Controlled cortical impingement is a widely accepted method to induce traumatic brain injury to establish a traumatic brain injury animal model.A strike depth of 1 mm at a certain speed is recommended for a moderate b...Controlled cortical impingement is a widely accepted method to induce traumatic brain injury to establish a traumatic brain injury animal model.A strike depth of 1 mm at a certain speed is recommended for a moderate brain injury and a depth of>2 mm is used to induce severe brain injury.However,the different effects and underlying mechanisms of these two model types have not been proven.This study investigated the changes in cerebral blood flow,differences in the degree of cortical damage,and differences in motor function under different injury parameters of 1 and 2 mm at injury speeds of 3,4,and 5 m/s.We also explored the functional changes and mitochondrial damage between the 1 and 2 mm groups in the acute(7 days)and chronic phases(30 days).The results showed that the cerebral blood flow in the injured area of the 1 mm group was significantly increased,and swelling and bulging of brain tissue,increased vascular permeability,and large-scale exudation occurred.In the 2 mm group,the main pathological changes were decreased cerebral blood flow,brain tissue loss,and cerebral vasospasm occlusion in the injured area.Substantial motor and cognitive impairments were found on day 7 after injury in the 2 mm group;at 30 days after injury,the motor function of the 2 mm group mice recovered significantly while cognitive impairment persisted.Transcriptome sequencing showed that compared with the 1 mm group,the 2 mm group expressed more ferroptosis-related genes.Morphological changes of mitochondria in the two groups on days 7 and 30 using transmission electron microscopy revealed that on day 7,the mitochondria in both groups shrank and the vacuoles became larger;on day 30,the mitochondria in the 1 mm group became larger,and the vacuoles in the 2 mm group remained enlarged.By analyzing the proportion of mitochondrial subgroups in different groups,we found that the model mice had different patterns of mitochondrial composition at different time periods,suggesting that the difference in the degree of damage among traumatic brain injury groups may reflect the mitochondrial changes.Taken together,differences in mitochondrial morphology and function between the 1 and 2 mm groups provide a new direction for the accurate classification of traumatic brain injury.Our results provide reliable data support and evaluation methods for promoting the establishment of standard mouse controlled cortical impingement model guidelines.展开更多
In order to provide practical fundamental data for rare-earth elements (REEs) recovery from phosphoric acid and to betterunderstand REEs behavior during the phosphoric acid evaporation process, the solubilities of R...In order to provide practical fundamental data for rare-earth elements (REEs) recovery from phosphoric acid and to betterunderstand REEs behavior during the phosphoric acid evaporation process, the solubilities of REEs in phosphoric acid with variousconcentrations of phosphorus at different temperatures were measured. A simple linear model between REEs solubility andphosphoric acid concentration is built and the experimental data are found to fit it very well (R2〉0.94). Hydrogen-ion concentration isfound to be the predominant factor controlling the solubility of REEs in phosphoric acid. In addition, the solubility of REEs inphosphoric acid is found to sharply decrease with increasing temperature, which can be attributed to the increase of the Gibbs energyof the REEPO4 dissolution reaction or the restraint of the disassociation of phosphoric acid molecules owing to the elevatedtemperature.展开更多
To understand the behavior of molybdenum and tungsten extracted by tri-alkyl phosphine oxide(TRPO)from peroxide solution,the extraction mechanism was studied by slope method and Raman and FTIR spectroscopy.The empiric...To understand the behavior of molybdenum and tungsten extracted by tri-alkyl phosphine oxide(TRPO)from peroxide solution,the extraction mechanism was studied by slope method and Raman and FTIR spectroscopy.The empirical formulas of molybdenum and tungsten extraction distribution ratio(D_(Mo)and D_(W))as functions of equilibrium pH,TRPO concentration and temperature were obtained by establishing mathematical models.Furthermore,the reliability of the empirical formula was verified in the H^(+)-W-Mo-H_(2)O_(2) solution.The results indicate that the calculated values of D_(Mo)or D_(W)were consistent with the experimental values.The apparent extraction equilibrium constants of molybdenum and tungsten wereK_(Mo)^(app)=8.51×10^(3)(0.74≤pH_(e)≤1.7),K_(Mo)^(app)=99.89×10^(3)(1.7<pH_(e)≤4.62)andK_(W)^(app)=2.65×10^(3)(0.92<pH_(e)<2.16)at 20°C,respectively.The main extraction complex of molybdenum or tungsten was[H_(2)(Mo or W)_(2)O_(3)(O_(2))_(4)(H_(2)O)_(2)]·2TRPO.These empirical formulas can be used to analyze and estimate the extraction and separation of Mo and W from low molybdenum and tungsten concentration solutions.展开更多
The thermodynamic equilibrium diagrams of CaMoO_(4)-CaSO_(4)-H_(2)SO_(4)-H_(2)O,CaMoO_(4)-HCl-H_(2)O and CaSO_(4)-CaCl_(2)-HCl-H_(2)O systems at 298 K were established.The calculation results demonstrated that HCl dis...The thermodynamic equilibrium diagrams of CaMoO_(4)-CaSO_(4)-H_(2)SO_(4)-H_(2)O,CaMoO_(4)-HCl-H_(2)O and CaSO_(4)-CaCl_(2)-HCl-H_(2)O systems at 298 K were established.The calculation results demonstrated that HCl displays a much higher solubility of CaSO_(4)than H_(2)SO_(4).The leaching mechanism of Mo from CaMoO_(4)calcine was systematically investigated from the perspective of the micro particle properties variation.HCl exhibits an excellent leaching performance for Mo from CaMoO_(4)calcine due to the elimination of surface coating and the dissolution of a mass of Mo embedded in CaSO_(4)matrix.Excellent Mo leaching efficiency of 99.7%was achieved under the optimal conditions of decomposing CaMoO_(4)calcine by 2.4 mol/L HCl with a liquid/solid ratio of 10:1 at 50°C for 60 min.Based on the experimental results,a highly efficient and green cycle leaching process of molybdenum from molybdenite was proposed,which eliminated surface coating and physical entraining,and converted most of the calcium from CaMoO_(4)calcine into high purity gypsum by-product.展开更多
Neural stem cell(NSC)transplantation is a promising strategy for replacing lost neurons following spinal cord injury.However,the survival and differentiation of transplanted NSCs is limited,possibly owing to the neuro...Neural stem cell(NSC)transplantation is a promising strategy for replacing lost neurons following spinal cord injury.However,the survival and differentiation of transplanted NSCs is limited,possibly owing to the neurotoxic inflammatory microenvironment.Because of the important role of glucose metabolism in M1/M2 polarization of microglia/macrophages,we hypothesized that altering the phenotype of microglia/macrophages by regulating the activity of aldose reductase(AR),a key enzyme in the polyol pathway of glucose metabolism,would provide a more beneficial microenvironment for NSC survival and differentiation.Here,we reveal that inhibition of host AR promoted the polarization of microglia/macrophages toward the M2 phenotype in lesioned spinal cord injuries.M2 macrophages promoted the differentiation of NSCs into neurons in vitro.Transplantation of NSCs into injured spinal cords either deficient in AR or treated with the AR inhibitor sorbinil promoted the survival and neuronal differentiation of NSCs at the injured spinal cord site and contributed to locomotor functional recovery.Our findings suggest that inhibition of host AR activity is beneficial in enhancing the survival and neuronal differentiation of transplanted NSCs and shows potential as a treatment of spinal cord injury.展开更多
The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive un...The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.展开更多
Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown ...Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown to enhance N-methyl-D-aspartate (NMDA)-induced currents in spinal outer lamina II (Iio) neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive (VGLUT2+) neurons. CCL2 increased NMDA- induced currents in CCR2+/VGLUT2+ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.展开更多
Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments ...Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments revealed that an antagonist of extracellular signal-regulated kinase(ERK)inhibited not only CCL2-induced inflammatory pain,but also pain responses induced by complete Freund’s adjuvant.We posed the question of the intracellular signaling cascade involved.Subsequent experiments showed that CCL2 up-regulated the expression of phosphorylated ERK(pERK)and N-methyl D-aspartate receptor[NMDAR]subtype 2B(GluN2B);meanwhile,antagonists of CCR2 and ERK effectively reversed these phenomena.Whole-cell patchclamp recordings revealed that CCL2 enhanced the NMDAR-induced currents via activating the pERK pathway,which was blocked by antagonists of GluN2B and ERK.In summary,we demonstrate that CCL2 directly interacts with CCR2 to enhance NMDAR-induced currents,eventually leading to inflammatory pain mainly through the CCL2-CCR2-pERK-GluN2B pathway.展开更多
Tweety-homolog 1(Ttyh1)is expressed in neural tissue and has been implicated in the generation of several brain diseases.However,its functional significance in pain processing is not understood.By disrupting the gene ...Tweety-homolog 1(Ttyh1)is expressed in neural tissue and has been implicated in the generation of several brain diseases.However,its functional significance in pain processing is not understood.By disrupting the gene encoding Ttyh1,we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice,along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey(PAG)in the basal state.More importantly,the peripheral inflammationevoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice.Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release.Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief.Thus,in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.展开更多
基金the financial support from the National Natural Science Foundation of China(No.52104354)the Joint Fund for Nuclear Technology Innovation Sponsored by the National Natural Science Foundation of China and the China National Nuclear Corporation(No.U2067201)。
基金supported by grants from the National Science and Technology Innovation 2030 Grant of China,No.2021ZD0201005(to SXW)Natural Science Foundation of China,Nos.81900489(to YZ),82101294(to GHC),81730035(to SXW)+1 种基金Natural Science Foundation of Shaanxi Province,No.2022JM-456(to YZ)Shaanxi Provincial Key Research and Development Program,Nos.2022SF-011(to GHC),2022ZDLSF01-02(to YZW)。
文摘Controlled cortical impingement is a widely accepted method to induce traumatic brain injury to establish a traumatic brain injury animal model.A strike depth of 1 mm at a certain speed is recommended for a moderate brain injury and a depth of>2 mm is used to induce severe brain injury.However,the different effects and underlying mechanisms of these two model types have not been proven.This study investigated the changes in cerebral blood flow,differences in the degree of cortical damage,and differences in motor function under different injury parameters of 1 and 2 mm at injury speeds of 3,4,and 5 m/s.We also explored the functional changes and mitochondrial damage between the 1 and 2 mm groups in the acute(7 days)and chronic phases(30 days).The results showed that the cerebral blood flow in the injured area of the 1 mm group was significantly increased,and swelling and bulging of brain tissue,increased vascular permeability,and large-scale exudation occurred.In the 2 mm group,the main pathological changes were decreased cerebral blood flow,brain tissue loss,and cerebral vasospasm occlusion in the injured area.Substantial motor and cognitive impairments were found on day 7 after injury in the 2 mm group;at 30 days after injury,the motor function of the 2 mm group mice recovered significantly while cognitive impairment persisted.Transcriptome sequencing showed that compared with the 1 mm group,the 2 mm group expressed more ferroptosis-related genes.Morphological changes of mitochondria in the two groups on days 7 and 30 using transmission electron microscopy revealed that on day 7,the mitochondria in both groups shrank and the vacuoles became larger;on day 30,the mitochondria in the 1 mm group became larger,and the vacuoles in the 2 mm group remained enlarged.By analyzing the proportion of mitochondrial subgroups in different groups,we found that the model mice had different patterns of mitochondrial composition at different time periods,suggesting that the difference in the degree of damage among traumatic brain injury groups may reflect the mitochondrial changes.Taken together,differences in mitochondrial morphology and function between the 1 and 2 mm groups provide a new direction for the accurate classification of traumatic brain injury.Our results provide reliable data support and evaluation methods for promoting the establishment of standard mouse controlled cortical impingement model guidelines.
基金Project(51674036)supported by the National Natural Science Foundation of ChinaProject(Z161100004916108)supported by the Beijing Nova Program,China
文摘In order to provide practical fundamental data for rare-earth elements (REEs) recovery from phosphoric acid and to betterunderstand REEs behavior during the phosphoric acid evaporation process, the solubilities of REEs in phosphoric acid with variousconcentrations of phosphorus at different temperatures were measured. A simple linear model between REEs solubility andphosphoric acid concentration is built and the experimental data are found to fit it very well (R2〉0.94). Hydrogen-ion concentration isfound to be the predominant factor controlling the solubility of REEs in phosphoric acid. In addition, the solubility of REEs inphosphoric acid is found to sharply decrease with increasing temperature, which can be attributed to the increase of the Gibbs energyof the REEPO4 dissolution reaction or the restraint of the disassociation of phosphoric acid molecules owing to the elevatedtemperature.
基金support from the National Natural Science Foundation of China(No.51604304)。
文摘To understand the behavior of molybdenum and tungsten extracted by tri-alkyl phosphine oxide(TRPO)from peroxide solution,the extraction mechanism was studied by slope method and Raman and FTIR spectroscopy.The empirical formulas of molybdenum and tungsten extraction distribution ratio(D_(Mo)and D_(W))as functions of equilibrium pH,TRPO concentration and temperature were obtained by establishing mathematical models.Furthermore,the reliability of the empirical formula was verified in the H^(+)-W-Mo-H_(2)O_(2) solution.The results indicate that the calculated values of D_(Mo)or D_(W)were consistent with the experimental values.The apparent extraction equilibrium constants of molybdenum and tungsten wereK_(Mo)^(app)=8.51×10^(3)(0.74≤pH_(e)≤1.7),K_(Mo)^(app)=99.89×10^(3)(1.7<pH_(e)≤4.62)andK_(W)^(app)=2.65×10^(3)(0.92<pH_(e)<2.16)at 20°C,respectively.The main extraction complex of molybdenum or tungsten was[H_(2)(Mo or W)_(2)O_(3)(O_(2))_(4)(H_(2)O)_(2)]·2TRPO.These empirical formulas can be used to analyze and estimate the extraction and separation of Mo and W from low molybdenum and tungsten concentration solutions.
基金financially supported by the Joint Fund for Nuclear Technology Innovation Sponsored by the National Natural Science Foundation of China and the China National Nuclear Corporation(No.U2067201)。
文摘The thermodynamic equilibrium diagrams of CaMoO_(4)-CaSO_(4)-H_(2)SO_(4)-H_(2)O,CaMoO_(4)-HCl-H_(2)O and CaSO_(4)-CaCl_(2)-HCl-H_(2)O systems at 298 K were established.The calculation results demonstrated that HCl displays a much higher solubility of CaSO_(4)than H_(2)SO_(4).The leaching mechanism of Mo from CaMoO_(4)calcine was systematically investigated from the perspective of the micro particle properties variation.HCl exhibits an excellent leaching performance for Mo from CaMoO_(4)calcine due to the elimination of surface coating and the dissolution of a mass of Mo embedded in CaSO_(4)matrix.Excellent Mo leaching efficiency of 99.7%was achieved under the optimal conditions of decomposing CaMoO_(4)calcine by 2.4 mol/L HCl with a liquid/solid ratio of 10:1 at 50°C for 60 min.Based on the experimental results,a highly efficient and green cycle leaching process of molybdenum from molybdenite was proposed,which eliminated surface coating and physical entraining,and converted most of the calcium from CaMoO_(4)calcine into high purity gypsum by-product.
基金supported by the National Natural Science Foundation of China,Nos.81601056(to KZ),81901252(to QZ)Shaanxi Key Research and Development Program of China,No.2020SF-083(to KZ)+1 种基金Sanming Project of Medicine in Shenzhen of China,No.SZSM201911011(to SXW)the Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration(Tongji University,Ministry of Education)of China(to KZ).
文摘Neural stem cell(NSC)transplantation is a promising strategy for replacing lost neurons following spinal cord injury.However,the survival and differentiation of transplanted NSCs is limited,possibly owing to the neurotoxic inflammatory microenvironment.Because of the important role of glucose metabolism in M1/M2 polarization of microglia/macrophages,we hypothesized that altering the phenotype of microglia/macrophages by regulating the activity of aldose reductase(AR),a key enzyme in the polyol pathway of glucose metabolism,would provide a more beneficial microenvironment for NSC survival and differentiation.Here,we reveal that inhibition of host AR promoted the polarization of microglia/macrophages toward the M2 phenotype in lesioned spinal cord injuries.M2 macrophages promoted the differentiation of NSCs into neurons in vitro.Transplantation of NSCs into injured spinal cords either deficient in AR or treated with the AR inhibitor sorbinil promoted the survival and neuronal differentiation of NSCs at the injured spinal cord site and contributed to locomotor functional recovery.Our findings suggest that inhibition of host AR activity is beneficial in enhancing the survival and neuronal differentiation of transplanted NSCs and shows potential as a treatment of spinal cord injury.
基金This work was supported by the National Natural Science Foundation of China(32271056,81671081,and 81701095)University Science and Technology Fund Planning Projects(2022XC002 and 2019XB006).
文摘The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.
基金supported by grants from the National Natural Science Foundation of China(31400949,81502102,31471059,81371498,and 31371121)NIH R01,USA Grants(DE17794,DE22743,and NS87988)
文摘Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown to enhance N-methyl-D-aspartate (NMDA)-induced currents in spinal outer lamina II (Iio) neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive (VGLUT2+) neurons. CCL2 increased NMDA- induced currents in CCR2+/VGLUT2+ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.
基金grants from the National Natural Science Foundation of China(81870867,31671088,31471059,and 81502102)the Natural Science Foundation of Shaanxi Province,China(2019SF-071 and 2017ZDJC-01)。
文摘Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments revealed that an antagonist of extracellular signal-regulated kinase(ERK)inhibited not only CCL2-induced inflammatory pain,but also pain responses induced by complete Freund’s adjuvant.We posed the question of the intracellular signaling cascade involved.Subsequent experiments showed that CCL2 up-regulated the expression of phosphorylated ERK(pERK)and N-methyl D-aspartate receptor[NMDAR]subtype 2B(GluN2B);meanwhile,antagonists of CCR2 and ERK effectively reversed these phenomena.Whole-cell patchclamp recordings revealed that CCL2 enhanced the NMDAR-induced currents via activating the pERK pathway,which was blocked by antagonists of GluN2B and ERK.In summary,we demonstrate that CCL2 directly interacts with CCR2 to enhance NMDAR-induced currents,eventually leading to inflammatory pain mainly through the CCL2-CCR2-pERK-GluN2B pathway.
基金the National Natural Science Foundation of China(31671088 and 31730041)the Natural Science Foundation of Shaanxi Province,China(2017ZDJC-01)。
文摘Tweety-homolog 1(Ttyh1)is expressed in neural tissue and has been implicated in the generation of several brain diseases.However,its functional significance in pain processing is not understood.By disrupting the gene encoding Ttyh1,we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice,along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey(PAG)in the basal state.More importantly,the peripheral inflammationevoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice.Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release.Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief.Thus,in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.