmRNAs, was significantly upregulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the DEmRNAs showed that they were mainly enriched in the mitogen-activated protein kinase (MAPK) pathway. The decrease in MWT induced by bone cancer was attenuated by Nav1.6 knockdown. Western blot analysis revealed that a p38 inhibitor decreased the expression of Nav1.6 and attenuated pain behavior. Our study shows that the upregulation of Nav1.6 expression by p38 MAPK in the DRGs of rats contributes to CIBP.

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Role of voltage-gated sodium channels in axonal signal propagation of trigeminal ganglion neurons after infraorbital nerve entrapment

Cited by 8 publications

References 68 publications

Local translation in primary afferents and its contribution to pain

Local translation in primary afferents and its contribution to pain

Intranasal CRMP2-Ubc9 inhibitor regulates NaV1.7 to alleviate trigeminal neuropathic pain

Upregulation of Nav1.6 Mediated by the p38 MAPK Pathway in the Dorsal Root Ganglia Contributes to Cancer-Induced Bone Pain in Rats

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