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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 2837

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 (3 papers)

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Research

30 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 1 | Viewed by 687
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 785
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 991
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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