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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 (31 December 2020) | Viewed by 29598

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Special Issue Editor

Prof. Dr. Dong Woon Kim

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Guest Editor

Department of Medical Science, Department of Anatomy and Cell Biology, Brain Research Institute, School of medicine, Chungnam National University, Daejeon 305-764, Korea
Interests: Neuropathic pain, Neuroinflammation, Microglia, Astrocyte, Nanomedicine

Special Issue Information

Dear Colleagues,

Neuropathic pain is a debilitating type of chronic pain that often results from chronic neuroinflammation after nerve injury. The pathogenesis of neuropathic pain has been studied extensively, and knowledge on pain has increased rapidly. Early studies focused on neurons and their activity to uncover the mechanisms of neuropathic pain. However, recent studies have identified key roles of microglia and astrocytes in the pathophysiology of neuropathic pain. Microglia and astrocyte activation after painful insults can have a detrimental role because of their contribution to the induction and development of neuroinflammation and pain. In this case, microglia/astrocytes usually show the harmful phenotype during the early phase and promote inflammation by releasing inflammatory cytokines and chemokines in response to neuronal activity after nerve injury. Conversely, alternative activated microglia/astrocytes are associated with upregulation of anti-inflammatory mediators, playing a vital role in reducing neuropathic pain. Thus, microglia and astrocytes in the spinal cord and brain may polarize to various phenotypes and play opposite roles in neuropathic pain. The understanding of the high microglia and astrocyte phenotype could offer better diagnostic and therapeutic approaches for neuropathic pain. This issue will be of interest to researchers working on glia biology, neuroimmunology, neural plasticity, and also to chemical biologists interested in drug discovery and clinicians for neuropathic pain.

Prof. Dr. Dong Woon Kim
Guest Editor

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Keywords

Neuroinflammation
Neuropathic pain
Microglia
Astrocyte

Published Papers (7 papers)

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Research

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11 pages, 3926 KiB

Open AccessArticle

Electroacupuncture at Neurogenic Spots in Referred Pain Areas Attenuates Hepatic Damages in Bile Duct-Ligated Rats

by Yoo Jung Yi, Do Hee Kim, Suchan Chang, Yeonhee Ryu, Sang Chan Kim and Hee Young Kim

Int. J. Mol. Sci. 2021, 22(4), 1974; https://doi.org/10.3390/ijms22041974 - 17 Feb 2021

Cited by 7 | Viewed by 1966

Abstract

Visceral pain frequently produces referred pain at somatic sites due to the convergence of somatic and visceral afferents. In skin overlying the referred pain, neurogenic spots characterized by hyperalgesia, tenderness and neurogenic inflammation are found. We investigated whether neurogenic inflammatory spots function as acupoints in the rat model of bile duct ligation-induced liver injury. The majority of neurogenic spots were found in the dorsal trunk overlying the referred pain and matched with locations of acupoints. The spots, as well as acupoints, showed high electrical conductance and enhanced expression of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP). Electroacupuncture at neurogenic spots reduced serum hepatocellular enzyme activities and histological patterns of acute liver injury in bile duct ligation (BDL) rats. The results suggest that the neurogenic spots have therapeutic effects as acupoints on hepatic injury in bile-duct ligated rats. Full article

(This article belongs to the Special Issue Neuroinflammation and Pain)

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14 pages, 2054 KiB

Open AccessArticle

Upregulation of TRESK Channels Contributes to Motor and Sensory Recovery after Spinal Cord Injury

by Gyu-Tae Kim, Adrian S. Siregar, Eun-Jin Kim, Eun-Shin Lee, Marie Merci Nyiramana, Min Seok Woo, Young-Sool Hah, Jaehee Han and Dawon Kang

Int. J. Mol. Sci. 2020, 21(23), 8997; https://doi.org/10.3390/ijms21238997 - 26 Nov 2020

Cited by 6 | Viewed by 2753

Abstract

TWIK (tandem-pore domain weak inward rectifying K⁺)-related spinal cord K⁺ channel (TRESK), a member of the two-pore domain K⁺ channel family, is abundantly expressed in dorsal root ganglion (DRG) neurons. It is well documented that TRESK expression is changed in several models of peripheral nerve injury, resulting in a shift in sensory neuron excitability. However, the role of TRESK in the model of spinal cord injury (SCI) has not been fully understood. This study investigates the role of TRESK in a thoracic spinal cord contusion model, and in transgenic mice overexpressed with the TRESK gene (TG_TRESK). Immunostaining analysis showed that TRESK was expressed in the dorsal and ventral neurons of the spinal cord. The TRESK expression was increased by SCI in both dorsal and ventral neurons. TRESK mRNA expression was upregulated in the spinal cord and DRG isolated from the ninth thoracic (T9) spinal cord contusion rats. The expression was significantly upregulated in the spinal cord below the injury site at acute time points (6, 24, and 48 h) after SCI (p < 0.05). In addition, TRESK expression was markedly increased in DRGs below and adjacent to the injury site. TRESK was expressed in inflammatory cells. In addition, the number and fluorescence intensity of TRESK-positive neurons increased in the dorsal and ventral horns of the spinal cord after SCI. TG_TRESK SCI mice showed faster paralysis recovery and higher mechanical threshold compared to wild-type (WT)-SCI mice. TG_TRESK mice showed lower TNF-α concentrations in the blood than WT mice. In addition, IL-1β concentration and apoptotic signals in the caudal spinal cord and DRG were significantly decreased in TG_TRESK SCI mice compared to WT-SCI mice (p < 0.05). These results indicate that TRESK upregulated following SCI contributes to the recovery of paralysis and mechanical pain threshold by suppressing the excitability of motor and sensory neurons and inflammatory and apoptotic processes. Full article

(This article belongs to the Special Issue Neuroinflammation and Pain)

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17 pages, 35206 KiB

Open AccessArticle

by Daisuke Ikutame, Kentaro Urata, Tatsuki Oto, Shintaro Fujiwara, Toshimitsu Iinuma, Ikuko Shibuta, Yoshinori Hayashi, Suzuro Hitomi, Koichi Iwata and Masamichi Shinoda

Int. J. Mol. Sci. 2020, 21(21), 7871; https://doi.org/10.3390/ijms21217871 - 23 Oct 2020

Cited by 6 | Viewed by 2293

Abstract

Activated microglia involved in the development of orofacial pain hypersensitivity have two major polarization states. The aim of this study was to assess the involvement of the aging-related phenotypic conversion of medullary microglia in the enhancement of intraoral pain sensitivity using senescence-accelerated mice (SAM)-prone/8 (SAMP8) and SAM-resistant/1 (SAMR1) mice. Mechanical head-withdrawal threshold (MHWT) was measured for 21 days post palatal mucosal incision. The number of CD11c-immunoreactive (IR) cells [affective microglia (M1)] and CD163-IR cells [protective microglia (M2)], and tumor-necrosis-factor-α (TNF-α)-IR M1 and interleukin (IL)-10-IR M2 were analyzed via immunohistochemistry on days 3 and 11 following incision. The decrease in MHWT observed following incision was enhanced in SAMP8 mice. M1 levels and the number of TNF-α-IR M1 were increased on day 3 in SAMP8 mice compared with those in SAMR1 mice. On day 11, M1 and M2 activation was observed in both groups, whereas IL-10-IR M2 levels were attenuated in SAMP8 mice, and the number of TNF-α-IR M1 cells increased, compared to those in SAMR1 mice. These results suggest that the mechanical allodynia observed following intraoral injury is potentiated and sustained in SAMP8 mice due to enhancement of TNF-α signaling, M1 activation, and an attenuation of M2 activation accompanying IL-10 release. Full article

(This article belongs to the Special Issue Neuroinflammation and Pain)

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12 pages, 2645 KiB

Open AccessArticle

CX3CR1-Targeted PLGA Nanoparticles Reduce Microglia Activation and Pain Behavior in Rats with Spinal Nerve Ligation

by Chan Noh, Hyo Jung Shin, Seounghun Lee, Song I Kim, Yoon-Hee Kim, Won Hyung Lee, Dong Woon Kim, Sun Yeul Lee and Young Kwon Ko

Int. J. Mol. Sci. 2020, 21(10), 3469; https://doi.org/10.3390/ijms21103469 - 14 May 2020

Cited by 15 | Viewed by 3052

Abstract

Activation of CX3CR1 in microglia plays an important role in the development of neuropathic pain. Here, we investigated whether neuropathic pain could be attenuated in spinal nerve ligation (SNL)-induced rats by reducing microglial activation through the use of poly(D,L-lactic-co-glycolic acid) (PLGA)-encapsulated CX3CR1 small-interfering RNA (siRNA) nanoparticles. After confirming the efficacy and specificity of CX3CR1 siRNA, as evidenced by its anti-inflammatory effects in lipopolysaccharide-stimulated BV2 cells in vitro, PLGA-encapsulated CX3CR1 siRNA nanoparticles were synthesized by sonication using the conventional double emulsion (W/O/W) method and administered intrathecally into SNL rats. CX3CR1 siRNA-treated rats exhibited significant reductions in the activation of microglia in the spinal dorsal horn and a downregulation of proinflammatory mediators, as well as a significant attenuation of mechanical allodynia. These data indicate that the PLGA-encapsulated CX3CR1 siRNA nanoparticles effectively reduce neuropathic pain in SNL-induced rats by reducing microglial activity and the expression of proinflammatory mediators. Therefore, we believe that PLGA-encapsulated CX3CR1 siRNA nanoparticles represent a valuable new treatment option for neuropathic pain. Full article

(This article belongs to the Special Issue Neuroinflammation and Pain)

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Review

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18 pages, 1350 KiB

Open AccessReview

Immune Actions on the Peripheral Nervous System in Pain

by Jessica Aijia Liu, Jing Yu and Chi Wai Cheung

Int. J. Mol. Sci. 2021, 22(3), 1448; https://doi.org/10.3390/ijms22031448 - 1 Feb 2021

Cited by 44 | Viewed by 8370

Abstract

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies. Full article

(This article belongs to the Special Issue Neuroinflammation and Pain)

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13 pages, 472 KiB

Open AccessReview

The Role of Astrocytes in the Modulation ofK⁺-Cl⁻-Cotransporter-2 Function

by Tomoya Kitayama

Int. J. Mol. Sci. 2020, 21(24), 9539; https://doi.org/10.3390/ijms21249539 - 15 Dec 2020

Cited by 3 | Viewed by 2379

Abstract

Neuropathic pain is characterized by spontaneous pain, pain sensations, and tactile allodynia. The pain sensory system normally functions under a fine balance between excitation and inhibition. Neuropathic pain arises when this balance is lost for some reason. In past reports, various mechanisms of neuropathic pain development have been reported, one of which is the downregulation of K⁺-Cl⁻-cotransporter-2 (KCC2) expression. In fact, various neuropathic pain models indicate a decrease in KCC2 expression. This decrease in KCC2 expression is often due to a brain-derived neurotrophic factor that is released from microglia. However, a similar reaction has been reported in astrocytes, and it is unclear whether astrocytes or microglia are more important. This review discusses the hypothesis that astrocytes have a crucial influence on the alteration of KCC2 expression. Full article

(This article belongs to the Special Issue Neuroinflammation and Pain)

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26 pages, 591 KiB

Open AccessReview

Overview of Neurological Mechanism of Pain Profile Used for Animal “Pain-Like” Behavioral Study with Proposed Analgesic Pathways

by Mun Fei Yam, Yean Chun Loh, Chuan Wei Oo and Rusliza Basir

Int. J. Mol. Sci. 2020, 21(12), 4355; https://doi.org/10.3390/ijms21124355 - 19 Jun 2020

Cited by 33 | Viewed by 8040

Abstract

Pain is the most common sensation installed in us naturally which plays a vital role in defending us against severe harm. This neurological mechanism pathway has been one of the most complex and comprehensive topics but there has never been an elaborate justification of the types of analgesics that used to reduce the pain sensation through which specific pathways. Of course, there have been some answers to curbing of pain which is a lifesaver in numerous situations—chronic and acute pain conditions alike. This has been explored by scientists using pain-like behavioral study methodologies in non-anesthetized animals since decades ago to characterize the analgesic profile such as centrally or peripherally acting drugs and allowing for the development of analgesics. However, widely the methodology is being practiced such as the tail flick/Hargreaves test and Von Frey/Randall–Selitto tests which are stimulus-evoked nociception studies, and there has rarely been a complete review of all these methodologies, their benefits and its downside coupled with the mechanism of the action that is involved. Thus, this review solely focused on the complete protocol that is being adapted in each behavioral study methods induced by different phlogogenic agents, the different assessment methods used for phasic, tonic and inflammatory pain studies and the proposed mechanism of action underlying each behavioral study methodology for analgesic drug profiling. It is our belief that this review could significantly provide a concise idea and improve our scientists’ understanding towards pain management in future research. Full article

(This article belongs to the Special Issue Neuroinflammation and Pain)

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