Neuropathic Pain Conditions Research Articles

An atlas of neuropathic pain-associated molecular pathological characteristics in the mouse spinal cord

Peripheral nerve injury (PNI)-induced neuropathic pain (NP) is a severe disease with high prevalence in clinics. Gene reprogramming and tissue remodeling in the dorsal root ganglia (DRG) and spinal cord (SC) drive the development and maintenance of neuropathic pain (NP). However, our understanding of the NP-associated spatial molecular processing landscape of SC and the non-synaptic interactions between DRG neurons and SC cells remains limited. We here integrate spatial transcriptomics (ST) with single-nucleus RNA-sequencing (snRNA-seq) and bulk RNA-sequencing (bulk RNA-seq) to characterize regional pathological heterogeneity of the SC under NP conditions. First, the SC of NP mice manifests unique spatial atlases of genes, cell populations, cell-cell cross-talks, signaling pathways, and transcriptional regulatory networks compared to sham mice. We further report that injured DRG sensory neurons and the corresponding ventral horn of the SC show similar expression patterns after PNI. In addition, for the first time, we systematically exhibit “cross-talk omics” between the DRG neurons and SC dorsal horn neurons and glial cells, indicating an altered communication profile under NP conditions. Together, our findings decode the spatial and cellular heterogeneity of molecular pathological mechanisms underlying NP, providing a foundation for designing therapeutic targets for this disorder.

Research Progress on Opioid Receptors and Ion Channels in Dorsal Root Ganglion Neurons

Dorsal root ganglion (DRG) neurons play a crucial role in the perception and modulation of pain signals, making them a critical focus in pain mechanism research. Opioid receptors, as classical analgesic targets, inhibit pain signals by regulating ion channels such as calcium channels, while ion channels are directly involved in the generation and transmission of pain signals. In recent years, the synergistic interaction between opioid receptors and ion channels has become a research hotspot, particularly under pathological pain conditions, where their complex interplay provides key insights into analgesic drug development. This paper systematically reviews the distribution and functional mechanisms of opioid receptors and ion channels in DRG neurons, explores their interaction in pain modulation, and discusses functional changes under inflammatory and neuropathic pain conditions. Additionally, it examines potential targeted therapeutic strategies based on their synergy and outlines their clinical application prospects.

A case series of new-onset headache and neurological issues after thoracolumbar spinal cord stimulators.

Although spinal cord stimulator (SCS) therapy is generally used safely to treat chronic neuropathic pain conditions, this document highlights the less reported complication of unusual neurological problems including headaches. These developed temporally after the initiation of SCS therapy despite initial positive response to pain. The mechanisms might include activation of trigeminal receptors and neuroplasticity after SCS. We present a series of four cases where patients developed new neurological symptoms like headaches, facial twitching, and tinnitus, that were related to SCS activation. Despite adjustments to the SCS settings and extensive evaluations, these symptoms persisted in all cases, leading to the decision to explant SCS which was otherwise helping pain.

Macrophage to neuron communication via extracellular vesicles in neuropathic pain conditions.

Neuropathic pain following peripheral nerve injury results from maladaptive changes in neurons and immune cells contribution to mechanisms underlying chronic pain. Specifically, in dorsal root ganglia (DRG), sensory neuron cell bodies release extracellular vesicles (EVs) which promote pro-inflammatory macrophage accumulation that facilitates nociceptive signalling. Here, we show that macrophages shuttle EVs to neurons. Indeed, bone marrow-derived macrophages (BMDMs) release EVs containing microRNA-155 (miR-155) which are taken up by cultured sensory neurons. EV-mediated transfer of miR-155 suppresses phosphatase Ship1 expression and increases cytokine interleukin-6 (IL-6) contents. Intrathecal-injected BMDM-derived EVs accumulate in lumbar DRG and EVs containing miR-155 antagomir result in Ship1 upregulation, Il6 downregulation in neurons in concomitance to attenuation of neuropathic mechanical hypersensitivity. These data suggest that, under neuropathic conditions, pro-inflammatory macrophages shuttle EV-containing miR-155 to neurons and contribute to the expression of pronociceptive IL-6 in DRG.

Electroacupuncture Alleviates Neuropathic Pain and Negative Emotion in Mice by Regulating Gut Microbiota.

Neuropathic pain (NP) is a prevalent chronic condition frequently accompanied by adverse emotional states. Previous research has demonstrated the clinical efficacy of electroacupuncture (EA) in mitigating neuropathic pain and its associated mood disorders. Recent studies have underscored a correlation between gut microbiota and both NP and negative emotional states. Nevertheless, the relationship between the modulation of gut microbiota by EA and the amelioration of NP remains inadequately understood. Mice were randomly assigned to one of the three groups: the Control (Con) group, the EA group, and the Chronic Constrictive Injury (CCI) group (n = 12 each). Starting from the 8th day post-CCI induction, the EA group underwent EA treatment once every two days, for a total of 20 sessions. To investigate the impact of gut microbiota on CCI mice, we employed a variety of methods, including various behavioral tests and 16S ribosomal DNA (rDNA) sequencing. The results indicated that EA significantly ameliorated mechanical allodynia and emotional dysfunction induced by CCI in mice. Analysis through 16S rDNA sequencing revealed that the gut microbiota of NP model mice exhibited a marked increase in diversity. However, EA could partially reverse changes in the diversity of gut microbiota. The abundance of Alloprevotella, A2, Roseburia, Muribaculum, Ruminiclostridium, and Rikenella was increased, and the abundance levels of Bacteroides were decreased at the genus level in CCI mice. Following EA treatment, the relative abundance of Alistipes, A2, Roseburia, and Rikenella was decreased, whereas the relative abundance of Alloprevotella and Parabacteroides was increased in EA group when compared with the CCI group. These findings suggested that EA exerted a significant therapeutic effect on NP, potentially through modulation of the gut microbiota.

A Non-Invasive Technique of Low Dosage Laser Treatment on Post Herpetic Neuralgia: A Systematic Review and Meta-Analysis

Introduction: Post herpetic neuralgia (PHN) is a chronic neuropathic pain condition that persists for months or even years following the resolution of herpes zoster (HZ) rash. The biological effects of Low-Level Laser Therapy (LLLT) on pain and tissue repair are multifaceted and complex. Methods: The research followed PRISMA guidelines and utilized search terms such as "postherpetic neuralgia OR PHN, pain, low level laser therapy OR LLLT, varicella-zoster virus OR VZV, herpes zoster OR HZ, Systematic review and Meta-analysis, Randomized controlled trial " across Scopus, ScienceDirect, and Web of Science, Embase, Cochrane Library databases. Studies meeting eligibility criteria were included, and a forest plot analysis was obtained using a random-effects model with standardized mean difference (SMD) of 95 confidence interval which was calculated based on visual analogue scale (VAS) outcomes from selected studies. Results: Four eligible studies were identified and subjected to both qualitative and quantitative evaluations. The pooled standardized mean difference data (SMD -6.39, CI -11.06 to -1.72, p 0.007) indicate that LLLT significantly reduces pain associated with PHN compared to conventional treatments. Conclusion: This systematic review and meta-analysis demonstrate that LLLT technology is more effective in reducing pain associated with PHN than conventional treatments. Importantly, there is no evidence suggesting adverse effects of LLLT treatment for PHN.

Comprehensive nursing care improves symptoms and quality of life in elderly patients with postherpetic neuralgia

This study evaluates the clinical impact of comprehensive nursing care on senior patients suffering from postherpetic neuralgia (PHN), a chronic neuropathic pain condition resulting from the reactivation of the varicella-zoster virus. A total of 102 elderly patients diagnosed with PHN and treated at our hospital were divided into two groups: the control group, which received conventional nursing care, and the intervention group, which received comprehensive nursing care. Comparative analyses were conducted on pain levels, sleep quality, symptoms of depression and anxiety before and after the intervention. After a two-month period of nursing care, both groups exhibited a significant reduction in pain levels (p < 0.05), with the intervention group demonstrating a more substantial decrease (p < 0.001). Sleep quality improved in both groups (p < 0.05), with the intervention group showing a significantly greater improvement (p < 0.05). Additionally, the intervention group experienced a notable reduction in anxiety and depression ratings compared to the control group. Comprehensive nursing care interventions may effectively alleviate clinical symptoms, and diminish levels of depression and anxiety, while improving sleep quality in elderly patients with PHN. These findings underscore the potential benefits of employing a comprehensive approach to managing PHN in the elderly population.

Reorganization of lateral habenula neuronal connectivity underlies pain-related impairment in spatial memory encoding.

Dysfunctional hyperactivity of the lateral habenula nucleus (LHb) has emerged as a critical marker for pain-related mood impairments. Acting as a central hub, the LHb filters and disseminates pertinent information to other brain structures during learning. However, it is not well understood how intra-LHb activity is altered during cognitive demand under neuropathic pain conditions. To address this gap, we implanted an optrode structure to record neuronal activity in adult male CD (rat strain without definition) rats during the execution of a delayed nonmatch-to-sample (DNMS) spatial working memory (WM) task. We selectively modulated intra-LHb network activity by optogenetically inhibiting local LHb CaMKIIα (calcium calmodulin-dependent protein kinase II alpha)-expressing neurons during the delay phase of the DNMS task. Behavioral assessments were conducted using a persistent rodent model of neuropathic pain-spared nerve injury. Our results showed that the induction of neuropathic pain disrupted WM encoding accuracy and intra-LHb functional neuronal connectivity. This disruption was reversed by optogenetic inhibition of LHb CaMKIIα-expressing neurons, which also produced antinociceptive effects. Together, our findings provide insight into how intra-LHb networks reorganize information to support different task contexts, suggesting that the abnormal pain-related intra-LHb dynamic segregation of information may contribute to poor cognitive accuracy in male rodents during pain experiences.

Temporal changes of spinal microglia in murine models of neuropathic pain: a scoping review.

Neuropathic pain (NP) is an ineffectively treated, debilitating chronic pain disorder that is associated with maladaptive changes in the central nervous system, particularly in the spinal cord. Murine models of NP looking at the mechanisms underlying these changes suggest an important role of microglia, the resident immune cells of the central nervous system, in various stages of disease progression. However, given the number of different NP models and the resource limitations that come with tracking longitudinal changes in NP animals, many studies fail to truly recapitulate the patterns that exist between pain conditions and temporal microglial changes. This review integrates how NP studies are being carried out in murine models and how microglia changes over time can affect pain behavior in order to inform better study design and highlight knowledge gaps in the field. 258 peer-reviewed, primary source articles looking at spinal microglia in murine models of NP were selected using Covidence. Trends in the type of mice, statistical tests, pain models, interventions, microglial markers and temporal pain behavior and microglia changes were recorded and analyzed. Studies were primarily conducted in inbred, young adult, male mice having peripheral nerve injury which highlights the lack of generalizability in the data currently being collected. Changes in microglia and pain behavior, which were both increased, were tested most commonly up to 2 weeks after pain initiation despite aberrant microglia activity also being recorded at later time points in NP conditions. Studies using treatments that decrease microglia show decreased pain behavior primarily at the 1- and 2-week time point with many studies not recording pain behavior despite the involvement of spinal microglia dysfunction in their development. These results show the need for not only studying spinal microglia dynamics in a variety of NP conditions at longer time points but also for better clinically relevant study design considerations.

Rate-Dependent Depression of the Hoffmann Reflex: Practical Applications in Painful Diabetic Neuropathy.

Measurement of the rate-dependent depression (RDD) of the Hoffmann (H) reflex, a technique developed over half a century ago, is founded on repeated stimulation of the H-reflex with tracking of sequentially evoked H-wave amplitudes in the resulting electromyogram. RDD offers insight into the integrity of spinal reflex pathways and spinal inhibitory regulation. Initially, RDD was predominantly utilized in the mechanistic exploration and evaluation of movement disorders characterized by spasticity symptoms, as may occur following spinal cord injury. However, there is increasing recognition that sensory input from the periphery is modified at the spinal level before ascending to the higher central nervous system and that some pain states can arise from, or be exaggerated by, disruption of spinal processing via a mechanism termed spinal disinhibition. This, along with the urgent clinical need to identify biological markers of pain generator and/or amplifier sites to facilitate targeted pain therapies, has prompted interest in RDD as a biomarker for the contribution of spinal disinhibition to neuropathic pain states. Current research in animals and humans with diabetes has revealed specific disorders of spinal GABAergic function associated with impaired RDD. Future investigations on RDD aim to further elucidate its underlying pathways and enhance its clinical applications.

The effects of chronic neuropathic pain states on the discriminative stimulus effect of fentanyl and other MOR agonists.

Pleasant subjective effects of drugs (e.g., euphoria) have been demonstrated to contribute to their abuse potential. In humans, there is some evidence that acute pain states may decrease the positive subjective effects of opioids; however, no studies have directly tested the impact of a long-lasting pain state. Therefore, the goal of this study was to directly evaluate the discriminative stimulus of mu opioid receptor (MOR) agonist, fentanyl, or the non-opioid drug of abuse, cocaine, in the presence or absence of spared nerve injury (SNI) induced chronic neuropathic pain. Prior to surgery, MOR agonists (fentanyl, morphine, nalbuphine) dose-dependently increased % fentanyl-like responding, as expected; surprisingly, after surgery, we saw small, significant rightward shifts in the fentanyl and morphine dose response curves in both sham and SNI groups suggesting that the observed shifts were not due to chronic pain. In both sham and SNI groups, there was an increase in the generalization of nalbuphine to the fentanyl-discriminative stimulus. There was no change in the discriminative stimulus of cocaine (or amphetamine substitutions) over 4 months of SNI-induced chronic neuropathic pain or sham states, suggesting that the SNI model failed to alter the discriminative stimuli of fentanyl and cocaine. Following induction of chronic neuropathic pain, there was an observed increase in quinpirole-induced generalization to the cocaine discriminative stimulus. In the future, studies should directly examine the abuse potential of low efficacy MOR agonists and dopaminergic agonists in the presence and absence of chronic pain states.

Antibody selection and automated quantification of TRPV1 immunofluorescence on human skin

Assessing localization of the transient receptor potential vanilloid-1 (TRPV1) in skin nerve fibers is crucial for understanding its role in peripheral neuropathy and pain. However, information on the specificity and sensitivity of TRPV1 antibodies used for immunofluorescence (IF) on human skin is currently lacking. To find a reliable TRPV1 antibody and IF protocol, we explored antibody candidates from different manufacturers, used rat DRG sections and human skin samples for screening and human TRPV1-expressing HEK293 cells for further validation. Final specificity assessment was done on human skin samples. Additionally, we developed two automated image analysis methods: a Python-based deep-learning approach and a Fiji-based machine-learning approach. These methods involve training a model or classifier for nerve fibers based on pre-annotations and utilize a nerve fiber mask to filter and count TRPV1 immunoreactive puncta and TRPV1 fluorescence intensity on nerve fibers. Both automated analysis methods effectively distinguished TRPV1 signals on nerve fibers from those in keratinocytes, demonstrating high reliability as evidenced by excellent intraclass correlation coefficient (ICC) values exceeding 0.75. This method holds the potential to uncover alterations in TRPV1 associated with neuropathic pain conditions, using a minimally invasive approach.

Activation of MSK-1 exacerbates neuropathic pain through histone H3 phosphorylation in the rats’ dorsal root ganglia and spinal dorsal horn

The exact mechanism underlies the development of neuropathic pain is not yet completely understood. Mitogen and stress-activated kinase 1 (MSK-1) is an important downstream kinase of the mitogen-activated protein kinase (MAPK). It has been extensively studied in the central nervous system, but whether MSK-1 is associated with the neuropathic pain remains elusive. In this experiment, Lumbar 5 spinal nerve ligation (SNL) was used to establish a neuropathic pain condition in the rats. Western blotting, qRT-PCR, immunohistochemistry, intrathecal catheterization and drugs delivery were evaluated to study the physiological responses of the animals. The results showed that SNL resulted in elevated phosphorylated MSK-1 (p-MSK-1) expression in the ipsilateral dorsal root ganglion (DRG) and the spinal dorsal horn in rats, while total MSK-1 (t-MSK-1) did not change significantly. Intrathecal injection of the MSK-1 inhibitor SB747651A partially reversed established neuropathic pain. Additionally, intrathecal administration of MSK-1 siRNA either preoperatively or 7 days postoperatively relieves the development and maintenance of pain, respectively. Meanwhile, the expression levels of p-H3S10, a downstream target of MSK-1, also displayed a significant increase after SNL. And these changes could be reversed by using MSK-1 siRNA. Collectively, the increase of MSK-1 induced by SNL participates in the development and maintenance of neuropathic pain by regulating the expression of p-H3S10 in DRG and spinal dorsal horn. Concentrating on MSK-1 may result in a novel approach to the treatment of neuropathic pain.

Biopsychosocial rehabilitation therapy in small fiber neuropathy: research protocol to study the effect of rehabilitation treatment.

Small fiber neuropathy (SFN) is a chronic neuropathic pain condition that can lead to a decreased quality of life (QOL) and disability. Current pain treatment is mainly symptomatic, consisting of analgesics, with often disappointing results. There is a need for new, more effective treatment modality. Treatment based on a biopsychosocial approach on SFN-related pain may be a promising alternative. A rehabilitation treatment study protocol is presented with the following main objective: to test the effect of a tailored interdisciplinary rehabilitation treatment targeting both cognitive and psychological factors related to pain, in decreasing disability, and improving QOL in SFN. Single-case experimental design. Ten participants with SFN will be included. Every patient will be offered a personalized program based on one of three rehabilitation treatment modules (graded activity, exposure in vivo or acceptance and commitment therapy) depending on the most prominent factor maintaining disability. Treatment will be provided for at least 8 weeks with 2 sessions a week. This is the first study investigating personalized rehabilitation treatment in patients with idiopathic SFN. The findings are expected to result in an effective treatment for SFN with an increase in QOL and a decrease in disability. ClinicalTrials.gov, identifier NCT05798949.

Microglia-dependent peripheral neuropathic pain in adulthood following adolescent exposure to morphine in male rats

Persistent effects of adolescent morphine exposure on neurobiological processes and behaviors in adulthood have been partially identified. Hypersensitivity following adolescent exposure to morphine is a complex and multifaceted phenomenon whose underlying mechanisms remain largely unknown. This study aimed to investigate the involvement of microglia in neuropathic pain sensitivity following adolescent morphine exposure, focused on hippocampal genes expression and plasticity. To achieve this, adolescent male Wistar rats received morphine, along with minocycline, to inhibit microglial activity. The allodynia and hyperalgesia of adult rats were evaluated using von-Frey filaments and the Hargreaves plantar test in both baseline and neuropathic pain conditions. Hippocampal genes expression was analyzed following the behavioral tests. The plasticity of the Schaffer-CA1 hippocampal synapses was also assessed using field potential recording following neuropathy. Results showed that adolescent morphine exposure exacerbated the allodynia and hyperalgesia in both baseline and neuropathic pain states in adult rats, which was significantly reduced by the co-administration of minocycline during adolescence. Neuropathy in adult rats was found to increase hippocampal expression of inflammatory mediators, but adolescent morphine prevented this effect. Additionally, we observed a reduction in the baseline synaptic transmission and long-term potentiation (LTP) at the Schaffer-CA1 hippocampal synapses after neuropathy in adult rats following adolescent exposure to morphine. The reduction of synaptic activity was not altered by the co-administration of minocycline with morphine during adolescence. It is concluded that microglia play an important role in mediating hypersensitivity induced by adolescent morphine exposure, although hippocampal microglia may not be directly involved in this process.

The Mechanism and Inflammatory Markers Involved in the Potential Use of N-acetylcysteine in Chronic Pain Management.

N-acetylcysteine (NAC) has established use as an antidote for acetaminophen overdose and treatment for pulmonary conditions and nephropathy. It plays a role in regulating oxidative stress and interacting with various cytokines including IL-1β, TNFα, IL-8, IL-6, IL-10, and NF-κB p65. The overexpression of reactive oxygen species (ROS) is believed to contribute to chronic pain states by inducing inflammation and accelerating disease progression, favoring pain persistence in neuropathic and musculoskeletal pain conditions. Through a comprehensive review, we aim to explore the mechanisms and inflammatory pathways through which NAC may manage neuropathic and musculoskeletal pain. Evidence suggests NAC can attenuate neuropathic and musculoskeletal pain through mechanisms such as inhibiting matrix metalloproteinases (MMPs), reducing reactive oxygen species (ROS), and enhancing glutamate transport. Additionally, NAC may synergize with opioids and other pain medications, potentially reducing opioid consumption and enhancing overall pain management. Further research is needed to fully elucidate its therapeutic potential and optimize its use in pain management. As an adjuvant therapy, NAC shows potential for chronic pain management, offering significant benefits for public health.

Surgical treatment of trigeminal pain

Surgical procedures for treating neuropathic pain, including trigeminal neuralgia (TGN), are categorized into three groups: decompression, ablation, and neuromodulation. Microvascular decompression is the only causal therapy for TGN, applicable favorably in cases of classical TGN due to avascular nerve conflict. Ablative procedures include both percutaneous and radiosurgical methods, which are mainly used for idiopathic trigeminal neuralgia. For irreversible neuropathies of the trigeminal nerve, the algorithm for other neuropathic pain conditions should be considered, along with the potential use of neuromodulatory techniques. When selecting a therapy, diagnosis, medication side effects, individual patient risks, and treatment outcomes must all be taken into account (current S1guideline from the German Society of Neurology).

ApoA-I binding protein (AIBP) regulates transient receptor potential vanilloid 1 (TRPV1) activity in rat dorsal root ganglion neurons by selective disruption of toll-like receptor 4 (TLR4)-lipid rafts

Toll-like receptor 4 (TLR4) and the transient receptor potential vanilloid subtype 1 (TRPV1) are both upregulated and play key roles in the induction and expression of paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Using Apolipoprotein A-I binding protein, non-specific cholesterol depletion, TLR4 mis-sense rats and a TLR4 inhibitor, we demonstrate that co-localization of TRPV1 with TLR4 to cholesterol-rich lipid membrane rafts in nociceptors is essential for its normal activation as well as for its exaggerated activation that underlies the development and expression of CIPN. The findings suggest that TLR4-lipid rafts may have an essential role in numerous neuroinflammatory and neuropathic pain conditions. This mechanism is also generalized to female rats for the first time.

Opioids and Cannabinoids in Neurology Practice.

Opioid and cannabinoid therapies for chronic pain conditions including neuropathic pain are controversial. Understanding patient and prescribing factors contributing to risks and implementing risk mitigation strategies optimizes outcomes. The ongoing transformation from a biomedical model of pain care toward a biopsychosocial model has been accompanied by a shift away from opioid therapy for pain, in particular for chronic pain. Opioid overdose deaths and opioid use disorder have greatly increased in the last several decades, initially because of increases in opioid prescribing and more recently associated with illicit drug use, in particular fentanyl derivatives. Opioid risk mitigation strategies may reduce risks related to opioid prescribing and tapering or discontinuation. Opioid therapy guidelines from the Centers for Disease Control and Prevention have become the consensus best practice for opioid therapy. Regulatory agencies and licensing medical boards have implemented restrictions and other mandates regarding opioid therapy. Meanwhile, interest in and use of cannabinoids for chronic pain has grown in the United States. Opioid therapy is generally not recommended for the chronic treatment of neuropathic pain conditions. Opioids may be considered for temporary use in patients with severe pain related to selected neuropathic pain conditions (such as postherpetic neuralgia), and only as part of a multimodal treatment regimen. Opioid risk mitigation strategies include careful patient selection and evaluation, patient education and informed consent, querying the state prescription drug monitoring programs, urine drug testing, and issuance of naloxone as potential rescue medication. Close follow-up when initiating or adjusting opioid therapy and frequent reevaluation during long-term opioid therapy is required. There is evidence for the efficacy of cannabinoids for neuropathic pain, with meaningful response rates in select patient populations.

Methylcobalamin as a candidate for chronic peripheral neuropathic pain therapy: review of molecular pharmacology actiona.

Chronic peripheral neuropathic pain therapy currently focuses on modulating neuroinflammatory conditions. Methylcobalamin (MeCbl), a neuroregenerative agent, modulates neuroinflammation. This review aimed to explore the molecular pharmacology action of MeCbl as a chronic peripheral neuropathic pain therapeutic agent. MeCbl plays a role in various cellular processes and may have therapeutic potential in neurodegenerative diseases. Intracellular MeCbl modulates inflammation by regulating the activity of T lymphocytes and natural killer cells as well as secretion of inflammatory cytokines, namely, tumor necrosis factor-α, interleukin-6, interleukin-1β, epidermal growth factor, and neuronal growth factor. MeCbl can reduce pain symptoms in chronic neuropathic pain conditions by decreasing excitation and hyperpolarization-induced ion channel activity in medium-sized dorsal root ganglion (DRG) neurons and the expression of transient receptor potential ankyrin 1, transient receptor potential cation channel subfamily M member 8, phosphorylated p38MAPK, transient receptor potential cation channel subfamily V members 1 and 4 in the DRG, and the voltage-gated sodium channel in axons.