Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key...Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis.This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels:(1)Peripheral Sensitization:CCL2/CCR2 modulates TRPV1,Nav1.8,and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain.(2)Spinal Cord Central Sensitization:CCL2/CCR2 contributes to NMDAR-dependent plasticity,glial activation,GABAergic disinhibition,and opioid receptor desensitization.(3)Supraspinal Central Networks:CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions,including the ACC,CeA,NAc,and hippocampus,and it also increases pain sensitization through the descending facilitation system.Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed,highlighting novel avenues for chronic pain management.展开更多
Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits.The dorsal hippocampus(dHPC),a well-defined region responsible for learning and memory,displays maladapt...Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits.The dorsal hippocampus(dHPC),a well-defined region responsible for learning and memory,displays maladaptive plasticity upon injury,which is assumed to underlie pain hypersensitivity and cognitive deficits.However,much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes.Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix(ECM)and decreases ECM rigidity in the dHPC.Despite this,it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits.Laminin,a key element of the ECM,consists ofα-,β-,andγ-chains and has been implicated in several pathophysiological processes.Here,we showed that peripheral nerve injury downregulates lamininβ1(LAMB1)in the dHPC.Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction.Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrinβ1,leading to decreased Ca2+levels in pyramidal neurons,which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits.In this study,we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits,and reveal a mechanism that conveys extracellular alterations to intracellular plasticity.Moreover,we identified hippocampal LAMB1/integrinβ1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.展开更多
基金supported by grants from the Ministry of Science and Technology of China(2021ZD0203205 and 2021ZD0203104)the National Natural Science Foundation of China(82371225,82171212,82571386,82330036 and 82221001)+2 种基金National Key Research and Development Program of China(2024YFC2510102)the Excellent Youth Science Foundation of Shaanxi Province(2025JC-JCQN-103)Shaanxi Province Sanqin Talent Program.
文摘Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis.This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels:(1)Peripheral Sensitization:CCL2/CCR2 modulates TRPV1,Nav1.8,and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain.(2)Spinal Cord Central Sensitization:CCL2/CCR2 contributes to NMDAR-dependent plasticity,glial activation,GABAergic disinhibition,and opioid receptor desensitization.(3)Supraspinal Central Networks:CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions,including the ACC,CeA,NAc,and hippocampus,and it also increases pain sensitization through the descending facilitation system.Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed,highlighting novel avenues for chronic pain management.
基金supported by the National Key Research and Development Program of China(2024YFC2510102)the National Natural Science Foundation of China(NSFC)grants(82330036 and 82221001)+9 种基金STI2030-Major Projects(2021ZD0203100(2021ZD0203104))the Innovation Teams in Priority Areas Accredited by Shaanxi Science and Technology(2022TD-49)to C.L.NSFC grant(82201370)China Postdoctoral Science Foundation grant(2021MD703955)to F.W.NSFC grants(82101293,82221001)to W.J.H.and S.X.W.NSFC grant(82201368)China Postdoctoral Science Foundation grant(2022M713847)to Z.Z.L.STI2030-Major Projects(2021ZD0203205)NSFC grants(82171212,82371225)to R.G.X.grant from Joint Founding Project of Innovation Research Institute,Xijing Hospital(LHJJ24JH08)Shaanxi Province Sanqin Talent Program to C.L.
文摘Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits.The dorsal hippocampus(dHPC),a well-defined region responsible for learning and memory,displays maladaptive plasticity upon injury,which is assumed to underlie pain hypersensitivity and cognitive deficits.However,much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes.Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix(ECM)and decreases ECM rigidity in the dHPC.Despite this,it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits.Laminin,a key element of the ECM,consists ofα-,β-,andγ-chains and has been implicated in several pathophysiological processes.Here,we showed that peripheral nerve injury downregulates lamininβ1(LAMB1)in the dHPC.Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction.Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrinβ1,leading to decreased Ca2+levels in pyramidal neurons,which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits.In this study,we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits,and reveal a mechanism that conveys extracellular alterations to intracellular plasticity.Moreover,we identified hippocampal LAMB1/integrinβ1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
