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Special Issue "Molecular Mechanisms of Neuropathic Pain and Nerve Injury"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 April 2021).

Special Issue Editor

Dr. Masamichi Shinoda
E-Mail Website
Guest Editor
Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
Interests: Orofacial Pain; Orofacial Nociception; Extrateritorial Pain; Trigeminal Ganglion; Trigeminal Subnucleus Caudalis

Special Issue Information

Dear Colleagues,

Neuropathic pain such as postherpetic neuralgia, post-stroke pain, and trigeminal neuralgia is known to occur as a result of peripheral and/or central neurological disturbances. Neuropathic pain is also clinically typified by intractable non-noxious stimulation-induced pain and thought to be a direct result of a lesion or disease that affects the peripheral somatosensory system. Once peripheral nerve damage occurs, various molecular and cellular responses are induced at the site of the nerve injury. First, a neuroinflammatory reaction is induced, associated with numerous changes in the immune cell microenvironment, surrounding the damaged peripheral nerve. It is reported that immune cells infiltrate the injury site. The injured neurons and Schwann cells release proinflammatory cytokines, chemokines and neuropeptides, which leads to peripheral neuronal hypersensitivity. The injured neurons themselves cause plastic changes associated with decrease of threshold, spontaneous activity, and hyper-responsiveness. The understanding of the involvement of nerve injury in molecular mechanisms of pain hypersensitivity could offer better diagnostic and therapeutic approaches for neuropathic pain. This Issue will be of interest to basic researchers and clinicians interested in neuropathic pain mechanism.

Dr. Masamichi Shinoda
Guest Editor

Manuscript Submission Information

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Keywords

  • neuropathic pain
  • nerve injury
  • nociception
  • sensory neuron
  • sensory ganglion
  • satellite cell
  • macrophage
  • neuronal plasticity
  • spinal dorsal horn
  • microglia
  • astrocyte
  • secondary neuron
  • synapse

Published Papers (4 papers)

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Research

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Open AccessArticle
Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing
Int. J. Mol. Sci. 2021, 22(1), 405; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010405 - 02 Jan 2021
Cited by 1 | Viewed by 590
Abstract
The sodium-activated potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (IKNa) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing [...] Read more.
The sodium-activated potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (IKNa) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated IKNa in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated IKNa may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)
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Open AccessArticle
Irisin Gene Delivery Ameliorates Burn-Induced Sensory and Motor Neuropathy
Int. J. Mol. Sci. 2020, 21(20), 7798; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207798 - 21 Oct 2020
Cited by 1 | Viewed by 792
Abstract
Burn-related neuropathy is common and often involves pain, paresthesia, or muscle weakness. Irisin, an exercise-induced myokine after cleavage from its membrane precursor fibronectin type III domain-containing 5 (FNDC5), exhibits neuroprotective and anti-inflammatory activities. A rat model of third-degree burn on the right hind [...] Read more.
Burn-related neuropathy is common and often involves pain, paresthesia, or muscle weakness. Irisin, an exercise-induced myokine after cleavage from its membrane precursor fibronectin type III domain-containing 5 (FNDC5), exhibits neuroprotective and anti-inflammatory activities. A rat model of third-degree burn on the right hind paw was used to investigate the therapeutic role of irisin/FNDC5. Rats received burn injury and were treated with intrathecal recombinant adenovirus containing the irisin sequence (Ad-irisin) at 3 weeks postburn. One week later, mechanical allodynia was examined. The expression of irisin in cerebrospinal fluid (CSF) was detected. Ipsilateral gastrocnemius muscle and lumbar spinal cord were also obtained for further investigation. Furthermore, the anti-apoptotic effect of recombinant irisin in SH-SY5Y cells was evaluated through tumor necrosis factor alpha (TNFα) stimulus to mimic burn injury. We noted intrathecal Ad-irisin attenuated pain sensitization and gastrocnemius muscle atrophy by modulating the level of irisin in CSF, and the expression of neuronal FNDC5/irisin and TNFα in the spinal cord. Ad-irisin also ameliorated neuronal apoptosis in both dorsal and ventral horns. Furthermore, recombinant irisin attenuated TNFα-induced SH-SY5Y cell apoptosis. In summary, irisin attenuated allodynia and muscle wasting by ameliorating neuroinflammation-induced neuronal apoptosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)
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Open AccessArticle
Microglia–Astrocyte Communication via C1q Contributes to Orofacial Neuropathic Pain Associated with Infraorbital Nerve Injury
Int. J. Mol. Sci. 2020, 21(18), 6834; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186834 - 17 Sep 2020
Viewed by 772
Abstract
Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which [...] Read more.
Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia–astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)
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Review

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Open AccessReview
Potential Therapeutic Strategies and Substances for Facial Nerve Regeneration Based on Preclinical Studies
Int. J. Mol. Sci. 2021, 22(9), 4926; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094926 - 06 May 2021
Viewed by 155
Abstract
Despite advances in microsurgical technology and an improved understanding of nerve regeneration, obtaining satisfactory results after facial nerve injury remains a difficult clinical problem. Among existing peripheral nerve regeneration studies, relatively few have focused on the facial nerve, particularly how experimental studies of [...] Read more.
Despite advances in microsurgical technology and an improved understanding of nerve regeneration, obtaining satisfactory results after facial nerve injury remains a difficult clinical problem. Among existing peripheral nerve regeneration studies, relatively few have focused on the facial nerve, particularly how experimental studies of the facial nerve using animal models play an essential role in understanding functional outcomes and how such studies can lead to improved axon regeneration after nerve injury. The purpose of this article is to review current perspectives on strategies for applying potential therapeutic methods for facial nerve regeneration. To this end, we searched Embase, PubMed, and the Cochrane library using keywords, and after applying exclusion criteria, obtained a total of 31 qualifying experimental studies. We then summarize the fundamental experimental studies on facial nerve regeneration, highlighting recent bioengineering studies employing various strategies for supporting facial nerve regeneration, including nerve conduits with stem cells, neurotrophic factors, and/or other therapeutics. Our summary of the methods and results of these previous reports reveal a common feature among studies, showing that various neurotrophic factors arising from injured nerves contribute to a microenvironment that plays an important role in functional recovery. In most cases, histological examinations showed that this microenvironmental influence increased axonal diameter as well as myelination thickness. Such an analysis of available research on facial nerve injury and regeneration represents the first step toward future therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain and Nerve Injury)
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