Thermal Effect of a Revolving Gaussian Beam on Activating Heat-Sensitive Nociceptors in Skin

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.

Electric-Induced Cycloelimination for Simulating Structural Plasticity in Organic Nociceptors

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.

Inhibition of Muscular Nociceptive Afferents via the Activation of Cutaneous Nociceptors in a Rat Model of Inflammatory Muscle Pain

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.

The hypothalamic-spinal dopaminergic system:a target for pain modulation

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.

Nanoscale All-Oxide-Heterostructured Bio-inspired Optoresponsive Nociceptor

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.

Minimum Energy Requirement for Inducing Withdrawal Reflex in Millimeter Wave Exposures

We consider the problem of inducing withdrawal reflex on a test subject via exposure to a millimeter wave beam. In our physical model, there are 10 physical parameters affecting the occurrence of withdrawal reflex. Our goal is to pinpoint the roles of these physical parameters in inducing withdrawal reflex. We first carry out non-dimensionalization to reduce the model to a non-dimensional system of only 3 composite parameters: non-dimensional beam power density, non-dimensional beam radius, and non-dimensional exposure time. If the beam power is kept on and steady, withdrawal reflex occurs eventually;the shortest exposure time for inducing withdrawal reflex corresponds to the smallest energy consumption at the given power density and beam radius. In the 2D space of power density and beam radius, the overall minimum energy occurs at the corner of very large power density and very small beam radius, which also produces a very large value of maximum skin temperature and a long time to withdrawal reflex. To reduce the burn injury risk, we introduce a cap on the maximum skin temperature. At each given total beam power, we carry out optimizations with respect to the beam radius, constrained by the prescribed temperature cap. The energy consumption varies negatively with the prescribed temperature cap: a lower temperature cap can be accommodated only with a higher energy consumption via the venue of a larger beam radius. The energy consumption is relatively flat with respect to the total beam power and attains a minimum at a moderately large total beam power. The time to withdrawal reflex is approximately inversely proportional to the total beam power. Our analysis demonstrates that a moderately large total beam power is a good compromise to achieve both low energy consumption and short time to withdrawal reflex.

Expert consensus of Chinese Association for the Study of Pain on the non-opioid analgesics for chronic musculoskeletal pain

Chronic musculoskeletal pain(CMP)is a common occurrence in clinical practice and there are a variety of options for the treatment of it.However,the pharmacological therapy is still considered to be a primary treatment.The recent years have witnessed the emergence of opioid crisis,yet there are no relevant guidelines on how to treat CMP with non-opioid analgesics properly.The Chinese Medical Association for the Study of Pain convened a panel meeting to develop clinical practice consensus for the treatment of CMP with non-opioid analgesics.The purpose of this consensus is to present the application of nonsteroidal antiinflammatory drugs,serotonin norepinephrine reuptake inhibitors,serotonin and norepinephrine reuptake inhibitors,muscle relaxants,ion channel drugs and topical drugs in CMP.

Non-Dimensional Analysis of Thermal Effect on Skin Exposure to an Electromagnetic Beam

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. We non-dimensionalize the problem to write the temperature as the product of a parameter-free function of non-dimensional variables and a function of beam parameters. This formulation allows studying beam parameters without knowing skin material parameters. We examine the effects of spot size, total power and distribution type of the electromagnetic beam on 3 quantities at reflex: 1) the time to reflex, 2) the maximum temperature increase, and 3) the total energy consumption. We find that the flat-top beam is the best, with the lowest energy consumption and the smallest maximum temperature increase. The Super-Gaussian beam is only slightly inferior to the flat-top. The Gaussian beam has by far the worst performance among these three.

Blockade of transient receptor potential cation channel subfamily V member 1 promotes regeneration after sciatic nerve injury

The transient receptor potential cation channel subfamily V member 1（TRPV1） provides the sensation of pain（nociception）. However, it remains unknown whether TRPV1 is activated after peripheral nerve injury, or whether activation of TRPV1 affects neural regeneration. In the present study, we established rat models of unilateral sciatic nerve crush injury, with or without pretreatment with AMG517（300 mg/kg）, a TRPV1 antagonist, injected subcutaneously into the ipsilateral paw 60 minutes before injury. At 1 and 2 weeks after injury, we performed immunofluorescence staining of the sciatic nerve at the center of injury, at 0.3 cm proximal and distal to the injury site, and in the dorsal root ganglia. Our results showed that Wallerian degeneration occurred distal to the injury site, and neurite outgrowth and Schwann cell regeneration occurred proximal to the injury. The number of regenerating myelinated and unmyelinated nerve clusters was greater in the AMG517-pretreated rats than in the vehicle-treated group, most notably 2 weeks after injury. TRPV1 expression in the injured sciatic nerve and ipsilateral dorsal root ganglia was markedly greater than on the contralateral side. Pretreatment with AMG517 blocked this effect. These data indicate that TRPV1 is activated or overexpressed after sciatic nerve crush injury, and that blockade of TRPV1 may accelerate regeneration of the injured sciatic nerve.

P2X_3 , but not P2X_1 , Receptors Mediate ATP-activated Current in Neurons Innervating Tooth-pulp

Summary： We developed a method that allows us to label nociceptive neurons innervating tooth-pulp in rat trigeminal ganglion neurons using a retrograde fluorescence-tracing method, to re- cord ATP-activated current in freshly isolated fluorescence-labeled neurons and to conduct single cell immunohistochemical staining for P2X1 and P2X3 subunits in the same neuron. Three types of ATP-activated current in these neurons （F, I and S） were recorded. The cells exhibiting the type F current mainly showed positive staining for P2X3, but negative staining for P2X1. The results provide direct and convincing evidence at the level of single native nociceptive neurons for correlation of the characteristics of ATP-activated currents with their composition of P2Xl and P2X3 subunits and cell size. The results also suggest that the P2X3, but not P2X1, is the main subunit that mediates the fast ATP-activated current in nociceptive neurons.

New models to study vulvodynia: hyperinnervation and nociceptor sensitization in the female genital tract

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.

Effect of Depth-Dependent Nociceptor Density on the Heat-Induced Withdrawal Reflex

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.

Artificial synaptic simulating pain-perceptual nociceptor and brain-inspired computing based on Au/Bi_(3.2)La_(0.8)Ti_(3)O_(12)/ITO memristor

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.

Optically modulated dual-mode memristor arrays based on core-shell CsPbBr_(3)@graphdiyne nanocrystals for fully memristive neuromorphic computing hardware

Artificial synapses and neurons are crucial milestones for neuromorphic computing hardware,and memristors with resistive and threshold switching characteristics are regarded as the most promising candidates for the construction of hardware neural networks.However,most of the memristors can only operate in one mode,that is,resistive switching or threshold switching,and distinct memristors are required to construct fully memristive neuromorphic computing hardware,making it more complex for the fabrication and integration of the hardware.Herein,we propose a flexible dual-mode memristor array based on core–shell CsPbBr3@graphdiyne nanocrystals,which features a 100%transition yield,small cycle-to-cycle and device-to-device variability,excellent flexibility,and environmental stability.Based on this dual-mode memristor,homo-material-based fully memristive neuromorphic computing hardware—a power-free artificial nociceptive signal processing system and a spiking neural network—are constructed for the first time.Our dual-mode memristors greatly simplify the fabrication and integration of fully memristive neuromorphic systems.

Intrinsic vacancy in 2D defective semiconductor In_(2)S_(3) for artificial photonic nociceptor

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.

In-depth analysis of core-shell filaments in nonvolatile NbO_(x) memristive device as an artificial synapse for multifunctional bionic applications

As a key building block of the biological cortex,synapses are powerful information processing units that enable highly complex nonlinear computations.The realization of artificial synapses with similar capabilities has important implications for building intelligent,neuromorphic systems.Here,we demonstrate an artificial synapse based on NbO_(x) nonvolatile memristor to mimic multifunctional bionic applications such as nociceptor and associative learning.Combined experimental characterization with COMSOL simulation,the traditional resistance switching characteristics,which are the decisive factor for the synapse properties are in-depth analyzed.It can be proposed that the I-V characteristics of Pt/NbO_(x)/TiN memristor are governed by core-shell filaments consisting of the shell region of sub-stoichiometric Nb_(2)O_(5-δ)and the core of NbO_(2).On the basis of the core-shell filament model,it can be reasonably explained that Ohmic conduction and Poole-Frenkel conduction take turns to dominate the current flowing in the memristive device,leading to the zigzag evolution of current during the operation process of NbO_(x)-based device.The simulations of synaptic plasticity,including long-term potentiation/depression(LTP/LTD),paired-pulse facilitation(PPF),and spike-timing-dependent plasticity(STDP),exhibiting that the NbO_(x) can be utilized for an artificial synapse.Furthermore,bionic functions such as hyperalgesia and allodynia of a nociceptor and a series of associative learning behaviors in Pavlovian dog experiment are mimicked,illustrating that the Pt/NbO_(x)/TiN have great potential for highly simplified artificial neural network applications.

Regulation of Pain and Itch by TRP Channels

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.

Melittin, the Major Pain-Producing Substance of Bee Venom

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.

Artificial nociceptor based on TiO nanosheet memristor

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.

Nuclear Factor I/A Controls A-fiber Nociceptor Development

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.