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Roles of the Immune System in Neuropathic Pain
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Roles of the Immune System in Neuropathic Pain

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

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 7351

Special Issue Editor

Dr. Wei-Zen Sun

E-Mail Website
Guest Editor
Department of Anesthesiology, National Taiwan University Hospital, Taipei, Taiwan
Interests: opioid; macrophage; spared nerve injury; acupuncture

Special Issue Information

Dear Colleagues,

Neuropathic pain is caused by lesions or diseases of the somatosensory system and is a major public health issue around the world. It is characterized by increased responses to nociceptive stimuli (hyperalgesia), unpleasant and abnormal sensations (dysesthesia), and pain in response to light tactile stimuli (allodynia). Studies show that neuropathic pain involves a series of pathophysiologic events when the nerve is damaged, including neuronal hyperexcitability, changes in perineuronal homeostasis, and neurogenic inflammation.

Although the treatment for neuropathic pain remains a great challenge, progress has been made in identifying key molecules and their roles in pain modulation and processing. Recent developments in the investigation of neurological disorders have led to an enhanced focus on the role of the immune response and the interaction between the immune system and the nervous system.

The main purpose of this Special Issue is to collect original research articles, reviews, and perspectives to further our understanding of the pathological immune responses and the role of the immune system in neuropathic pain, which can be used as therapeutic targets for pain treatment. Both animal models and human studies are welcome.

Dr. Wei-Zen Sun
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • opioid
  • macrophage
  • spared nerve injury
  • acupuncture

Published Papers (4 papers)

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Research

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16 pages, 4186 KiB  
Article
Microglia and p38 MAPK Inhibitors Suppress Development of Mechanical Allodynia in Both Sexes in a Mouse Model of Antiretroviral-Induced Neuropathic Pain
by Maryam W. Alhadlaq and Willias Masocha
Int. J. Mol. Sci. 2023, 24(16), 12805; https://doi.org/10.3390/ijms241612805 - 15 Aug 2023
Cited by 1 | Viewed by 1256
Abstract
Microglia activation in the spinal cord play a major role in the pathogenesis of neuropathic pain. The p38 mitogen-activated protein kinase (MAPK) regulates microglia activation. Previously, 2′,3′-dideoxycytidine (ddC), a nucleoside reverse transcriptase inhibitor (NRTI), was found to induce mechanical allodynia and microglia activation [...] Read more.
Microglia activation in the spinal cord play a major role in the pathogenesis of neuropathic pain. The p38 mitogen-activated protein kinase (MAPK) regulates microglia activation. Previously, 2′,3′-dideoxycytidine (ddC), a nucleoside reverse transcriptase inhibitor (NRTI), was found to induce mechanical allodynia and microglia activation in the spinal cords of male and female mice. In this study, we investigated the role of spinal microglia and p38 MAPK signaling in the development of mechanical allodynia using immunofluorescence staining and treatment with microglia and p38 MAPK inhibitors in both sexes. Male and female mice (BALB/c strain) treated intraperitoneally once daily with ddC 25 mg/kg for five consecutive days developed mechanical allodynia, assessed using the dynamic plantar aesthesiometer. Treatment with ddC increased microglia markers CD11b and ionized calcium-binding adapter molecule 1 (Iba1) staining intensity in male mice, while only CD11b was increased in female mice. Both sexes had increased phosphorylated p38 MAPK staining intensity. The administration of minocycline, an inhibitor of microglia activation, and adezmapimod, a selective p38 MAPK inhibitor, suppressed mechanical allodynia in both sexes at day 7 after ddC treatment. Therefore, microglia activation and p38 MAPK signaling are important for the development of antiretroviral drug-induced mechanical allodynia. Full article
(This article belongs to the Special Issue Roles of the Immune System in Neuropathic Pain)
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16 pages, 3332 KiB  
Article
Local Inflammatory Mediators Involved in Neuropathic Pain
by Patricia García-Fernández, Colette Reinhold, Nurcan Üçeyler and Claudia Sommer
Int. J. Mol. Sci. 2023, 24(9), 7814; https://doi.org/10.3390/ijms24097814 - 25 Apr 2023
Cited by 1 | Viewed by 1544
Abstract
Polyneuropathy (PNP) is a term to describe diseases of the peripheral nervous system, 50% of which present with neuropathic pain. In some types of PNP, pain is restricted to the skin distally in the leg, suggesting a local regulatory process leading to pain. [...] Read more.
Polyneuropathy (PNP) is a term to describe diseases of the peripheral nervous system, 50% of which present with neuropathic pain. In some types of PNP, pain is restricted to the skin distally in the leg, suggesting a local regulatory process leading to pain. In this study, we proposed a pro-inflammatory pathway mediated by NF-κB that might be involved in the development of pain in patients with painful PNP. To test this hypothesis, we have collected nerve and skin samples from patients with different etiologies and levels of pain. We performed RT-qPCR to analyze the gene expression of the proposed inflammatory pathway components in sural nerve and in distal and proximal skin samples. In sural nerve, we showed a correlation of TLR4 and TNFα to neuropathic pain, and an upregulation of TNFα in patients with severe pain. Patients with an inflammatory PNP also presented a lower expression of TRPV1 and SIRT1. In distal skin, we found a reduced expression of TLR4 and miR-146-5p, in comparison to proximal skin. Our findings thus support our hypothesis of local inflammatory processes involved in pain in PNP, and further show disturbed anti-inflammatory pathways involving TRPV1 and SIRT1 in inflammatory PNP. Full article
(This article belongs to the Special Issue Roles of the Immune System in Neuropathic Pain)
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12 pages, 5832 KiB  
Article
The Iridoid Glycoside Loganin Modulates Autophagic Flux Following Chronic Constriction Injury-Induced Neuropathic Pain
by Kuang-I Cheng, Yu-Chin Chang, Li-Wen Chu, Su-Ling Hsieh, Li-Mei An, Zen-Kong Dai and Bin-Nan Wu
Int. J. Mol. Sci. 2022, 23(24), 15873; https://doi.org/10.3390/ijms232415873 - 14 Dec 2022
Cited by 2 | Viewed by 1618
Abstract
Autophagy facilitates the degradation of organelles and cytoplasmic proteins in a lysosome-dependent manner. It also plays a crucial role in cell damage. Whether loganin affects autophagy in chronic constriction injury (CCI)-induced neuropathic pain remains unclear. We investigated the neuroprotective effect of loganin on [...] Read more.
Autophagy facilitates the degradation of organelles and cytoplasmic proteins in a lysosome-dependent manner. It also plays a crucial role in cell damage. Whether loganin affects autophagy in chronic constriction injury (CCI)-induced neuropathic pain remains unclear. We investigated the neuroprotective effect of loganin on the autophagic–lysosomal pathway in the rat CCI model. Sprague–Dawley rats were divided into sham, CCI, sham + loganin, and CCI + loganin. Loganin (5 mg/kg/day) was intraperitoneally injected once daily, and rats were sacrificed on day 7 after CCI. This study focused on the mechanism by which loganin modulates autophagic flux after CCI. CCI enhanced the autophagic marker LC3B-II in the ipsilateral spinal cord. The ubiquitin-binding protein p62 binds to LC3B-II and integrates into autophagosomes, which are degraded by autophagy. CCI caused the accumulation of p62, indicating the interruption of autophagosome turnover. Loganin significantly attenuated the expression of Beclin-1, LC3B-II, and p62. Double immunofluorescence staining was used to confirm that LC3B-II and p62 were reduced by loganin in the spinal microglia and astrocytes. Loganin also lessened the CCI-increased colocalization of both proteins. Enhanced lysosome-associated membrane protein 2 (LAMP2) and pro-cathepsin D (pro-CTSD) in CCI rats were also attenuated by loganin, suggesting that loganin improves impaired lysosomal function and autophagic flux. Loganin also attenuated the CCI-increased apoptosis protein Bax and cleaved caspase-3. Loganin prevents CCI-induced neuropathic pain, which could be attributed to the regulation of neuroinflammation, neuronal autophagy, and associated cell death. These data suggest autophagy could be a potential target for preventing neuropathic pain. Full article
(This article belongs to the Special Issue Roles of the Immune System in Neuropathic Pain)
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Review

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30 pages, 1312 KiB  
Review
α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain
by Irina Shelukhina, Andrei Siniavin, Igor Kasheverov, Lucy Ojomoko, Victor Tsetlin and Yuri Utkin
Int. J. Mol. Sci. 2023, 24(7), 6524; https://doi.org/10.3390/ijms24076524 - 30 Mar 2023
Cited by 10 | Viewed by 2507
Abstract
Nicotinic acetylcholine receptors (nAChRs) present as many different subtypes in the nervous and immune systems, muscles and on the cells of other organs. In the immune system, inflammation is regulated via the vagus nerve through the activation of the non-neuronal α7 nAChR subtype, [...] Read more.
Nicotinic acetylcholine receptors (nAChRs) present as many different subtypes in the nervous and immune systems, muscles and on the cells of other organs. In the immune system, inflammation is regulated via the vagus nerve through the activation of the non-neuronal α7 nAChR subtype, affecting the production of cytokines. The analgesic properties of α7 nAChR-selective compounds are mostly based on the activation of the cholinergic anti-inflammatory pathway. The molecular mechanism of neuropathic pain relief mediated by the inhibition of α9-containing nAChRs is not fully understood yet, but the role of immune factors in this process is becoming evident. To obtain appropriate drugs, a search of selective agonists, antagonists and modulators of α7- and α9-containing nAChRs is underway. The naturally occurring three-finger snake α-neurotoxins and mammalian Ly6/uPAR proteins, as well as neurotoxic peptides α-conotoxins, are not only sophisticated tools in research on nAChRs but are also considered as potential medicines. In particular, the inhibition of the α9-containing nAChRs by α-conotoxins may be a pathway to alleviate neuropathic pain. nAChRs are involved in the inflammation processes during AIDS and other viral infections; thus they can also be means used in drug design. In this review, we discuss the role of α7- and α9-containing nAChRs in the immune processes and in pain. Full article
(This article belongs to the Special Issue Roles of the Immune System in Neuropathic Pain)
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