Topical irritants such as capsaicin(CAP),peppermint oil(PO),and mustard oil(MO)are effective in relieving inflammatory muscle pain.We investigated the effects of topical irritants in a rat model of inflammatory muscle...Topical irritants such as capsaicin(CAP),peppermint oil(PO),and mustard oil(MO)are effective in relieving inflammatory muscle pain.We investigated the effects of topical irritants in a rat model of inflammatory muscle pain produced by injecting complete Freund's adjuvant(CFA)into the tibialis anterior muscle.CFAinduced mechanical hypersensitivity and the spontaneous activity of muscular nociceptive afferents,and decreased weight-bearing of the hindlimb were relieved by topical application of CAP,PO,or MO on the skin overlying the inflamed muscle.The effects of topical irritants were abolished when applied to the skin on the ipsilateral plantar region or on the contralateral leg,or when the relevant cutaneous nerve or dorsal root was transected.Our results demonstrated that topical irritants may alleviate inflammatory muscle pain via activating cutaneous nociceptors and subsequently inhibiting the abnormal activity of muscular nociceptive neurons.展开更多
Noxious mechanical information is transmitted through molecularly distinct nociceptors,with pinprickevoked sharp sensitivity via A-fiber nociceptors marked by developmental expression of the neuropeptide Y receptor 2(...Noxious mechanical information is transmitted through molecularly distinct nociceptors,with pinprickevoked sharp sensitivity via A-fiber nociceptors marked by developmental expression of the neuropeptide Y receptor 2(Npy2 r)and von Frey filament-evoked punctate pressure information via unmyelinated C fiber nociceptors marked by MrgprD.However,the molecular programs controlling their development are only beginning to be understood.Here we demonstrate that Npy2 r-expressing sensory neurons are in fact divided into two groups,based on transient or persistent Npy2 r expression.Npy2 r-transient neurons are myelinated,likely including A-fiber nociceptors,whereas Npy2 r-persistent ones belong to unmyelinated pruriceptors that co-express Nppb.We then showed that the transcription factors NFIA and Runx1 are necessary for the development of Npy2 r-transient A-fiber nociceptors and MrgprD^+C-fiber nociceptors,respectively.Behaviorally,mice with conditional knockout of Nfia,but not Runx1 showed a marked attenuation of pinprick-evoked nocifensive responses.Our studies therefore identify a transcription factor controlling the development of myelinated nociceptors.展开更多
Retina nociceptor,as a key sensory receptor,not only enables the transport of warning signals to the human central nervous system upon its exposure to noxious stimuli,but also triggers the motor response that minimize...Retina nociceptor,as a key sensory receptor,not only enables the transport of warning signals to the human central nervous system upon its exposure to noxious stimuli,but also triggers the motor response that minimizes potential sensitization.In this study,the capability of two-dimensional all-oxide-heterostructured artificial nociceptor as a single device with tunable properties was confirmed.Newly designed nociceptors utilize ultra-thin sub-stoichiometric TiO2–Ga2O3 heterostructures,where the thermally annealed Ga2O3 films play the role of charge transfer controlling component.It is discovered that the phase transformation in Ga2O3 is accompanied by substantial jump in conductivity,induced by thermally assisted internal redox reaction of Ga2O3 nanostructure during annealing.It is also experimentally confirmed that the charge transfer in alloxide heterostructures can be tuned and controlled by the heterointerfaces manipulation.Results demonstrate that the engineering of heterointerfaces of two-dimensional(2D)films enables the fabrication of either high-sensitive TiO2–Ga2O3(Ar)or high-threshold TiO2–Ga2O3(N2)nociceptors.The hypersensitive nociceptor mimics the functionalities of corneal nociceptors of human eye,whereas the delayed reaction of nociceptor is similar to high-threshold nociceptive characteristics of human sensory system.The long-term stability of 2D nociceptors demonstrates the capability of heterointerfaces engineering for e ective control of charge transfer at 2D heterostructured devices.展开更多
We consider the problem of inducing withdrawal reflex on a test subject by exposing the subject’s skin to an electromagnetic beam. Heat-sensitive nociceptors in the skin are activated wherever the temperature is abov...We consider the problem of inducing withdrawal reflex on a test subject by exposing the subject’s skin to an electromagnetic beam. Heat-sensitive nociceptors in the skin are activated wherever the temperature is above the activation temperature. Withdrawal reflex occurs when the activated volume reaches a threshold. Previously we studied static beams with 3 types of power density distribution: Gaussian, super-Gaussian, and flat-top. We found that the flaptop is the best and the Gaussian is the worst in their performance with regard to 1) minimizing the time to withdrawal reflex, 2) minimizing the energy consumption and 3) minimizing the maximum temperature increase. The less-than-desirable performance of Gaussian beams is attributed to the uneven distribution of power density resulting in low energy efficiency: near the beam center the high power density does not contribute proportionally to increasing the activated volume;outside the beam effective radius the low power density fails to activate nociceptors. To overcome the drawbacks of Gaussian beams, in this study, we revolve a Gaussian beam around a fixed point to make the power density more uniformly distributed. We optimize the performance over two parameters: the spot size of static beam and the radius of beam revolution. We find that in comparison with a static Gaussian beam, a revolving Gaussian beam can reduce the energy consumption, and at the same time lower the maximum temperature.展开更多
Vulvodynia is a prevalent form of chronic pain, most com- monly affecting the vaginal vestibule （vestibulodynia） （Pukall et al., 2016）. Women with vulvodynia describe intense pain in response to light touch of the...Vulvodynia is a prevalent form of chronic pain, most com- monly affecting the vaginal vestibule （vestibulodynia） （Pukall et al., 2016）. Women with vulvodynia describe intense pain in response to light touch of the affected region, such that sexual function and other activities can be severely limited. Medical costs associated with vulvodynia are high, exceeding $21 billion annually in the United States （Xie et al., 2012）. The high level of direct medical costs has been linked to high treatment failure rates. Many women with the disorder consult multiple practitioners and undergo multiple courses of treatment with limited benefit.展开更多
Previously we introduced a concise dose-response model for the heat-induced withdrawal reflex caused by millimeter wave radiation. The model predicts the occurrence of withdrawal reflex from the given spatial temperat...Previously we introduced a concise dose-response model for the heat-induced withdrawal reflex caused by millimeter wave radiation. The model predicts the occurrence of withdrawal reflex from the given spatial temperature profile. It was formulated on the assumption that the density of nociceptors in skin is uniform, independent of the depth. The model has only two parameters: the activation temperature of heat-sensitive nociceptors and the critical threshold on the activated volume for triggering withdrawal reflex. In this study, we consider the case of depth-dependent nociceptor density in skin. We use a general parametric form with a scaling parameter in the depth direction to represent the nociceptor density. We analyze system behaviors for four density types of this form. Based on the theoretical results, we develop a methodology for 1) identifying from test data the density form of nociceptors distribution, 2) finding from test data the scaling parameter in the density form, and 3) determining from test data the activation temperature of nociceptors.展开更多
With the development of technology,the learning and memory functions of artificial memristor synapses are necessary for realizing artificial neural networks and neural neuromorphic computing.Owing to their high scalab...With the development of technology,the learning and memory functions of artificial memristor synapses are necessary for realizing artificial neural networks and neural neuromorphic computing.Owing to their high scalability performance,nanosheet materials have been widely employed in cellular-level learning,but the behaviors of nociceptor based on nanosheet materials have rarely been studied.Here,we present a memristor with an Al/TiO_(2)/Pt structure.After electroforming,the memristor device showed a gradual conductance regulation and could simulate synaptic functions such as the potentiation and depression of synaptic weights.We also designed a new scheme that verifies the pain sensitization,desensitization,allodynia,and hyperalgesia behaviors of real nociceptors in the fabricated memristor.Memristors with these behaviors can significantly improve the quality of intelligent electronic devices.Data fitting showed that the high resistance and low resistance states were consistent with the hopping conduction mechanism.This work promises the application of TiO_(2)-based devices in next-generation neuromorphological systems.展开更多
Recently, memristors have garnered widespread attention as neuromorphic devices that can simulate synaptic behavior, holding promise for future commercial applications in neuromorphic computing. In this paper, we pres...Recently, memristors have garnered widespread attention as neuromorphic devices that can simulate synaptic behavior, holding promise for future commercial applications in neuromorphic computing. In this paper, we present a memristor with an Au/Bi_(3.2)La_(0.8)Ti_(3)O_(12) (BLTO)/ITO structure, demonstrating a switching ratio of nearly 103 over a duration of 104 s. It successfully simulates a range of synaptic behaviors, including long-term potentiation and depression, paired-pulse facilitation, spike-timing-dependent plasticity, spike-rate-dependent plasticity etc. Interestingly, we also employ it to simulate pain threshold, sensitization, and desensitization behaviors of pain-perceptual nociceptor (PPN). Lastly, by introducing memristor differential pairs (1T1R-1T1R), we train a neural network, effectively simplifying the learning process, reducing training time, and achieving a handwriting digit recognition accuracy of up to 97.19 %. Overall, the proposed device holds immense potential in the field of neuromorphic computing, offering possibilities for the next generation of high-performance neuromorphic computing chips.展开更多
Continuous lifelong acquisition,updating,and finetuning of knowledge and skills is of crucial significance for the survival of humans.However,current neuromorphic devices exhibit obvious catastrophic forgetting when r...Continuous lifelong acquisition,updating,and finetuning of knowledge and skills is of crucial significance for the survival of humans.However,current neuromorphic devices exhibit obvious catastrophic forgetting when restimulated by new information.This remains a challenge for neuromorphic devices and artificial intelligence to achieve continuous learning.Herein,we propose an electric-induced cycloelimination strategy to realize an organic transistor nociceptor that can simulate synaptic and structural plasticity.The system benefits from the ring-opening characteristics of cross-linked poly(vinyl cinnamate)under a strong pulse voltage,during which new energy-level trap states are formed.The prepared organic transistor nociceptors exhibit both structural and synaptic plasticity.They simulate the characteristics of human nociceptors,including threshold,relaxation,sensitization,and maladaptation behavior.For the first time,we have simulated and explored the structural plasticity behavior in organisms based on electronic devices.More remarkably,the transistor nociceptors realize the reinput of information without forgetting the initial informa tion.The strategy developed for the preparation of organic transistor nociceptors provides insights for addressing the catastrophic forgetting in the lifelong learning of intelligent neuromorphic devices.展开更多
It is crucial to develop an advanced artificially intelligent optoelectronic information system that accurately simulates photonic nociceptors like the activation process of a human visual nociceptive pathway.Visible ...It is crucial to develop an advanced artificially intelligent optoelectronic information system that accurately simulates photonic nociceptors like the activation process of a human visual nociceptive pathway.Visible light reaches the retina for human visual perception,but its excessive exposure can damage nearby tissues.However,there are relatively few reports on visible light–triggered nociceptors.Here,we introduce a two-dimensional natural defectiveⅢ–Ⅵsemiconductorβ-In_(2)S_(3)and utilize its broad spectral response,including visible light brought by intrinsic defects,for visible light–triggered artificial photonic nociceptors.The response mode of the device,under visible light excitation,is very similar to that of the human eye.It perfectly reproduces the pain perception characteristics of the human visual system,such as‘threshold,’‘relaxation,’‘no adaptation’,and‘sensitization’.Its working principle is attributed to the mechanism of charge trapping associated with the intrinsic vacancies in In_(2)S_(3)nanosheets.This work provides an attractive material system(intrinsic defective semiconductors)for broadband artificial photonic nociceptors.展开更多
作为祖国医学的重要组成部分,针刺与热灸等体表刺激在镇痛与调节内脏功能等方面发挥着不可替代的治疗效应。随着现代神经生理学、分子生物学及基因编辑技术等快速发展,研究者可通过不同生物标记技术探究既往无法区分的细胞亚型,为以分...作为祖国医学的重要组成部分,针刺与热灸等体表刺激在镇痛与调节内脏功能等方面发挥着不可替代的治疗效应。随着现代神经生理学、分子生物学及基因编辑技术等快速发展,研究者可通过不同生物标记技术探究既往无法区分的细胞亚型,为以分子标记物为切入点探究体表不同类型感受器介导针灸调节效应的作用机制提供了新的研究范式。然而,针对上述研究进展的系统归纳目前尚且缺如。鉴于此,本文综述了瞬时受体电位(transient receptor potential,TRP)离子通道家族、Mas相关G蛋白偶联受体(Mas related G protein-coupled receptor,MRGPR)家族等分子标记的C类多模态伤害感受器(C-polymodal nociceptor,CPN)在针灸镇痛及内脏调节中的作用效应及机制探讨,以期为针灸传入相关始动因素的分子特性及功能研究提供思路,亦为传统与现代医学的融合发展提供潜在探索方向。展开更多
Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular se...Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.展开更多
Nociceptive signals conveyed to the dorsal horn of the spinal cord by primary nociceptors are subject to extensive modulation by local neurons and by supraspinal descending pathways to the spinal cord before being rel...Nociceptive signals conveyed to the dorsal horn of the spinal cord by primary nociceptors are subject to extensive modulation by local neurons and by supraspinal descending pathways to the spinal cord before being relayed to higher brain centers. Descending modulatory pathways to the spinal cord comprise,among others, noradrenergic, serotonergic, γ-aminobutyric acid(GABA)ergic, and dopaminergic fibers.The contributions of noradrenaline, serotonin, and GABA to pain modulation have been extensively investigated. In contrast, the contributions of dopamine to pain modulation remain poorly understood.The focus of this review is to summarize the current knowledge of the contributions of dopamine to pain modulation. Hypothalamic A11 dopaminergic neurons project to all levels of the spinal cord and provide the main source of spinal dopamine. Dopamine receptors are expressed in primary nociceptors as well as in spinal neurons located in different laminae in the dorsal horn of the spinal cord, suggesting that dopamine can modulate pain signals by acting at both presynaptic and postsynaptic targets. Here, I will review the literature on the effects of dopamine and dopamine receptor agonists/antagonists on the excitability of primary nociceptors, the effects of dopamine on the synaptic transmission between primary nociceptors and dorsal horn neurons, and the effects of dopamine on pain in rodents. Published data support both anti-nociceptive effects of dopamine mediated by D2-like receptors and pro-nociceptive effects mediated by D1-like receptors.展开更多
Melittin is a basic 26-amino-acid polypeptide that constitutes 40-60% of dry honeybee（Apis mellifera）venom.Although much is known about its strong surface activity on lipid membranes,less is known about its painprod...Melittin is a basic 26-amino-acid polypeptide that constitutes 40-60% of dry honeybee（Apis mellifera）venom.Although much is known about its strong surface activity on lipid membranes,less is known about its painproducing effects in the nervous system.In this review,we provide lines of accumulating evidence to support the hypothesis that melittin is the major pain-producing substance of bee venom.At the psychophysical and behavioral levels,subcutaneous injection of melittin causes tonic pain sensation and pain-related behaviors in both humans and animals.At the cellular level,melittin activates primary nociceptor cells through direct and indirect effects.On one hand,melittin can selectively open thermal nociceptor transient receptor potential vanilloid receptor channels via phospholipase A2-lipoxygenase/cyclooxygenase metabolites,leading to depolarization of primary nociceptor cells.On the other hand,algogens and inflammatory/proinflammatory mediators released from the tissue matrix by melittin＇s pore-forming effects can activate primary nociceptor cells through both ligand-gated receptor channels and the G-protein-coupled receptor-mediated opening of transient receptor potential canonical channels.Moreover,subcutaneous melittin up-regulates Nav1.8 and Nav1.9subunits,resulting in the enhancement of tetrodotoxinresistant Na~＋currents and the generation of long-term action potential firing.These nociceptive responses in the periphery finally activate and sensitize the spinal dorsal horn pain-signaling neurons,resulting in spontaneous nociceptive paw flinches and pain hypersensitivity to thermal and mechanical stimuli.Taken together,it is concluded that melittin is the major pain-producing substance of bee venom,by which peripheral persistent pain and hyperalgesia（or allodynia）,primary nociceptive neuronal sensitization,and CNS synaptic plasticity（or metaplasticity） can be readily induced and the molecular and cellular mechanisms underlying naturally-occurring venomous biotoxins can be experimentally unraveled.展开更多
基金We thank Bo Yuan and Tao Wang from the Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,Beijing,China,for technical assistance.This work was supported by the National Natural Science Foundation of China(81771205,91632113)the Natural Science Foundation and Major Basic Research Program of Shanghai Municipality,China(16JC1420500 and 16JC1420502)+1 种基金the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2017-I2M-3-008)the National Natural Science Foundation for Young Scientists of China(81600956).
文摘Topical irritants such as capsaicin(CAP),peppermint oil(PO),and mustard oil(MO)are effective in relieving inflammatory muscle pain.We investigated the effects of topical irritants in a rat model of inflammatory muscle pain produced by injecting complete Freund's adjuvant(CFA)into the tibialis anterior muscle.CFAinduced mechanical hypersensitivity and the spontaneous activity of muscular nociceptive afferents,and decreased weight-bearing of the hindlimb were relieved by topical application of CAP,PO,or MO on the skin overlying the inflamed muscle.The effects of topical irritants were abolished when applied to the skin on the ipsilateral plantar region or on the contralateral leg,or when the relevant cutaneous nerve or dorsal root was transected.Our results demonstrated that topical irritants may alleviate inflammatory muscle pain via activating cutaneous nociceptors and subsequently inhibiting the abnormal activity of muscular nociceptive neurons.
基金supported by the National Natural Science Foundation of China (31771621,31171071 and 31671093)the Research Foundation for Advanced Talents from Hangzhou Normal University and the New York State Stem Cell Science contracts C026429 and C030133。
文摘Noxious mechanical information is transmitted through molecularly distinct nociceptors,with pinprickevoked sharp sensitivity via A-fiber nociceptors marked by developmental expression of the neuropeptide Y receptor 2(Npy2 r)and von Frey filament-evoked punctate pressure information via unmyelinated C fiber nociceptors marked by MrgprD.However,the molecular programs controlling their development are only beginning to be understood.Here we demonstrate that Npy2 r-expressing sensory neurons are in fact divided into two groups,based on transient or persistent Npy2 r expression.Npy2 r-transient neurons are myelinated,likely including A-fiber nociceptors,whereas Npy2 r-persistent ones belong to unmyelinated pruriceptors that co-express Nppb.We then showed that the transcription factors NFIA and Runx1 are necessary for the development of Npy2 r-transient A-fiber nociceptors and MrgprD^+C-fiber nociceptors,respectively.Behaviorally,mice with conditional knockout of Nfia,but not Runx1 showed a marked attenuation of pinprick-evoked nocifensive responses.Our studies therefore identify a transcription factor controlling the development of myelinated nociceptors.
基金supported by Research and Development Program of the Ghent University Global Campus,South Korea.
文摘Retina nociceptor,as a key sensory receptor,not only enables the transport of warning signals to the human central nervous system upon its exposure to noxious stimuli,but also triggers the motor response that minimizes potential sensitization.In this study,the capability of two-dimensional all-oxide-heterostructured artificial nociceptor as a single device with tunable properties was confirmed.Newly designed nociceptors utilize ultra-thin sub-stoichiometric TiO2–Ga2O3 heterostructures,where the thermally annealed Ga2O3 films play the role of charge transfer controlling component.It is discovered that the phase transformation in Ga2O3 is accompanied by substantial jump in conductivity,induced by thermally assisted internal redox reaction of Ga2O3 nanostructure during annealing.It is also experimentally confirmed that the charge transfer in alloxide heterostructures can be tuned and controlled by the heterointerfaces manipulation.Results demonstrate that the engineering of heterointerfaces of two-dimensional(2D)films enables the fabrication of either high-sensitive TiO2–Ga2O3(Ar)or high-threshold TiO2–Ga2O3(N2)nociceptors.The hypersensitive nociceptor mimics the functionalities of corneal nociceptors of human eye,whereas the delayed reaction of nociceptor is similar to high-threshold nociceptive characteristics of human sensory system.The long-term stability of 2D nociceptors demonstrates the capability of heterointerfaces engineering for e ective control of charge transfer at 2D heterostructured devices.
文摘We consider the problem of inducing withdrawal reflex on a test subject by exposing the subject’s skin to an electromagnetic beam. Heat-sensitive nociceptors in the skin are activated wherever the temperature is above the activation temperature. Withdrawal reflex occurs when the activated volume reaches a threshold. Previously we studied static beams with 3 types of power density distribution: Gaussian, super-Gaussian, and flat-top. We found that the flaptop is the best and the Gaussian is the worst in their performance with regard to 1) minimizing the time to withdrawal reflex, 2) minimizing the energy consumption and 3) minimizing the maximum temperature increase. The less-than-desirable performance of Gaussian beams is attributed to the uneven distribution of power density resulting in low energy efficiency: near the beam center the high power density does not contribute proportionally to increasing the activated volume;outside the beam effective radius the low power density fails to activate nociceptors. To overcome the drawbacks of Gaussian beams, in this study, we revolve a Gaussian beam around a fixed point to make the power density more uniformly distributed. We optimize the performance over two parameters: the spot size of static beam and the radius of beam revolution. We find that in comparison with a static Gaussian beam, a revolving Gaussian beam can reduce the energy consumption, and at the same time lower the maximum temperature.
基金A project described in this work regarding innervation changes in the murine vagina in response to inflammation was supported by a grant from the Centre for Neuroscience,Flinders University,Australia
文摘Vulvodynia is a prevalent form of chronic pain, most com- monly affecting the vaginal vestibule （vestibulodynia） （Pukall et al., 2016）. Women with vulvodynia describe intense pain in response to light touch of the affected region, such that sexual function and other activities can be severely limited. Medical costs associated with vulvodynia are high, exceeding $21 billion annually in the United States （Xie et al., 2012）. The high level of direct medical costs has been linked to high treatment failure rates. Many women with the disorder consult multiple practitioners and undergo multiple courses of treatment with limited benefit.
文摘Previously we introduced a concise dose-response model for the heat-induced withdrawal reflex caused by millimeter wave radiation. The model predicts the occurrence of withdrawal reflex from the given spatial temperature profile. It was formulated on the assumption that the density of nociceptors in skin is uniform, independent of the depth. The model has only two parameters: the activation temperature of heat-sensitive nociceptors and the critical threshold on the activated volume for triggering withdrawal reflex. In this study, we consider the case of depth-dependent nociceptor density in skin. We use a general parametric form with a scaling parameter in the depth direction to represent the nociceptor density. We analyze system behaviors for four density types of this form. Based on the theoretical results, we develop a methodology for 1) identifying from test data the density form of nociceptors distribution, 2) finding from test data the scaling parameter in the density form, and 3) determining from test data the activation temperature of nociceptors.
基金financially supported by the National Natural Science Foundation of China(61674050 and 61874158)the Project of Distinguished Youth of Hebei Province(A2018201231)+5 种基金the Hundred Persons Plan of Hebei Province(E2018050004 and E2018050003)the Supporting Plan for 100 Excellent Innovative Talents in Colleges and Universities of Hebei Province(SLRC2019018)the Special Project of Strategic Leading Science and Technology of Chinese Academy of Sciences(XDB44000000-7)the Outstanding Young Scientific Research and Innovation Team of Hebei Universitythe Highlevel Talent Research Startup Project of Hebei University(521000981426)the Special Support Funds for National High Level Talents(041500120001 and 521000981429)。
文摘With the development of technology,the learning and memory functions of artificial memristor synapses are necessary for realizing artificial neural networks and neural neuromorphic computing.Owing to their high scalability performance,nanosheet materials have been widely employed in cellular-level learning,but the behaviors of nociceptor based on nanosheet materials have rarely been studied.Here,we present a memristor with an Al/TiO_(2)/Pt structure.After electroforming,the memristor device showed a gradual conductance regulation and could simulate synaptic functions such as the potentiation and depression of synaptic weights.We also designed a new scheme that verifies the pain sensitization,desensitization,allodynia,and hyperalgesia behaviors of real nociceptors in the fabricated memristor.Memristors with these behaviors can significantly improve the quality of intelligent electronic devices.Data fitting showed that the high resistance and low resistance states were consistent with the hopping conduction mechanism.This work promises the application of TiO_(2)-based devices in next-generation neuromorphological systems.
基金This work was financially supported by the National Natural Science Foundation of China(Grant Nos.11574057 and 12172093)the Guangdong Basic and Applied Basic Research Foundation(Grant No.2021A1515012607).
文摘Recently, memristors have garnered widespread attention as neuromorphic devices that can simulate synaptic behavior, holding promise for future commercial applications in neuromorphic computing. In this paper, we present a memristor with an Au/Bi_(3.2)La_(0.8)Ti_(3)O_(12) (BLTO)/ITO structure, demonstrating a switching ratio of nearly 103 over a duration of 104 s. It successfully simulates a range of synaptic behaviors, including long-term potentiation and depression, paired-pulse facilitation, spike-timing-dependent plasticity, spike-rate-dependent plasticity etc. Interestingly, we also employ it to simulate pain threshold, sensitization, and desensitization behaviors of pain-perceptual nociceptor (PPN). Lastly, by introducing memristor differential pairs (1T1R-1T1R), we train a neural network, effectively simplifying the learning process, reducing training time, and achieving a handwriting digit recognition accuracy of up to 97.19 %. Overall, the proposed device holds immense potential in the field of neuromorphic computing, offering possibilities for the next generation of high-performance neuromorphic computing chips.
基金the National Key R&D Program(grant no.2018YFA0703200)the National Natural Science Foundation of China(grant nos.61890940 and 52003274)+3 种基金the Chinese Academy of Sciences(CAS)Project for Young Scientists in Basic Research(grant no.YSBR-053)the Strategic Priority Research Program of the CAS(grant no.XDB30000000)the CAS-Croucher Funding Scheme for Joint Laboratories,the CAS Cooperation Projects(grant no.121111KYSB20200036)Lu Jiaxi international team(grant no.GJTD-2020-02).
文摘Continuous lifelong acquisition,updating,and finetuning of knowledge and skills is of crucial significance for the survival of humans.However,current neuromorphic devices exhibit obvious catastrophic forgetting when restimulated by new information.This remains a challenge for neuromorphic devices and artificial intelligence to achieve continuous learning.Herein,we propose an electric-induced cycloelimination strategy to realize an organic transistor nociceptor that can simulate synaptic and structural plasticity.The system benefits from the ring-opening characteristics of cross-linked poly(vinyl cinnamate)under a strong pulse voltage,during which new energy-level trap states are formed.The prepared organic transistor nociceptors exhibit both structural and synaptic plasticity.They simulate the characteristics of human nociceptors,including threshold,relaxation,sensitization,and maladaptation behavior.For the first time,we have simulated and explored the structural plasticity behavior in organisms based on electronic devices.More remarkably,the transistor nociceptors realize the reinput of information without forgetting the initial informa tion.The strategy developed for the preparation of organic transistor nociceptors provides insights for addressing the catastrophic forgetting in the lifelong learning of intelligent neuromorphic devices.
基金the National Key Research and Development Program of China(2022YFB3505301)the National Natural Science Foundation of China(12174237,12241403 and 52002232).
文摘It is crucial to develop an advanced artificially intelligent optoelectronic information system that accurately simulates photonic nociceptors like the activation process of a human visual nociceptive pathway.Visible light reaches the retina for human visual perception,but its excessive exposure can damage nearby tissues.However,there are relatively few reports on visible light–triggered nociceptors.Here,we introduce a two-dimensional natural defectiveⅢ–Ⅵsemiconductorβ-In_(2)S_(3)and utilize its broad spectral response,including visible light brought by intrinsic defects,for visible light–triggered artificial photonic nociceptors.The response mode of the device,under visible light excitation,is very similar to that of the human eye.It perfectly reproduces the pain perception characteristics of the human visual system,such as‘threshold,’‘relaxation,’‘no adaptation’,and‘sensitization’.Its working principle is attributed to the mechanism of charge trapping associated with the intrinsic vacancies in In_(2)S_(3)nanosheets.This work provides an attractive material system(intrinsic defective semiconductors)for broadband artificial photonic nociceptors.
文摘作为祖国医学的重要组成部分,针刺与热灸等体表刺激在镇痛与调节内脏功能等方面发挥着不可替代的治疗效应。随着现代神经生理学、分子生物学及基因编辑技术等快速发展,研究者可通过不同生物标记技术探究既往无法区分的细胞亚型,为以分子标记物为切入点探究体表不同类型感受器介导针灸调节效应的作用机制提供了新的研究范式。然而,针对上述研究进展的系统归纳目前尚且缺如。鉴于此,本文综述了瞬时受体电位(transient receptor potential,TRP)离子通道家族、Mas相关G蛋白偶联受体(Mas related G protein-coupled receptor,MRGPR)家族等分子标记的C类多模态伤害感受器(C-polymodal nociceptor,CPN)在针灸镇痛及内脏调节中的作用效应及机制探讨,以期为针灸传入相关始动因素的分子特性及功能研究提供思路,亦为传统与现代医学的融合发展提供潜在探索方向。
基金supported by the National Institutes of Health,USA(DE018549,UL1TR001117,P30AR066527,and AR48182 to WL,AR48182-S1 to WL as co-investigatorF33DE024668 and K12DE022793 to YC)+1 种基金the US Department of Defense(W81XWH-13-1-0299 to WL)the Harrington Discovery Institute,Cleveland OH(to WL)
文摘Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.
基金supported by internal funds to MP from the Department of Anesthesiology,Stony Brook Medicine,USA
文摘Nociceptive signals conveyed to the dorsal horn of the spinal cord by primary nociceptors are subject to extensive modulation by local neurons and by supraspinal descending pathways to the spinal cord before being relayed to higher brain centers. Descending modulatory pathways to the spinal cord comprise,among others, noradrenergic, serotonergic, γ-aminobutyric acid(GABA)ergic, and dopaminergic fibers.The contributions of noradrenaline, serotonin, and GABA to pain modulation have been extensively investigated. In contrast, the contributions of dopamine to pain modulation remain poorly understood.The focus of this review is to summarize the current knowledge of the contributions of dopamine to pain modulation. Hypothalamic A11 dopaminergic neurons project to all levels of the spinal cord and provide the main source of spinal dopamine. Dopamine receptors are expressed in primary nociceptors as well as in spinal neurons located in different laminae in the dorsal horn of the spinal cord, suggesting that dopamine can modulate pain signals by acting at both presynaptic and postsynaptic targets. Here, I will review the literature on the effects of dopamine and dopamine receptor agonists/antagonists on the excitability of primary nociceptors, the effects of dopamine on the synaptic transmission between primary nociceptors and dorsal horn neurons, and the effects of dopamine on pain in rodents. Published data support both anti-nociceptive effects of dopamine mediated by D2-like receptors and pro-nociceptive effects mediated by D1-like receptors.
基金supported by grants from the National Basic Research Development Program of China (2013CB 835100)the National Natural Science Foundation of China (81171049,31300919,and 31400948)+1 种基金the National Key Technology R&D Program,China (2013BAI04B04)the Twelfth Five-Year Project of China (AWS12J004)
文摘Melittin is a basic 26-amino-acid polypeptide that constitutes 40-60% of dry honeybee（Apis mellifera）venom.Although much is known about its strong surface activity on lipid membranes,less is known about its painproducing effects in the nervous system.In this review,we provide lines of accumulating evidence to support the hypothesis that melittin is the major pain-producing substance of bee venom.At the psychophysical and behavioral levels,subcutaneous injection of melittin causes tonic pain sensation and pain-related behaviors in both humans and animals.At the cellular level,melittin activates primary nociceptor cells through direct and indirect effects.On one hand,melittin can selectively open thermal nociceptor transient receptor potential vanilloid receptor channels via phospholipase A2-lipoxygenase/cyclooxygenase metabolites,leading to depolarization of primary nociceptor cells.On the other hand,algogens and inflammatory/proinflammatory mediators released from the tissue matrix by melittin＇s pore-forming effects can activate primary nociceptor cells through both ligand-gated receptor channels and the G-protein-coupled receptor-mediated opening of transient receptor potential canonical channels.Moreover,subcutaneous melittin up-regulates Nav1.8 and Nav1.9subunits,resulting in the enhancement of tetrodotoxinresistant Na~＋currents and the generation of long-term action potential firing.These nociceptive responses in the periphery finally activate and sensitize the spinal dorsal horn pain-signaling neurons,resulting in spontaneous nociceptive paw flinches and pain hypersensitivity to thermal and mechanical stimuli.Taken together,it is concluded that melittin is the major pain-producing substance of bee venom,by which peripheral persistent pain and hyperalgesia（or allodynia）,primary nociceptive neuronal sensitization,and CNS synaptic plasticity（or metaplasticity） can be readily induced and the molecular and cellular mechanisms underlying naturally-occurring venomous biotoxins can be experimentally unraveled.
基金The project was supported by the Na-tional Natural Science Foundation of China(No.30371729,30400131)the Foundation of Education Ministry of China for Doctor Degree Candidate Training(20020698033,20040698022)the Shaanxi Province Natural Science Foundation of China(2004C225).
