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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 -
European Journal of Pharmacology Aug 2023Chronic stress affects millions of people around the world, and it can trigger different behavioral disorders like nociceptive hypersensitivity and anxiety, among...
Chronic stress affects millions of people around the world, and it can trigger different behavioral disorders like nociceptive hypersensitivity and anxiety, among others. However, the mechanisms underlaying these chronic stress-induced behavioral disorders have not been yet elucidated. This study was designed to understand the role of high-mobility group box-1 (HMGB1) and toll-like receptor 4 (TLR4) in chronic stress-induced nociceptive hypersensitivity. Chronic restraint stress induced bilateral tactile allodynia, anxiety-like behaviors, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) and activation of spinal microglia. Moreover, chronic stress enhanced HMGB1 and TLR4 protein expression at the dorsal root ganglion, but not at the spinal cord. Intrathecal injection of HMGB1 or TLR4 antagonists reduced tactile allodynia and anxiety-like behaviors induced by chronic stress. Additionally, deletion of TLR4 diminished the establishment of chronic stress-induced tactile allodynia in male and female mice. Lastly, the antiallodynic effect of HMGB1 and TLR4 antagonists were similar in stressed male and female rats and mice. Our results suggest that chronic restraint stress induces nociceptive hypersensitivity, anxiety-like behaviors, and up-regulation of spinal HMGB1 and TLR4 expression. Blockade of HMGB1 and TLR4 reverses chronic restraint stress-induced nociceptive hypersensitivity and anxiety-like behaviors and restores altered HMGB1 and TLR4 expression. The antiallodynic effects of HMGB1 and TLR4 blockers in this model are sex independent. TLR4 could be a potential pharmacological target for the treatment of the nociceptive hypersensitivity associated with widespread chronic pain.
Topics: Animals; Female; Male; Mice; Rats; Alarmins; Chronic Disease; HMGB1 Protein; Hyperalgesia; Nociception; p38 Mitogen-Activated Protein Kinases; Spinal Cord; Toll-Like Receptor 4
PubMed: 37244377
DOI: 10.1016/j.ejphar.2023.175804 -
Neuroscience Bulletin Feb 2024As a main structure of the limbic system, the hippocampus plays a critical role in pain perception and chronicity. The ventral hippocampal CA1 (vCA1) is closely...
As a main structure of the limbic system, the hippocampus plays a critical role in pain perception and chronicity. The ventral hippocampal CA1 (vCA1) is closely associated with negative emotions such as anxiety, stress, and fear, yet how vCA1 neurons encode nociceptive information remains unclear. Using in vivo electrophysiological recording, we characterized vCA1 pyramidal neuron subpopulations that exhibited inhibitory or excitatory responses to plantar stimuli and were implicated in encoding stimuli modalities in naïve rats. Functional heterogeneity of the vCA1 pyramidal neurons was further identified in neuropathic pain conditions: the proportion and magnitude of the inhibitory response neurons paralleled mechanical allodynia and contributed to the confounded encoding of innocuous and noxious stimuli, whereas the excitatory response neurons were still instrumental in the discrimination of stimulus properties. Increased theta power and theta-spike coupling in vCA1 correlated with nociceptive behaviors. Optogenetic inhibition of vCA1 pyramidal neurons induced mechanical allodynia in naïve rats, whereas chemogenetic reversal of the overall suppressed vCA1 activity had analgesic effects in rats with neuropathic pain. These results provide direct evidence for the representations of nociceptive information in vCA1.
Topics: Rats; Animals; CA1 Region, Hippocampal; Hyperalgesia; Nociception; Neural Pathways; Hippocampus; Pyramidal Cells; Neuralgia
PubMed: 37440103
DOI: 10.1007/s12264-023-01086-x -
Molecular Pain 2024Recent studies have demonstrated that activated microglia were involved in the pathogenesis of central sensitization characterized by cutaneous allodynia in migraine....
Recent studies have demonstrated that activated microglia were involved in the pathogenesis of central sensitization characterized by cutaneous allodynia in migraine. Activation of microglia is accompanied by increased expression of its receptors and release of inflammatory mediators. Acupuncture and its developed electroacupuncture (EA) have been recommended as an alternative therapy for migraine and are widely used for relieving migraine-associated pain. However, it remains rare studies that show whether EA exerts anti-migraine effects via inhibiting microglial activation related to a release of microglial receptors and the inflammatory pathway. Therefore, this study aimed to investigate EA' ability to ameliorate central sensitization via modulation of microglial activation, microglial receptor, and inflammatory response using a rat model of migraine induced by repeated epidural chemical stimulation. In the present study, a rat model of migraine was established by epidural repeated inflammatory soup (IS) stimulation and treated with EA at Fengchi (GB20) and Yanglingquan (GB34) and acupuncture at sham-acupoints. Pain hypersensitivity was further determined by measuring the mechanical withdrawal threshold using the von-Frey filament. The changes in c-Fos and ionized calcium binding adaptor molecule 1 (Ibal-1) labeled microglia in the trigeminal nucleus caudalis (TNC) were examined by immunflurescence to assess the central sensitization and whether accompanied with microglia activation. In addition, the expression of Ibal-1, microglial purinoceptor P2X4, and its associated inflammatory signaling pathway mediators, including interleukin (IL)-1β, NOD-like receptor protein 3 (NLRP3), and Caspase-1 in the TNC were investigated by western blot and real-time polymerase chain reaction analysis. Allodynia increased of c-Fos, and activated microglia were observed after repeated IS stimulation. EA alleviated the decrease in mechanical withdrawal thresholds, reduced the activation of c-Fos and microglia labeled with Ibal-1, downregulated the level of microglial purinoceptor P2X4, and limited the inflammatory response (NLRP3/Caspase-1/IL-1β signaling pathway) in the TNC of migraine rat model. Our results indicate that the anti-hyperalgesia effects of EA ameliorate central sensitization in IS-induced migraine by regulating microglial activation related to P2X4R and NLRP3/IL-1β inflammatory pathway.
Topics: Animals; Electroacupuncture; Receptors, Purinergic P2X4; Microglia; Hyperalgesia; Migraine Disorders; Rats, Sprague-Dawley; Disease Models, Animal; Male; Inflammation; Central Nervous System Sensitization; Rats; NLR Family, Pyrin Domain-Containing 3 Protein; Proto-Oncogene Proteins c-fos
PubMed: 38744426
DOI: 10.1177/17448069241258113 -
Neuroscience Letters Nov 2023The antisense oligonucleotide (ASO) is an FDA-approved strategy in the treatment of neurological diseases. We have shown the viability of using intrathecal ASO to...
OBJECTIVE
The antisense oligonucleotide (ASO) is an FDA-approved strategy in the treatment of neurological diseases. We have shown the viability of using intrathecal ASO to suppress nerve injury-specific long noncoding RNA (NIS-lncRNA) in dorsal root ganglion (DRG), resulting in a stable and long-lasting antinociceptive effect on NP. This study examined whether systemic administration of NIS-lncRNA ASO relieved the chronic constriction injury (CCI)-induced nociceptive hypersensitivity.
METHODS
A single subcutaneous injection of NIS-lncRNA ASO at a dose of 1,000 µg was carried out 7 days after CCI or sham surgery in male mice. Behavioral tests were performed one day before surgery and at different days after surgery. DRG and spinal cord were finally collected for quantitative real-time RT-PCR and Western blot assays.
RESULTS
NIS-lncRNA ASO significantly alleviated CCI-induced mechanical allodynia, heat hyperalgesia, and cold hyperalgesia starting on day 14 or 21 post-ASO injection and lasting for at least 7 days on the ipsilateral side. Additionally, CCI-induced spontaneous pain and ipsilateral dorsal horn neuronal and astrocyte hyperactivation were blocked on day 28 after NIS-lncRNA ASO injection. As predicted, the CCI-induced increases in the levels of NIS-lncRNA and its downstream target C-C motif chemokine ligand 2 in the ipsilateral lumbar 3 and 4 DRGs were attenuated on day 28 following NIS-lncRNA ASO injection.
CONCLUSION
Our findings indicate that systemic administration of NIS-lncRNA ASO also produces a stable and long-lasting antinociceptive effect on neuropathic pain. NIS-lncRNA ASO may have potential clinical application in the treatment of this disorder.
Topics: Animals; Male; Mice; Analgesics; Chronic Pain; Ganglia, Spinal; Hyperalgesia; Neuralgia; Oligonucleotides, Antisense; Rats, Sprague-Dawley; RNA, Long Noncoding; Spinal Cord Dorsal Horn; Rats
PubMed: 37806431
DOI: 10.1016/j.neulet.2023.137512 -
Journal of Ethnopharmacology Dec 2023Shaoyao Gancao Decoction (SGD) is well known as an effective prescription for analgesia composed of two herbs, and is noted as traditional Chinese medicine morphine. It...
ETHNOPHARMACOLOGICAL RELEVANCE
Shaoyao Gancao Decoction (SGD) is well known as an effective prescription for analgesia composed of two herbs, and is noted as traditional Chinese medicine morphine. It is widely used in various conditions causing pain, including migraine. However, there is currently no research exploring the mechanism of action in the treatment of migraines.
AIM OF THE STUDY
The current research was devised to determine the underlying regulatory mechanism of SGD, by verifying its role in the NGF/TRPV1/COX-2 signal pathway.
MATERIALS AND METHODS
The active components in SGD were identified by UHPLC-MS. A migraine model was prepared by subcutaneous (s.c.) injection of nitroglycerin (NTG) into the neck to detect migraine-like behavior, orbital hyperalgesia threshold changes, and the therapeutic effect of SGD. The mechanism of SGD in remedying migraine was studied through transcriptome sequencing (RNA-seq), which was further validated utilizing Elisa, Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting (WB) experiments.
RESULTS
In the SGD chemical composition analysis, 45 components were identified including gallic acid, paeoniflorin and albiforin. In the behavioral experiments, SGD treatment significantly decreased the score of migraine-like head scratching in the NTG-induced migraine model (Mod) rats, while the hyperalgesia threshold increased outstandingly on days 10, 12, and 14 (P < 0.01, P < 0.001 or P < 0.0001). In migraine biomarkers experiment, compared with the Mod group, the 5-hydroxytryptamine (5-HT) contents were outstandingly enhanced by SGD treatment, while nitric oxide (NO) contents were markedly declined (P < 0.01). In the RNA-seq test, the down-regulated genes of SGD inhibiting hyperalgesia migraine included the neurotrophic factor (NGF) and transient receptor potential vanillic acid subfamily protein 1 receptor (TRPV1). The down-regulation pathway is the inflammatory mediator regulation of TRP channels. In gene set enrichment analysis (GSEA), SGD decreased the over-expression of protooncogene tyrosine-protein kinase Src (SRC) and TRPV1 in this pathway, and the two genes clustered at its lower end, with similar functions. PPI network results show that NGF interacts with TRPV1. Further verification shows that when compared with Mod group, the plasma cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) protein expression levels and the dura mater calcitonin gene-related peptide (CGRP), extracellular signal-regulated kinase (ERK), p-ERK, SRC and NGF protein expression levels in the SGD group were remarkably decreased (P < 0.01, P < 0.001 or P < 0.0001), and the expression level of TRPV1 protein showed a downward trend (P = 0.06). The expression levels of COX-2, NO, CGRP, TRPV1, SRC and NGF mRNA in the dura mater was overtly down-regulated (P < 0.05, P < 0.01 or P < 0.001).
CONCLUSIONS
SGD has a significant inhibitory effect on the NGF/TRPV1/COX-2 signaling pathway that mediates central hyperalgesia migraine, thus suggesting the molecular mechanism of SGD in improving the symptoms of migraine may be related to the central hyperalgesia neurotransmitter that regulates the pathogenesis of migraine.
Topics: Rats; Animals; Hyperalgesia; Nitroglycerin; Cyclooxygenase 2; Calcitonin Gene-Related Peptide; Signal Transduction; Extracellular Signal-Regulated MAP Kinases; Pain; Migraine Disorders
PubMed: 37315643
DOI: 10.1016/j.jep.2023.116781 -
Biomedicine & Pharmacotherapy =... Dec 2023Clinically, neuropathic pain treatment remains a challenging issue because the major therapy, centred around pharmacological intervention, is not satisfactory enough to...
Clinically, neuropathic pain treatment remains a challenging issue because the major therapy, centred around pharmacological intervention, is not satisfactory enough to patient by reason of low effectiveness and more adverse reaction. Therefore, it is still necessary to find more effective and safe therapy to ameliorate neuropathic pain. The purpose of this study was to explore the antinociceptive effect of Echinacoside (ECH), an active compound of Cistanche deserticola Ma, on peripheral neuropathic pain induced by chronic constriction injury (CCI) in mice, and to demonstrate its potential mechanism in vivo and vitro. In the present study, results showed that intraperitoneal administration of ECH (50, 100, and 200 mg/kg) could alleviate mechanical allodynia, cold allodynia and thermal hyperalgesia via behavioural test. Moreover, the structure and function of injured sciatic nerve by CCI were taken a turn for the better to a certain extent after ECH treatment using histopathological and electrophysiological test. Furthermore, ECH repressed the expression of the P2X7R and FKN and reduced the expression and release of the IL-1β, IL-6 and TNF-α. Besides, ECH could decrease Ca influx and Cats efflux and inhibit phosphorylation of p38MAPK. To sum up, the present study illustrated that ECH could alleviate peripheral neuropathic pain by inhibiting microglia overactivation and inflammation through P2X7R/FKN/CX3CR1 signalling pathway in spinal cord. This study would provide a new perspective and strategy for the pharmacological treatment on neuropathic pain.
Topics: Animals; Mice; Analgesics; CX3C Chemokine Receptor 1; Hyperalgesia; Neuralgia; Neuroprotective Agents; Sciatic Nerve; Spinal Cord
PubMed: 37812887
DOI: 10.1016/j.biopha.2023.115675 -
Current Neuropharmacology 2024Pathological pain imposes a huge burden on the economy and the lives of patients. At present, drugs used for the treatment of pathological pain have only modest efficacy... (Review)
Review
Pathological pain imposes a huge burden on the economy and the lives of patients. At present, drugs used for the treatment of pathological pain have only modest efficacy and are also plagued by adverse effects and risk for misuse and abuse. Therefore, understanding the mechanisms of pathological pain is essential for the development of novel analgesics. Several lines of evidence indicate that interleukin-17 (IL-17) is upregulated in rodent models of pathological pain in the periphery and central nervous system. Besides, the administration of IL-17 antibody alleviated pathological pain. Moreover, IL-17 administration led to mechanical allodynia which was alleviated by the IL-17 antibody. In this review, we summarized and discussed the therapeutic potential of targeting IL-17 for pathological pain. The upregulation of IL-17 promoted the development of pathological pain by promoting neuroinflammation, enhancing the excitability of dorsal root ganglion neurons, and promoting the communication of glial cells and neurons in the spinal cord. In general, the existing research shows that IL-17 is an attractive therapeutic target for pathologic pain, but the underlying mechanisms still need to be investigated.
Topics: Rats; Animals; Humans; Interleukin-17; Rats, Sprague-Dawley; Pain; Hyperalgesia; Neuroglia
PubMed: 37581321
DOI: 10.2174/1570159X21666230811142713 -
Neuropharmacology Nov 2023Neuropathic pain (NP) is a prevalent clinical problem for which satisfactory treatment options are unavailable. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid...
Neuropathic pain (NP) is a prevalent clinical problem for which satisfactory treatment options are unavailable. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S. Moore, possesses anti-inflammatory and immune-modulatory properties. Chemokine-like factor 1 (CKLF1) is known to play a crucial role in both peripheral and central inflammatory processes. This study aimed to investigate the potential anti-NP effects of TET and the involvement of CKLF1 in the action of TET. A male C57BL/6J mice model of NP caused by spared nerve injury (SNI) was established and mechanical withdrawal thresholds were measured using von Frey filaments. The results showed that TET improved mechanical allodynia in SNI mice and the propofol-induced sleep assay demonstrated that the TET group did not exhibit central inhibition, while the pregabalin (PGB) group showed significant central inhibition. Western blotting and immunofluorescence staining showed that TET significantly inhibited spinal protein expression levels of CKLF1, p-NF-κB/NF-κB, p-IKK/IKK, pro-inflammatory cytokines IL-1β and TNF-α, and increased protein expression levels of the anti-inflammatory cytokine IL-10, while inhibiting the expression levels of microglia and astrocyte markers IBA-1 and GFAP of SNI mice. Moreover, immunofluorescence double-labeling results revealed that CKLF1 was predominantly colocalized with microglia of the spinal cord (SC) in SNI mice. C19 (an antagonism peptide of CKLF1) alleviated SNI-induced mechanical pain hypersensitivity, while C27 (an analog peptide of CKLF1) induced mechanical allodynia in normal mice. TET significantly attenuated mechanical allodynia induced by C27 in mice. TET may effectively alleviate NP by reducing neuroinflammation and decreasing CKLF1.
Topics: Rats; Male; Mice; Animals; NF-kappa B; Rats, Sprague-Dawley; Hyperalgesia; Mice, Inbred C57BL; Cytokines; Spinal Cord; Benzylisoquinolines; Anti-Inflammatory Agents; Neuralgia
PubMed: 37517461
DOI: 10.1016/j.neuropharm.2023.109673 -
Journal of Psychiatric Research Aug 2023Morphine is one of the most effective and widely used analgesic drugs. However, chronic morphine use caused opioid-induced hyperalgesia (OIH). The development of OIH...
Morphine is one of the most effective and widely used analgesic drugs. However, chronic morphine use caused opioid-induced hyperalgesia (OIH). The development of OIH limits the use of morphine. The mechanisms of OIH are not fully understood. Toll-like receptor4 (TLR4) and glutamate receptors in the periaqueductal gray (PAG) are critical in OIH, however, the association between TLR4 and N-methyl-D-aspartate Receptors (NMDARs) activation in PAG remains unclear. Microglia activation, increased TLR4/p65 nuclear factor-kappa B (p65 NF-κB) and proinflammatory cytokines in microglia, and phosphorylation of NMDAR1 subunit (NR1) and NMDAR2B subunit (NR2B) in neurons were observed in PAG of OIH mice. Up-regulations of TLR4/p65 NF-κB and proinflammatory cytokines (IL-1β, IL-6, TNF-α) in BV2 cells were prevented by inhibiting and knocking down TLR4. By inhibiting myeloid differentiation factor 2 (MD2) and knocking down the High-mobility group box 1 (HMGB1), we found that morphine activated TLR4 by HMGB1 but not MD2. We co-cultured Neuro-2a (N2A) with BV2 microglial cell line and found that instead of directly phosphorylating NMDAR subunits, morphine increased the phosphorylation of NR1 and NR2B by inducing TLR4-mediated microglia inflammation. Knocking TLR4 out of PAG by Lentivirus-GFP-TLR4 shRNA reversed these changes and relieved OIH. Our findings suggested that the secretion of HMGB1 induced by morphine-activated TLR4 in microglia, and the proinflammatory factors released by activated microglia phosphorylated NR1 and NR2B of adjacent neurons, induced increased neuronal excitability. In conclusion, TLR4/NMDARs in PAG were involved in the development and maintenance of OIH and supported novel strategies for OIH treatment.
Topics: Mice; Animals; Morphine; Hyperalgesia; NF-kappa B; Microglia; Toll-Like Receptor 4; Periaqueductal Gray; Signal Transduction; HMGB1 Protein; Inflammation; Analgesics, Opioid; Cytokines; Neurons
PubMed: 37352811
DOI: 10.1016/j.jpsychires.2023.05.082