Language：Japanese   Publisher：The Japanese Pharmacological Society  

<p>Lesion or diseases affecting the somatosensory system causes neuropathic pain, a debilitating chronic pain condition. Previous studies using its experimental models have demonstrated the critical contribution of microglia to the development of neuropathic pain. Upon sensing nerve damage, spinal cord microglia alter their morphology, gene expression and function, which lead to an increase in the excitability of pain-transmission neural pathway, causing the pain onset. Recently, newly identified CD11c-positive microglia as a subset that increases during the remission phase of neuropathic pain has been shown to be required for spontaneous remission of neuropathic pain and to play an important role in maintaining the remission state. Thus, these findings suggest that the functions and roles of microglia under neuropathic pain conditions are not one-dimensional but change during the onset, maintenance, and remission phases, and they also provide a clue to establish a new strategy to decipher neuropathic pain and other neurological diseases from the heterogeneity of microglia.</p>

DOI： 10.1254/fpj.22157

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CiNii Research

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.tins.2023.05.001

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Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Neuropathic pain is a pathological pain state caused by a lesion or disease affecting the somatosensory system. Because existing analgesics often do not work, the development of new drugs for neuropathic pain is needed. A mouse model of neuropathic pain in which the fourth lumbar spinal nerve is transected (SpNT: spinal nerve transection) shows pain behavior that is resolved spontaneously. Recently, we found that a CD11c+ microglia subset emerged in the spinal cord after SpNT is necessary for the pain resolution. However, the role of CD11c+ microglia in other neuropathic pain models remains to be determined, especially in spared nerve injury (SNI) model that does not exhibit the spontaneous resolution of pain behavior. In this study, we found the number of CD11c+ microglia in the spinal cord was lower in the SNI model than the SpNT model, suggesting that prolonged behavioral pain hypersensitivity in the SNI model may be related to an impaired emergence of CD11c+ microglia. In addition, increasing the number of CD11c+ microglia by a cytokine administrated exogenously facilitated the resolution of pain behavior in both models. The alleviating effect was abolished by depletion of spinal CD11c+ microglia. Thus, increasing CD11c+ microglia or augmenting their function could be a new therapeutic strategy for neuropathic pain.</p>

DOI： 10.1254/jpssuppl.97.0_1-b-o01-4

CiNii Research

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：American Association for the Advancement of Science (AAAS)  

Neuropathic pain is often caused by injury and diseases that affect the somatosensory system. Although pain development has been well studied, pain recovery mechanisms remain largely unknown. Here, we found that CD11c-expressing spinal microglia appear after the development of behavioral pain hypersensitivity following nerve injury. Nerve-injured mice with spinal CD11c ⁺ microglial depletion failed to recover spontaneously from this hypersensitivity. CD11c ⁺ microglia expressed insulin-like growth factor-1 (IGF1), and interference with IGF1 signaling recapitulated the impairment in pain recovery. In pain-recovered mice, the depletion of CD11c ⁺ microglia or the interruption of IGF1 signaling resulted in a relapse in pain hypersensitivity. Our findings reveal a mechanism for the remission and recurrence of neuropathic pain, providing potential targets for therapeutic strategies.

DOI： 10.1126/science.abf6805

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Language：English   Publishing type：Research paper (scientific journal)  

We have recently developed a mouse monoclonal antibody (12-10H) binding to the head domain region in rat P2X4 receptor (rP2X4R, which is crucial for the pathogenesis of neuropathic pain) expressed on the cell with the highest binding affinity (KD = 20 nM). However, the 12-10H antibody failed to detect endogenously expressed P2X4Rs in microglia isolated from the spinal cord of rats whose spinal nerves were injured. Then, we prepared R5 mutant, in which five arginine residues were introduced into variable regions except for the "hot spot" in the 12-10H antibody to increase electrostatic interactions with the head domain, an anionic region, in rP2X4R. The mutation resulted in an increase of 50-fold in the affinity of the R5 mutant for the head domain with respect to the intact 12-10H antibody. As a result, detection of P2X4Rs endogenously expressed on primary cultured microglial cells originated from the neonatal rat brain and spinal cord microglia isolated from a rat model of neuropathic pain was achieved. These findings suggest a strategy to improve the affinity of a monoclonal antibody for an anionic antigen by the introduction of several arginine residues into variable regions other than the "hot spot" in the paratope.

DOI： 10.1038/s41598-021-03784-w

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PubMed

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Event date： 2023.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神戸   Country：Japan  

Language：Japanese   Publisher：(公社)日本薬理学会  

体性感覚神経系の傷害や疾患によって神経障害性疼痛という慢性疼痛が発症する.病態モデル等を用いたこれまでの研究から,神経障害性疼痛の発症におけるミクログリアの寄与が示されてきた.神経損傷等を感知したミクログリアは,細胞形態や遺伝子発現を伴いその細胞機能を変化させ,痛覚伝達神経の興奮性を高めて疼痛の発症を誘導する.しかし最近,神経障害性疼痛の寛解期に増加するミクログリアサブセット(CD11c陽性)が新たに特定され,疼痛の自然寛解に必要であることと,その後も寛解状態の維持に重要な役割を担うことが明らかになった.すなわち,神経損傷によって変化したミクログリアの機能や役割は一元的ではなく,発症・維持・寛解という各フェーズにおいてダイナミックに変化することが示唆される.これらのミクログリアの多様性とその役割に関する新しい知見から,神経障害性疼痛や他の神経疾患を読み解く新しいストラテジーの確立が期待される.(著者抄録)