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Cells
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Molecular Mechanisms of Neuropathic Pain
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Molecular Mechanisms of Neuropathic Pain

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: 20 July 2025 | Viewed by 5734

Special Issue Editors

Prof. Dr. Hiroshi Ueda

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Guest Editor
Emer. Prof. of Nagasaki Univ. Laboratory for the Study of Pain Research Institute for Production Development 15 Shimogamo Morimoto-cho, Sakyo-ku, Kyoto 606-0805, Japan
Interests: prothymosin α; stroke; DAMPs/alarmins; chronic pain; fibromyalgia; opioid receptor
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Norimitsu Morioka

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Guest Editor
Department of Pharmacology, Graduate School of Biomedical Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734–8551, Japan
Interests: proinflammatory cytokines; neuroprharmacology; connexin43

Special Issue Information

Dear Colleagues,

With the ageing of the global population and the social instability caused by various epidemics, disasters and conflicts, the number of patients with chronic pain continues to increase. According to a recent proposal, nociplastic pain such as fibromyalgia is categorized as both a chronic and neuropathic pain. Some medicines that are able to treat chronic pain are now available, but they often have effects events during long-term treatments. Ideally, we should consider short-term and radical treatments that suppress the pain memory. For this purpose, it is necessary to clarify the mechanisms of prolonged pain and search for new mechanism-based drug targets. Over the past decade, pain research has focused on primary sensory nerves and spinal dorsal horn, and has yielded numerous findings. More recent studies have revealed that repeated pain stimuli also affect various brain regions and that changes in the structure and function of neural networks may contribute to prolonged pain. This Special Issue, therefore, focuses on the latest findings underlying the pain persistence associated with changes in the neural networks mediated by neurons, glial cells and immune cells in various brain regions, and with the brain–immune connection in the development of chronic pain.

Prof. Dr. Hiroshi Ueda
Prof. Dr. Norimitsu Morioka
Guest Editors

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Keywords

  • neuropathic pain
  • nociplastic pain
  • fibromyalgia
  • brain-immune connection
  • sexual dimorphism
  • glial cells
  • lysophosphatidic acid

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Published Papers (7 papers)

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Research

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14 pages, 2022 KiB  
Article
Male-Dominant Spinal Microglia Contribute to Neuropathic Pain by Producing CC-Chemokine Ligand 4 Following Peripheral Nerve Injury
by Fumihiro Saika, Tetsuya Sato, Takeru Nakabayashi, Yohji Fukazawa, Shinjiro Hino, Kentaro Suzuki and Norikazu Kiguchi
Cells 2025, 14(7), 484; https://doi.org/10.3390/cells14070484 - 23 Mar 2025
Viewed by 343
Abstract
Recent studies have revealed marked sex differences in pathophysiological roles of spinal microglia in neuropathic pain, with microglia contributing to pain exacerbation exclusively in males. However, the characteristics of pain-enhancing microglia, which are more prominent in males, remain poorly understood. Here, we reanalyzed [...] Read more.
Recent studies have revealed marked sex differences in pathophysiological roles of spinal microglia in neuropathic pain, with microglia contributing to pain exacerbation exclusively in males. However, the characteristics of pain-enhancing microglia, which are more prominent in males, remain poorly understood. Here, we reanalyzed a previously published single-cell RNA sequencing dataset and identified a microglial subpopulation that significantly increases in the spinal dorsal horn (SDH) of male mice following peripheral nerve injury. CC-chemokine ligand 4 (CCL4) was highly expressed in this subpopulation and its mRNA levels were increased in the SDH after partial sciatic nerve ligation (PSL) only in male mice. Notably, CCL4 expression was reduced in male mice following microglial depletion, indicating that microglia are the primary source of CCL4. Intrathecal administration of maraviroc, an inhibitor of the CCL4–CC-chemokine receptor 5 (CCR5) signaling pathway, after PSL, significantly suppressed mechanical allodynia only in male mice. Furthermore, intrathecal administration of CCL4 induced mechanical allodynia in both sexes, accompanied by increased expression of c-fos, a neuronal excitation marker, in the SDH. These findings highlight a sex-biased difference in the gene expression profile of spinal microglia following peripheral nerve injury, with elevated CCL4 expression in male mice potentially contributing to pain exacerbation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain)
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15 pages, 2763 KiB  
Article
Association Between Synovial NTN4 Expression and Pain Scores, and Its Effects on Fibroblasts and Sensory Neurons in End-Stage Knee Osteoarthritis
by Ayumi Tsukada, Yui Uekusa, Etsuro Ohta, Akito Hattori, Manabu Mukai, Dai Iwase, Jun Aikawa, Yoshihisa Ohashi, Gen Inoue, Masashi Takaso and Kentaro Uchida
Cells 2025, 14(6), 395; https://doi.org/10.3390/cells14060395 - 8 Mar 2025
Viewed by 728
Abstract
Osteoarthritis (OA) is a chronic joint disease marked by synovial inflammation, cartilage degradation, and persistent pain. Although Netrin-4 (NTN4) has been implicated in pain modulation in rheumatoid arthritis (RA), its role in OA pain remains less understood. Previous research has documented that NTN4 [...] Read more.
Osteoarthritis (OA) is a chronic joint disease marked by synovial inflammation, cartilage degradation, and persistent pain. Although Netrin-4 (NTN4) has been implicated in pain modulation in rheumatoid arthritis (RA), its role in OA pain remains less understood. Previous research has documented that NTN4 promotes axonal growth in rodent-derived neurons; however, its effects on human sensory neurons are yet to be fully explored. NTN4 also plays a multifactorial role in various non-neuronal cells, such as endothelial cells, tumor cells, and stromal cells. Nevertheless, its specific impact on synovial fibroblasts, which are key components of the synovium and have been linked to OA pain, is still unclear. This study examined the correlation between NTN4 expression levels and pain severity in OA, specifically investigating its effects on human iPSC-derived sensory neurons (iPSC-SNs) and synovial fibroblasts from OA patients. Our findings indicate a positive correlation between synovial NTN4 expression and pain severity. Recombinant human Netrin-4 (rh-NTN4) was also shown to enhance neurite outgrowth in human iPSC-SNs, suggesting a potential role in neuronal sensitization. Additionally, rh-NTN4 stimulated the production of pro-inflammatory cytokines (IL-6, IL-8) and chemokines (CXCL1, CXCL6, CXCL8) in synovium-derived fibroblastic cells, implicating it in synovial inflammation. Collectively, these results suggest that NTN4 may contribute to KOA pathology by promoting synovial inflammation and potentially sensitizing sensory neurons, thereby influencing the mechanisms of underlying pain. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain)
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29 pages, 23158 KiB  
Article
The Antinociceptive Effects and Sex-Specific Neurotransmitter Modulation of Metformin in a Mouse Model of Fibromyalgia
by Hanin Abdulbaset AboTaleb, Hani A. Alturkistani, Gamal S. Abd El-Aziz, Emad A. Hindi, Mervat M. Halawani, Mona Ali Al-Thepyani and Badrah S. Alghamdi
Cells 2024, 13(23), 1986; https://doi.org/10.3390/cells13231986 - 30 Nov 2024
Cited by 2 | Viewed by 1180
Abstract
Fibromyalgia (FM) is a chronic and debilitating condition characterized by diffuse pain, often associated with symptoms such as fatigue, cognitive disturbances, and mood disorders. Metformin, an oral hypoglycemic agent, has recently gained attention for its potential benefits beyond glucose regulation. It has shown [...] Read more.
Fibromyalgia (FM) is a chronic and debilitating condition characterized by diffuse pain, often associated with symptoms such as fatigue, cognitive disturbances, and mood disorders. Metformin, an oral hypoglycemic agent, has recently gained attention for its potential benefits beyond glucose regulation. It has shown promise in alleviating neuropathic and inflammatory pain, suggesting that it could offer a novel approach to managing chronic pain conditions like FM. This study aimed to further explore metformin’s analgesic potential by evaluating its effects in an experimental FM model induced by reserpine in both male and female mice. After the administration of 200 mg/kg metformin to male and female mice, the FM-related symptoms were assessed, including mechanical allodynia, thermal hyperalgesia, and depressive-like behaviors. A histological examination of the thalamus, hippocampus, and spinal cord was conducted using haematoxylin and eosin staining. The neurotransmitter and proinflammatory cytokines levels were measured in the brains and spinal cords. Our results have shown that metformin treatment for seven days significantly reversed these FM-like symptoms, reducing pain sensitivity and improving mood-related behaviors in both the male and female mice. Additionally, metformin exhibited neuroprotective effects, mitigating reserpine-induced damage in the hippocampus, thalamus, and spinal cord. It also significantly lowered the levels of the proinflammatory cytokine interleukin 1-beta (IL-1β) in the brain and spinal cord. Notably, metformin modulated the neurotransmitter levels differently between the sexes, decreasing glutamate and increasing serotonin and norepinephrine in the male mice, but not in the females. These findings underscore metformin’s potential as an alternative therapy for FM, with sex-specific differences suggesting distinct mechanisms of action. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain)
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12 pages, 3027 KiB  
Article
Intranasal Treatment with Cannabinoid 2 Receptor Agonist HU-308 Ameliorates Cold Sensitivity in Mice with Traumatic Trigeminal Neuropathic Pain
by Simeng Ma, Yoki Nakamura, Suzuna Uemoto, Kenta Yamamoto, Kazue Hisaoka-Nakashima and Norimitsu Morioka
Cells 2024, 13(23), 1943; https://doi.org/10.3390/cells13231943 - 22 Nov 2024
Viewed by 1154
Abstract
Post-traumatic trigeminal neuropathy (PTTN) is a sensory abnormality caused by injury to the trigeminal nerve during orofacial surgery. However, existing analgesics are ineffective against PTTN. Abnormal microglial activation in the caudal part of the spinal trigeminal nucleus caudal part (Sp5C), where the central [...] Read more.
Post-traumatic trigeminal neuropathy (PTTN) is a sensory abnormality caused by injury to the trigeminal nerve during orofacial surgery. However, existing analgesics are ineffective against PTTN. Abnormal microglial activation in the caudal part of the spinal trigeminal nucleus caudal part (Sp5C), where the central trigeminal nerve terminals reside, plays an important role in PTTN pathogenesis. Therefore, regulating microglial activity in Sp5C appears to be an important approach to controlling pain in PTTN. Cannabinoid receptor 2 (CB2) is expressed in immune cells including microglia, and its activation has anti-inflammatory effects. The current study demonstrates that the repeated intranasal administration of CB2 agonist HU-308 ameliorates the infraorbital nerve cut (IONC)-induced hyperresponsiveness to acetone (cutaneous cooling). The therapeutic efficacy of oral HU-308 was found to be less pronounced in alleviating cold hypersensitivity in IONC mice compared to intranasal administration, indicating the potential advantages of the intranasal route. Furthermore, repeated intranasal administration of HU-308 suppressed the activation of Sp5C microglia in IONC mice. Additionally, pretreatment with the CB2 antagonist, SR 144528, significantly blocked the anti-nociceptive effect of repeated intranasal administration of HU-308 on cold hypersensitization in IONC mice. These data suggest that the continuous stimulation of CB2 ameliorates PTTN-induced pain via the inhibition of microglial activation. Thus, CB2 agonists are potential candidates for novel therapeutic agents against PTTN. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain)
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11 pages, 1116 KiB  
Communication
Effects of Tryptophan and Physical Exercise on the Modulation of Mechanical Hypersensitivity in a Fibromyalgia-like Model in Female Rats
by Rafael Marins Rezende, Roney Santos Coimbra, Markus Kohlhoff, Lukiya Silva Campos Favarato, Hércia Stampini Duarte Martino, Luciano Bernardes Leite, Leoncio Lopes Soares, Samuel Encarnação, Pedro Forte, António Miguel de Barros Monteiro, Maria do Carmo Gouveia Peluzio and Antônio José Natali
Cells 2024, 13(19), 1647; https://doi.org/10.3390/cells13191647 - 3 Oct 2024
Viewed by 1215
Abstract
Though the mechanisms are not fully understood, tryptophan (Trp) and physical exercise seem to regulate mechanical hypersensitivity in fibromyalgia. Here, we tested the impact of Trp supplementation and continuous low-intensity aerobic exercise on the modulation of mechanical hypersensitivity in a fibromyalgia-like model induced [...] Read more.
Though the mechanisms are not fully understood, tryptophan (Trp) and physical exercise seem to regulate mechanical hypersensitivity in fibromyalgia. Here, we tested the impact of Trp supplementation and continuous low-intensity aerobic exercise on the modulation of mechanical hypersensitivity in a fibromyalgia-like model induced by acid saline in female rats. Twelve-month-old female Wistar rats were randomly divided into groups: [control (n = 6); acid saline (n = 6); acid saline + exercise (n = 6); acid saline + Trp (n = 6); and acid saline + exercise + Trp (n = 6)]. Hypersensitivity was caused using two intramuscular jabs of acid saline (20 μL; pH 4.0; right gastrocnemius), 3 days apart. The tryptophan-supplemented diet contained 7.6 g/hg of Trp. The three-week exercise consisted of progressive (30–45 min) treadmill running at 50 to 60% intensity, five times (Monday to Friday) per week. We found that acid saline induced contralateral mechanical hypersensitivity without changing the levels of Trp, serotonin (5-HT), and kynurenine (KYN) in the brain. Hypersensitivity was reduced by exercise (~150%), Trp (~67%), and its combination (~160%). The Trp supplementation increased the levels of Trp and KYN in the brain, and the activity of indoleamine 2,3-dioxygenase (IDO), and decreased the ratio 5-HT:KYN. Exercise did not impact the assessed metabolites. Combining the treatments reduced neither hypersensitivity nor the levels of serotonin and Trp in the brain. In conclusion, mechanical hypersensitivity induced by acid saline in a fibromyalgia-like model in female rats is modulated by Trp supplementation, which increases IDO activity and leads to improved Trp metabolism via the KYN pathway. In contrast, physical exercise does not affect mechanical hypersensitivity through brain Trp metabolism via either the KYN or serotonin pathways. Because this is a short study, generalizing its findings warrants caution. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain)
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Review

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18 pages, 1386 KiB  
Review
Protein Kinases as Mediators for miRNA Modulation of Neuropathic Pain
by Leah Chang, Zala Čok and Lei Yu
Cells 2025, 14(8), 577; https://doi.org/10.3390/cells14080577 - 11 Apr 2025
Viewed by 50
Abstract
Neuropathic pain is a chronic condition resulting from injury or dysfunction in the somatosensory nervous system, which leads to persistent pain and a significant impairment of quality of life. Research has highlighted the complex molecular mechanisms that underlie neuropathic pain and has begun [...] Read more.
Neuropathic pain is a chronic condition resulting from injury or dysfunction in the somatosensory nervous system, which leads to persistent pain and a significant impairment of quality of life. Research has highlighted the complex molecular mechanisms that underlie neuropathic pain and has begun to delineate the roles of microRNAs (miRNAs) in modulating pain pathways. miRNAs, which are small non-coding RNAs that regulate gene expression post-transcriptionally, have been shown to influence key cellular processes, including neuroinflammation, neuronal excitability, and synaptic plasticity. These processes contribute to the persistence of neuropathic pain, and miRNAs have emerged as critical regulators of pain behaviors by modulating signaling pathways that control pain sensitivity. miRNAs can influence neuropathic pain by targeting genes that encode protein kinases involved in pain signaling. This review focuses on miRNAs that have been demonstrated to modulate neuropathic pain behavior through their effects on protein kinases or their immediate upstream regulators. The relationship between miRNAs and neuropathic pain behaviors is characterized as either an upregulation or a downregulation of miRNA levels that leads to a reduction in neuropathic pain. In the case of miRNA upregulation resulting in an alleviation of neuropathic pain behaviors, protein kinases exhibit a positive correlation with neuropathic pain, whereas decreased protein kinase levels correlate with diminished neuropathic pain behaviors. The only exception is GRK2, which shows an inverse correlation with neuropathic pain. In the case of miRNA downregulation resulting in a reduction in neuropathic pain behaviors, protein kinases display mixed relationships to neuropathic pain, with some kinases exhibiting positive correlation, while others exhibit negative correlation. By exploring how protein kinases mediate miRNA modulation of neuropathic pain, valuable insight may be gained into the pathophysiology of neuropathic pain, offering potential therapeutic targets for developing more effective strategies for pain management. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain)
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35 pages, 1992 KiB  
Review
BDNF Signaling and Pain Modulation
by Mariacristina Mazzitelli, Takaki Kiritoshi, Peyton Presto, Zachary Hurtado, Nico Antenucci, Guangchen Ji and Volker Neugebauer
Cells 2025, 14(7), 476; https://doi.org/10.3390/cells14070476 - 22 Mar 2025
Viewed by 481
Abstract
Brain-derived neurotrophic factor (BDNF) is an important neuromodulator of nervous system functions and plays a key role in neuronal growth and survival, neurotransmission, and synaptic plasticity. The effects of BDNF are mainly mediated by the activation of tropomyosin receptor kinase B (TrkB), expressed [...] Read more.
Brain-derived neurotrophic factor (BDNF) is an important neuromodulator of nervous system functions and plays a key role in neuronal growth and survival, neurotransmission, and synaptic plasticity. The effects of BDNF are mainly mediated by the activation of tropomyosin receptor kinase B (TrkB), expressed in both the peripheral and central nervous system. BDNF has been implicated in several neuropsychiatric conditions such as schizophrenia and anxio-depressive disorders, as well as in pain states. This review summarizes the evidence for a critical role of BDNF throughout the pain system and describes contrasting findings of its pro- and anti-nociceptive effects. Different cellular sources of BDNF, its influence on neuroimmune signaling in pain conditions, and its effects in different cell types and regions are described. These and endogenous BDNF levels, downstream signaling mechanisms, route of administration, and approaches to manipulate BDNF functions could explain the bidirectional effects in pain plasticity and pain modulation. Finally, current knowledge gaps concerning BDNF signaling in pain are discussed, including sex- and pathway-specific differences. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain)
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