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Acta Biomaterialia Oct 2023Chronic low back pain mainly attributed to intervertebral disc (IVD) degeneration. Endogenous damage-associated molecular patterns (DAMPs) in the injured IVD,...
Chronic low back pain mainly attributed to intervertebral disc (IVD) degeneration. Endogenous damage-associated molecular patterns (DAMPs) in the injured IVD, particularly mitochondria-derived nucleic acid molecules (CpG DNA), play a primary role in the inflammatory responses in macrophages. M1-type macrophages form a chronic inflammatory microenvironment by releasing pro-inflammatory factors and nerve growth factor (NGF) that induce nerve growth into the inner annulus fibrosus, resulting in persistent hyperalgesia. We fabricated an amphiphilic polycarbonate that naturally forms cationic nanoparticles (cNP) in aqueous solutions, with the hydrophobic core loaded with TrkA-IN-1, an antagonist against the NGF receptor (TrkA). The drug delivery nanoparticles were denoted as TI-cNP. TrkA-IN-1 and TI-cNP were added to the decellularized annulus fibrosus matrix (DAF) hydrogel to form hybrid hydrogels, denoted as TI-DAF and TI-cNP-DAF, respectively. As a result, TrkA-IN-1 showed a delayed release profile both in TI-DAF and TI-cNP-DAF. Each mole of cNP could bind approximately 3 mol of CpG DNA to inhibit inflammation. cNP-DAF and TI-cNP-DAF significantly inhibited the M1 phenotype induced by CpG DNA. TI-DAF and TI-cNP-DAF reduced neurite branching and axon length, and inhibited the expression of neurogenic mediators (CGRP and substance P) in the presence of NGF. Besides, TI-cNP-DAF relieved mechanical hyperalgesia, reduced CGRP and substance P expression in the dorsal root ganglion, and downregulated GFAP and c-FOS signaling in the spinal cord in the rat disc herniation model. Summarily, TI-cNP-DAF, a novel composite IVD hydrogel, efficiently mediated the inflammatory environment, inhibited nerve ingrowth and sensitization, and could be clinically applied for treating discogenic pain. STATEMENT OF SIGNIFICANCE: Discogenic lower back pain, related to intervertebral disc degeneration (IDD), imposes a tremendous health and economic burden globally. M1-type macrophages release pro-inflammatory factors and nerve growth factor (NGF) that induce nerve growth into the inner annulus fibrosus, resulting in persistent hyperalgesia and discogenic pain. Reconstructing matrix integrity and modulating the inflammatory microenvironment are promising strategies for preventing the ingrowth and activation of neurites. The TI-cNP-DAF hydrogel recovers tissue integrity, alleviates inflammation, and delivers the TrkA antagonist to inhibit the activity of NGF, thus restraining hyperinnervation and nociceptive input. Due to its simple production process, injectability, and acellular strategy, the hydrogel is operable and holds great potential for treating discogenic lower back pain.
PubMed: 37598791
DOI: 10.1016/j.actbio.2023.08.028 -
The Journal of Allergy and Clinical... Apr 2024Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display... (Review)
Review
Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations, including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in AD. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system, including common mediators (such as serotonin, endothelin-1, IL-33, and thymic stromal lymphopoietin), receptors (such as members of the G protein-coupled receptor family and Toll-like receptors), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C-C [CCL2, CCL5] and C-X-C [CXCL] motif ligands) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of μ-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in AD.
Topics: Humans; Dermatitis, Atopic; Pruritus; Pain; Cytokines; Signal Transduction
PubMed: 38103700
DOI: 10.1016/j.jaci.2023.10.034 -
Journal of Translational Medicine Aug 2023Peripheral nerve injury can cause neuroinflammation and neuromodulation that lead to mitochondrial dysfunction and neuronal apoptosis in the dorsal root ganglion (DRG)...
BACKGROUND
Peripheral nerve injury can cause neuroinflammation and neuromodulation that lead to mitochondrial dysfunction and neuronal apoptosis in the dorsal root ganglion (DRG) and spinal cord, contributing to neuropathic pain and motor dysfunction. Hyperbaric oxygen therapy (HBOT) has been suggested as a potential therapeutic tool for neuropathic pain and nerve injury. However, the specific cellular and molecular mechanism by which HBOT modulates the development of neuropathic pain and motor dysfunction through mitochondrial protection is still unclear.
METHODS
Mechanical and thermal allodynia and motor function were measured in rats following sciatic nerve crush (SNC). The HBO treatment (2.5 ATA) was performed 4 h after SNC and twice daily (12 h intervals) for seven consecutive days. To assess mitochondrial function in the spinal cord (L2-L6), high-resolution respirometry was measured on day 7 using the OROBOROS-O2k. In addition, RT-PCR and Immunohistochemistry were performed at the end of the experiment to assess neuroinflammation, neuromodulation, and apoptosis in the DRG (L3-L6) and spinal cord (L2-L6).
RESULTS
HBOT during the early phase of the SNC alleviates mechanical and thermal hypersensitivity and motor dysfunction. Moreover, HBOT modulates neuroinflammation, neuromodulation, mitochondrial stress, and apoptosis in the DRG and spinal cord. Thus, we found a significant reduction in the presence of macrophages/microglia and MMP-9 expression, as well as the transcription of pro-inflammatory cytokines (TNFa, IL-6, IL-1b) in the DRG and (IL6) in the spinal cord of the SNC group that was treated with HBOT compared to the untreated group. Notable, the overexpression of the TRPV1 channel, which has a high Ca permeability, was reduced along with the apoptosis marker (cleaved-Caspase3) and mitochondrial stress marker (TSPO) in the DRG and spinal cord of the HBOT group. Additionally, HBOT prevents the reduction in mitochondrial respiration, including non-phosphorylation state, ATP-linked respiration, and maximal mitochondrial respiration in the spinal cord after SNC.
CONCLUSION
Mitochondrial dysfunction in peripheral neuropathic pain was found to be mediated by neuroinflammation and neuromodulation. Strikingly, our findings indicate that HBOT during the critical period of the nerve injury modulates the transition from acute to chronic pain via reducing neuroinflammation and protecting mitochondrial function, consequently preventing neuronal apoptosis in the DRG and spinal cord.
Topics: Rats; Animals; Peripheral Nerve Injuries; Rats, Sprague-Dawley; Neuroinflammatory Diseases; Neuralgia; Hyperalgesia; Sciatic Nerve; Spinal Cord; Mitochondria
PubMed: 37582750
DOI: 10.1186/s12967-023-04414-x -
JCI Insight Jul 2023Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes a dose-limiting peripheral neurotoxicity. There is no...
Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes a dose-limiting peripheral neurotoxicity. There is no clinically effective preventative treatment for vincristine-induced sensory peripheral neurotoxicity (VIPN), and mechanistic details of this side effect remain poorly understood. We hypothesized that VIPN is dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons. Using a xenobiotic transporter screen, we identified OATP1B3 as a neuronal transporter regulating the uptake of vincristine. In addition, genetic or pharmacological inhibition of the murine orthologue transporter OATP1B2 protected mice from various hallmarks of VIPN - including mechanical allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes and neuronal morphology - without negatively affecting plasma levels or antitumor effects of vincristine. Finally, we identified α-tocopherol from an untargeted metabolomics analysis as a circulating endogenous biomarker of neuronal OATP1B2 function, and it could serve as a companion diagnostic to guide dose selection of OATP1B-type transport modulators given in combination with vincristine to prevent VIPN. Collectively, our findings shed light on the fundamental basis of VIPN and provide a rationale for the clinical development of transporter inhibitors to prevent this debilitating side effect.
Topics: Mice; Animals; Vincristine; Xenobiotics; Peripheral Nervous System Diseases; Hyperalgesia; Ganglia, Spinal; Membrane Transport Proteins
PubMed: 37347545
DOI: 10.1172/jci.insight.164646 -
Journal of Clinical Medicine Oct 2023Patient-centered care (PCC) is recognized as a standard in healthcare for determining high quality. Honoring patients' values, experiences, needs, and preferences in... (Review)
Review
Patient-centered care (PCC) is recognized as a standard in healthcare for determining high quality. Honoring patients' values, experiences, needs, and preferences in devising, coordinating, and delivering care underscores the enhancement of the therapeutic rapport between patients and healthcare providers. Wound treatment involves a multi-stage process encompassing diagnostics and local wound dressing, which reduces the risk of infection through a coordinated interdisciplinary team. Within this team, nurses undertake specific professional functions and roles. The implementation of local therapy using innovative and scientifically substantiated methods may be hindered by a deficit of knowledge or inappropriate knowledge among staff and patients themselves. This study presents the challenges concerning the care of patients with chronic wounds treated using Lucilia sericata larvae, based on a review of the current scientific literature. A critical analysis of the literature spanning from 2002 to 2022 was conducted using the Medline, PubMed, Cochrane, and Termedia databases, employing keywords such as "maggot debridement therapy" in relation to acceptance and perception. As a result of the preliminary selection, 472 papers were identified, of which 12 publications were included in the development of this concept. The acquired data were organized and presented in the concluding section in the form of tables, accompanied by descriptions and references to individual studies. Negative psychological and somatic sensations were among the most prominent challenges among patients treated with Maggot Debridement Therapy (MDT). Pain related to peripheral ischemia or infection in this group of patients requires pain prophylaxis, including hyperalgesia and allodynia, in order to improve method tolerance. On the other hand, augmenting patients' understanding of MDT diminishes negative emotions, reinforces positive behaviors, and mitigates anxiety levels. MDT constitutes an effective and safe method. Its widespread use for chronic wounds requires substantial knowledge among healthcare professionals and patient education, along with that of their caregivers, to develop a positive attitude.
PubMed: 37959326
DOI: 10.3390/jcm12216862 -
Chinese Medicine Jul 2023Gout results from disturbed uric acid metabolism, which causes urate crystal deposition in joints and surrounding tissues. Gout pain management is largely limited to...
BACKGROUND
Gout results from disturbed uric acid metabolism, which causes urate crystal deposition in joints and surrounding tissues. Gout pain management is largely limited to colchicine and nonsteroidal anti-inflammatory drugs. Constant usage of these medications leads to severe side effects. We previously showed electroacupuncture (EA) is effective for relieving pain in animal model of gout arthritis. Here we continued to study the mechanisms underlying how EA alleviates gout pain.
METHODS
Monosodium urate was injected into ankle joint to establish gout arthritis model in mice. EA or sham EA was applied at ST36 and BL60 acupoints of model animals. Biochemical assays, immunostaining, live cell Ca imaging and behavioral assays were applied.
RESULTS
Model mice displayed obvious mechanical allodynia, accompanied with gait impairments. EA attenuated mechanical hypersensitivities and improved gait impairments. EA reduced the overexpression of NLRP3 inflammasome signaling molecules in ankle joints of model animals. EA-induced anti-allodynia, as well as inhibition on NLRP3 inflammasome, were mimicked by antagonizing but abolished by activating NLRP3 inflammasome via pharmacological methods. EA attenuated oxidative stress, an upstream signaling of NLRP3 inflammasome in ankle joints of model mice. Exogenously increasing oxidative stress abolished EA's inhibitory effect on NLRP3 inflammasome and further reversed EA's anti-allodynic effect. EA reduced neutrophil infiltrations in ankle joint synovium, a major mechanism contributing to oxidative stress in gout. Pharmacological blocking NLRP3 inflammasome or EA reduced TRPV1 channel overexpression in dorsal root ganglion (DRG) neurons. Ca imaging confirmed that EA could reduce functional enhancement in TRPV1 channel in DRG neurons during gout.
CONCLUSIONS
Our results demonstrate that EA reduces gout pain possibly through suppressing ROS-mediated NLRP3 inflammasome activation in inflamed ankle joints and TRPV1 upregulation in sensory neurons, supporting EA as a treatment option for gout pain.
PubMed: 37464384
DOI: 10.1186/s13020-023-00800-1 -
Journal of Traditional Chinese Medicine... Oct 2023To evaluate the effect of berberine on morphine analgesia, tolerance, and hyperalgesia.
OBJECTIVE
To evaluate the effect of berberine on morphine analgesia, tolerance, and hyperalgesia.
METHODS
Morphine-induced acute tolerance model: mice received intraperitoneal berberine at doses of 2.5, 5.0, and 10 mg/kg; 30 min later, subcutaneous morphine 10 mg/kg was injected every hour for nine continuous h. Morphine 10 mg/kg alone was administered at 24 and 48 h. Morphine-induced chronic tolerance model: mice received intraperitoneal berberine 2.5, 5.0, and 10 mg/kg; 30 min later, 10 mg/kg morphine was injected subcutaneously for eight consecutive days. On the ninth day, morphine 10 mg/kg was given alone. Morphine-induced established tolerance model: mice were injected subcutaneously with morphine 10 mg/kg once a day for eight consecutive days. Berberine 2.5 mg/kg was administered on day one, four, and seven and morphine 10 mg/kg alone on day nine. The baseline latency (T0) and post-treatment latency (T1) were determined by the hot plate test, and the maximum possible analgesic effect (MPAE) was calculated. Nitric oxide synthase (NOS) activity and nitric oxide (NO) content in the spinal cord were measured by spectrophotometer. Verification of berberine analgesic effect by blocking N-methyl-D-aspartate (NMDA) receptor: HT-22 and HEK-293 cells transfected with NMDA plasmid were randomly divided into five groups: control group, NMDA group, berberine low-dose, medium-dose, and high-dose groups (5, 10, 20 μmol/L, respectively). Except for the control group, cells were treated with NMDA (HT-22 cells: 20 mmol/L; HEK-293 cells: 50 μmol/L). After 24 h, cell viability was detected by cell counting kit-8. The molecular mechanism between berberine and the NMDA receptor was studied by molecular docking.
RESULTS
Berberine 2.5 and 5.0 mg/kg could prolong the analgesic time of morphine. In acute and chronic morphine tolerance models, berberine could inhibit the decrease of MPAE and baseline latency (0.05). In the established tolerance model, berberine could rapidly reverse the decreased MPAE (0.05). The combination of berberine and morphine on day one could effectively inhibit the morphine-induced increase of NOS activity and NO content in the spinal cord (0.05). Berberine significantly increased the cell viability of NMDA-induced nerve injury in HT-22 and HEK-293 cells (0.05). Molecular docking showed that berberine binds to the receptor pocket of NMDA.
CONCLUSIONS
Berberine could effectively enhance and prolong the duration of morphine analgesia and inhibit the development of morphine-induced tolerance and hyperalgesia. Furthermore, berberine has a certain neuroprotective effect, which may be related to the inhibition of NMDA activity.
Topics: Humans; Animals; Mice; Hyperalgesia; Morphine; Berberine; HEK293 Cells; Molecular Docking Simulation; N-Methylaspartate; Nitric Oxide
PubMed: 37679979
DOI: 10.19852/j.cnki.jtcm.20230802.006 -
Drug Design, Development and Therapy 2023The aim of this study was to investigate the effect of Zhiqiao Gancao decoction (ZQGCD) on hyperalgesia in lumbar disc herniation (LDH) and its mechanism.
PURPOSE
The aim of this study was to investigate the effect of Zhiqiao Gancao decoction (ZQGCD) on hyperalgesia in lumbar disc herniation (LDH) and its mechanism.
METHODS
The potential mechanism of ZQGCD's therapeutic effect on LDH was investigated through network pharmacology, which involved screening the targets of eight components that were absorbed into the bloodstream. The effects of CCR2 inhibitors and ZQGCD-containing serum on the excitability of the CCL2/CCR2 signaling pathway and dorsal root ganglion neurons (DRGn) were investigated in vitro. The effects of CCR2 inhibitors and ZQGCD on the expression of the CCL2/CCR2 signaling pathway and ASIC3 in the rat intervertebral disc and dorsal root ganglion (DRG), the degree of disc degeneration, the threshold of foot retreat, and the latency of foot retreat in LDH rats were examined in vivo. The binding affinities and interaction modes between CCR2 and the components absorbed into the blood were analyzed using the AutodockVina 1.2.2 software.
RESULTS
Network pharmacology revealed that ZQGCD could treat LDH through a mechanism involving the chemokine signaling pathway. It was observed that the CCR2 inhibitor and ZQGCD-containing serum downregulated CCR2 and ASIC3 expression and decreased cell excitability in DRGn. The CCL2/CCR2 signaling pathway was activated in the degenerated intervertebral disc and DRG of LDH rats, increased the expression of ASIC3, and decreased the mechanical allodynia domain and thermal hyperalgesia domain. However, a CCR2 inhibitor or ZQGCD could ameliorate the above changes in LDH rats. The target proteins, CCL2 and CCR2, exhibited a robust affinity for the eight components that were absorbed into the bloodstream.
CONCLUSION
The CCL2/CCR2 pathway was activated in the intervertebral disc and DRG of LDH rats. This was accompanied by upregulation of ASIC3 expression, increased excitability of DRGn, and the occurrence of hyperalgesia. ZQGCD improves hyperalgesia in LDH rats by inhibiting the CCL2/CCR2 pathway and downregulating ASIC3 expression.
Topics: Rats; Animals; Hyperalgesia; Intervertebral Disc Displacement; Rats, Sprague-Dawley; Signal Transduction
PubMed: 37533973
DOI: 10.2147/DDDT.S415127 -
Brain, Behavior, and Immunity Jul 2023Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of chemotherapy for cancer, and has limited effective treatment...
Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of chemotherapy for cancer, and has limited effective treatment options. Autologous conditioned serum (ACS) is an effective biologic therapy used by intra-articular injection for patients with osteoarthritis. However, ACS has not been systematically tested in the treatment of peripheral neuropathies such as CIPN. It has been generally assumed that the analgesic effect of this biologic therapy results from augmented concentrations of anti-inflammatory cytokines and growth factors. Here we report that a single intrathecal injection of human conditioned serum (hCS) produced long-lasting inhibition of paclitaxel chemotherapy-induced neuropathic pain (mechanical allodynia) in mice, without causing motor impairment. Strikingly, the analgesic effect of hCS in our experiments was maintained even 8 weeks after the treatment, compared with non-conditioned human serum (hNCS). Furthermore, the hCS transfer-induced pain relief in mice was fully recapitulated by rat or mouse CS transfer to mice of both sexes, indicating cross-species and cross-sex effectiveness. Mechanistically, CS treatment blocked the chemotherapy-induced glial reaction in the spinal cord and improved nerve conduction. Compared to NCS, CS contained significantly higher concentrations of anti-inflammatory and pro-resolving mediators, including IL-1Ra, TIMP-1, TGF-β1, and resolvins D1/D2. Intrathecal injection of anti-TGF-β1 and anti-Il-1Ra antibody transiently reversed the analgesic action of CS. Nanoparticle tracking analysis revealed that rat conditioned serum contained a significantly greater number of exosomes than NCS. Importantly, the removal of exosomes by high-speed centrifugation largely diminished the CS-produced pain relief, suggesting a critical involvement of small vesicles (exosomes) in the beneficial effects of CS. Together, our findings demonstrate that intrathecal CS produces a remarkable resolution of neuropathic pain mediated through a combination of small vesicles/exosomes and neuroimmune/neuroglial modulation.
Topics: Male; Female; Mice; Rats; Humans; Animals; Exosomes; Neuralgia; Paclitaxel; Hyperalgesia; Spinal Cord; Analgesics; Antineoplastic Agents
PubMed: 37150265
DOI: 10.1016/j.bbi.2023.04.013 -
CNS Neuroscience & Therapeutics Apr 2024Painful diabetic neuropathy (PDN) is a common complication of diabetes. Previous studies have implicated that mitochondrial dysfunction plays a role in the development...
INTRODUCTION
Painful diabetic neuropathy (PDN) is a common complication of diabetes. Previous studies have implicated that mitochondrial dysfunction plays a role in the development of PDN, but its pathogenesis and mechanism have not been fully investigated.
METHODS
In this study, we used high-fat diet/low-dose streptozotocin-induced rats as a model of type 2 diabetes mellitus. Behavioral testing, whole-cell patch-clamp recordings of dorsal root ganglion (DRG) neurons, and complex sensory nerve conduction velocity studies were used to assess peripheral neuropathy. Mitochondrial membrane potential (MMP), ATP, tissue reactive oxygen species, and transmission electron microscopy were used to evaluate the function and morphology of mitochondria in DRG. Real-time PCR, western blot, and immunofluorescence were performed to investigate the mechanism.
RESULTS
We found that damaged mitochondria were accumulated and mitophagy was inhibited in PDN rats. The expression of sirtuin 3 (SIRT3), which is an NAD-dependent deacetylase in mitochondria, was inhibited. Overexpression of SIRT3 in DRG neurons by intrathecally administered LV-SIRT3 lentivirus ameliorated neurological and mitochondrial dysfunctions. This was evidenced by the reversal of allodynia and nociceptor hyperexcitability, as well as the restoration of MMP and ATP levels. Overexpression of SIRT3 restored the inhibited mitophagy by activating the FoxO3a-PINK1-Parkin signaling pathway. The effects of SIRT3 overexpression, including the reversal of allodynia and nociceptor hyperexcitability, the improvement of impaired mitochondria and mitophagy, and the restoration of PINK1 and Parkin expression, were counteracted when FoxO3a siRNA was intrathecally injected.
CONCLUSION
These results showed that SIRT3 overexpression ameliorates PDN via activation of FoxO3a-PINK1-Parkin-mediated mitophagy, suggesting that SIRT3 may become an encouraging therapeutic strategy for PDN.
Topics: Animals; Rats; Adenosine Triphosphate; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Hyperalgesia; Mitophagy; Protein Kinases; Signal Transduction; Sirtuin 3; Ubiquitin-Protein Ligases
PubMed: 38572816
DOI: 10.1111/cns.14703