The paper introduces Professor LIU Xing's clinical experience and characteristics of integrative acupuncture and medication in treatment of primary trigeminal neuralgia (PTN). It is believed that the essential pathogenesis of PTN is pathogenic wind, and qi and blood obstruction results from invasion of pathogenic wind. Hence, dispelling wind is the key principle of treatment. Palpation is done at first in the neck, face and buccal mucosal region to detect the masses in treatment. Acupotomy is operated at the masses distributed at Shangguan (GB3), Xiaguan (ST7) and the white line of buccal mucosa, so as to release masses. Additionally, five-wind points (Fengfu [GV16], bilateral Fengchi [GB20], Yifeng [TE17], Bingfeng [SI12] and Fengmen [BL12]), three-nape points (bilateral Naokong [GB19], Tianzhu [BL10] and Jianjing [GB21]) and three-governor-vessel points (Baihui [GV20], Zhiyang [GV9] and Yintang [GV24⁺]) are selected to dispel wind and stop pain. Besides, herbal decoction (wu feng tang) and blood-letting at ear apex are administered in combination. The integration of acupuncture and medication obtains a holistic effect on PTN by dispelling wind pathogen, and promoting qi and blood circulation.
Humans ; Trigeminal Neuralgia/drug therapy* ; Acupuncture Therapy ; Acupuncture Points ; Female ; Male ; Middle Aged ; Drugs, Chinese Herbal/administration & dosage* ; Combined Modality Therapy ; Adult ; Aged

OBJECTIVES: Pain sensitization, as a core feature of neuropathic pain (NP), is closely associated with inflammatory imbalance within the central nervous system. To investigate the effects of intrathecal injection of noggin (NOG) on mechanical hypersensitivity, microglial (MG) activation and polarization, and iron metabolism in a spinal nerve ligation (SNL)-induced rat model of NP, and to explore the role of signal transducer and activator of transcription 3 (STAT3) in MG phenotypic transformation. METHODS: Sixty-six Sprague-Dawley (SD) rats were randomly divided into 3 groups: Sham, SNL, and SNL+NOG. Paw withdrawal threshold (PWT) was assessed using von Frey filaments. Western blotting and real-time polymerase chain reaction (RT-PCR) were used to detect spinal cord expression of MG activation marker CD11b, STAT3, phosphorylated STAT3 (p-STAT3), M1 polarization markers [CD86, CD32, interleukin (IL)-1β], tumor necrosis factor-alpha (TNF-α), and CC chemokine receptor 2 (CCR2), M2 markers [CD204, CD163, CX3C chemokine receptor 1 (CX3CR1), IL-10, and arginase-1 (ARG-1)], and iron metabolism-related proteins including ferroportin (FPN, gene: SLC40A1), hepcidin (gene: HAMP), transferrin receptor (gene: TFRC), and divalent metal transporter 1 (DMT-1, gene: SLC11A2). p-STAT3 localization in MGs was visualized via immunofluorescence. In vitro, primary MGs were divided into Control, bone morphogenetic protein-4 (BMP4), and BMP4+Stattic (STAT3 inhibitor) groups to examine the effects of STAT3 inhibition on MG activation, polarization, and iron regulation. RESULTS: In vivo, compared with the Sham group, the SNL and SNL+NOG groups exhibited significantly decreased PWT (P<0.05), elevated spinal CD11b and p-STAT3 protein levels (all P<0.05), increased M1 markers (CD86, CD32, IL-1β, TNF-α, and CCR2) (all P<0.05), and decreased M2 markers (CD204 protein; mRNA of CD204, ARG-1) (all P<0.05). Hepcidin protein and mRNA levels of HAMP, SLC11A2, and TFRC were significantly elevated, while FPN protein and SLC40A1 mRNA were reduced (all P<0.05). Compared to SNL alone, the SNL+NOG group showed increased PWT, decreased CD11b, p-STAT3, and M1 marker expression (except TNF-α), increased M2 marker expression, reduced hepcidin and HAMP levels, and increased FPN and SLC40A1 expression (all P<0.05). In vitro, BMP4 treatment increased CD11b, STAT3, p-STAT3, CD86, and hepcidin levels, while reducing CD204 and FPN (all P<0.05). Inhibition STAT3 with Stattic reversed these changes (all P<0.05). CONCLUSIONS NOG alleviates SNL-induced NP by antagonizing the STAT3 signaling pathway, thereby rebalancing microglial polarization and restoring iron metabolism.
Animals ; Neuralgia/drug therapy* ; Rats, Sprague-Dawley ; Microglia/cytology* ; STAT3 Transcription Factor/metabolism* ; Rats ; Iron/metabolism* ; Male ; Signal Transduction/drug effects* ; Carrier Proteins/therapeutic use* ; Homeostasis/drug effects* ; Spinal Cord/metabolism*

Astrocytes in the spinal dorsal horn (SDH) exhibit diverse reactive phenotypes under neuropathic conditions, yet the mechanisms driving this diversity and its implications in chronic pain remain unclear. Here, we report that spared nerve injury (SNI) induces marked upregulation of both complement component 3 (C3⁺, A1-like) and S100 calcium-binding protein A10 (S100A10⁺, A2-like) astrocyte subpopulations in the SDH, with elevated microglial cytokines including interleukin-1α, tumor necrosis factor-α, and complement component 1q. Transcriptomic, immunohistochemical, and Western blot analyses reveal co-activation of multiple reactive astrocyte states over a unidirectional shift toward an A1-like phenotype. Fibroblast growth factor 8 (FGF8), a neuroprotective factor via FGFR3, mitigated microglia-induced C3⁺ astrocyte reactivity in vitro and suppressed spinal C3 expression and mechanical allodynia following intrathecal administration in SNI mice. These findings reveal a microglia-astrocyte signaling axis that promotes A1 reactivity and position FGF8 as a promising therapeutic candidate for neuropathic pain by modulating astrocyte heterogeneity.
Animals ; Astrocytes/drug effects* ; Neuralgia/pathology* ; Receptor, Fibroblast Growth Factor, Type 3/metabolism* ; Signal Transduction/physiology* ; Male ; Mice ; Microglia/drug effects* ; Fibroblast Growth Factor 8/pharmacology* ; Mice, Inbred C57BL ; Hyperalgesia/drug therapy* ; Spinal Cord/drug effects* ; Complement C3/metabolism* ; Spinal Cord Dorsal Horn/metabolism*

Excitatory toxicity(ET) is an important factor of neuropathic pain(NPP) induced by central sensitization(CS), and the association of pannexin-1(Panx1)-Src-N-methyl-D-aspartate receptor subunit 2 B(NMDAR-2 B) is an important new pathway for ET to initiate CS. The present study confirmed whether the central analgesic effect of Chuanxiong Rhizoma extract(CRE) was achieved through the synchronous regulation of the brain and spinal pathways of Panx1-Src-NMDAR-2 B. In this study, dynamic and simulta-neo-us microdialysis of the brain and spinal cord in vivo combined with behavioristics, high performance liquid chromatography(HPLC)-fluorescence detection, microdialysis analysis(ISCUS~(flex)), ultrasensitive multifactorial electrochemiluminescence immunoassay, ELISA, and Western blot was employed to investigate the protein expression of NMDAR-2 B, Src, and Panx1, extracellular excitatory amino acids, cytokines, energy metabolites, and substance P in spinal dorsal horn(SDH) and anterior cingulate cortex(ACC) after CRE intervention with the rat model of spared sciatic nerve injury(SNI) as the experimental tool. Compared with the sham group, the SNI group exhibited diminished mechanical withdrawal threshold(MWT)(P<0.01), increased cold spray scores(P<0.01), glutamate(Glu), D-serine(D-Ser), and glycine(Gly) in extracellular fluids of ACC, and Glu, D-Ser, interleukin-1β(IL-1β), and lactic acid(Lac) in extracellular fluids of SDH(P<0.05), dwindled tumor necrosis factor(TNF-α)(P<0.05), and elevated protein levels of NMDAR-2 B, Src, and Panx1 in ACC(P<0.05). Compared with the SNI model rats, high-and medium-dose CRE(CRE-H/M) could potentiate the analgesic activity as revealed by the MWT test(P<0.05) and CRE-M enabled the decrease in cold spray scores(P<0.05). CRE-H/M could inhibit the levels of Glu, D-Ser and Gly in the extracellular fluids of ACC(P<0.05), and the levels of Glu in the extracellular fluids of SDH(P<0.05) in SNI rats. CRE-M significantly increased the levels of glucose(Gluc), Lac, interferon-gamma(IFN-γ), keratinocyte chemoattractant/human growth-regulated oncogenes(KC/GRO), and IL-4 in extracellular fluids of SDH in SNI rats(P<0.05). CRE-H/M/L could also inhibit the levels of NMDAR-2 B, Src and Panx1 in ACC and SDH in SNI rats(P<0.05). The central analgesic effect of CRE is presumedly related to the inhibited release of excitatory amino acid transmitters(Glu, D-Ser and Gly) in ACC and SDH of SNI rats, decreased protein expression of NMDAR-2 B, Src and Panx1 in the two regions, and the regulation of the Panx1-Src-NMDAR-2 B pathway in the spinal cord and brain. The above findings partially clarified the scientific basis of clinical analgesic effect of Chuanxiong Rhizoma.
Animals ; Central Nervous System Sensitization ; Neuralgia/drug therapy* ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Signal Transduction ; Spinal Cord/metabolism*

OBJECTIVE: To investigate the mechanisms underlying elemene-induced analgesia in rats with spared nerve injury (SNI). METHODS: Sixty-five rats were equally divided into 5 groups using a random number table: naive group, sham group, SNI group, SNI + elemene (40 mg·kg RESULTS: The SNI rat model exhibited a significant decrease in paw withdrawal threshold and exploratory behaviour in the EPM (P<0.05). Consecutive administration of elemene alleviated SNI-induced mechanical allodynia and anxiety in rats (P<0.05). Immunohistochemical data showed that elemene decreased SNI-induced upregulation of NDRG2 within the SDH (P<0.05). Double immunofluorescent staining data further showed that elemene decreased SNI-induced upregulation of the number of GFAP immunoreactive (-ir), NDRG-ir, and GFAP/NDRG2 double-labelled cells within the SDH (P<0.05). Immunoblotting data showed that elemene decreased SNI-induced upregulation of GFAP and NDRG2 within the SDH (P<0.05). CONCLUSION Elemene possibly alleviated neuropathic pain by downregulating the expression of NDRG2 in spinal astrocytes in a rat model of SNI.
Animals ; Astrocytes ; Disease Models, Animal ; Emulsions ; Hyperalgesia/drug therapy* ; Nerve Tissue Proteins ; Neuralgia/drug therapy* ; Rats ; Rats, Sprague-Dawley ; Sesquiterpenes ; Spinal Cord ; Spinal Cord Dorsal Horn

OBJECTIVE: To investigate the effect of escin in relieving chemotherapy-induced peripheral neuropathic pain in rats and explore and the underlying mechanism. METHODS: Eighteen SD rats were randomly divided into 3 groups ( RESULTS: The rats in both the escin preconditioning group and escin postconditioning group showed obviously increased thresholds of mechanical allodynia and thermal hyperalgesia as compared with those in the control group ( CONCLUSIONS Escin can alleviate chemotherapy-induced peripheral neuropathic pain in rats possibly by upregulating the expressions of autophagy-related proteins in the spinal cord.
Animals ; Antineoplastic Agents/therapeutic use* ; Autophagy ; Escin/therapeutic use* ; Hyperalgesia/drug therapy* ; Mice ; Neuralgia/drug therapy* ; Rats ; Rats, Sprague-Dawley ; Spinal Cord

Objective To investigate the effects of simvastatin on diabetic neuropathic pain and systematic inflammation in diabetic rats and explore their molecular mechanisms.Methods Totally 24 rats were equally randomized into the normal+vehicle(NV)group,diabetic+vehicle(DV)group,and diabetic+simvastatin(DS)group using the random number table.Streptozotocin(STZ)was used to establish the rat models of diabetes.Blood glucose,body mass,paw withdrawal mechanical threshold(PWMT),and paw withdrawal thermal latency(PWTL)in each group were observed on days 7,14,21,and 28 after STZ injection.On day 28 after STZ injection,rats were sacrificed,and the lumbar spinal dorsal horn and serum were collected.Western blotting was used to detect the expression of receptor for advanced glycation end products(RAGE)and the phosphorylation levels of protein kinase B(AKT),extracellular signal-regulated kinase(ERK),p38,and c-Jun N-terminal kinase(JNK)in the spinal dorsal horn of rats in each group.Enzyme-linked immunosorbent assay was performed to determine the serum concentrations of oxidized low density lipoprotein(ox-LDL)and interleukin-1β(IL-1β).Results On days 14,21 and 28 after STZ injection,the PWMT in DV group were(8.6 ± 0.8),(7.1 ± 1.6),and(7.8 ± 0.8)g respectively,which were significantly lower than (12.0 ± 0.9)(=8.482, =0.000),(11.6 ± 1.5)(=11.309, =0.000),and(11.7 ± 1.5)g(=9.801, =0.000)in NV group.The PWMT in DS group on days 21 and 28 were(9.4 ± 1.4)(=5.780, =0.000)and(9.7 ± 0.9)g(=4.775, =0.003),respectively,which were significantly improved comparing with those of DV group.On days 7,14,21,and 28,there were no significant differences in PWTL among these three groups (all <0.05).The expression of RAGE in the spinal dorsal horn of DV group was significantly higher than those of NV group(=6.299, =0.000)and DS group(=2.891, =0.025).The phosphorylation level of AKT in the spinal dorsal horn of DV group was significantly higher than those of NV group(=8.915,=0.000)and DS group(=4.103,=0.003).The phosphorylation levels of ERK( =8.313,=0.000),p38( =2.965, =0.022),and JNK(=7.459, =0.000)in the spinal dorsal horn of DV group were significantly higher than those of NV group;the phosphorylation level of JNK in the spinal dorsal horn of DS group was significant lower than that of DV group(=3.866, =0.004);however,there were no significant differences in the phosphorylation levels of ERK(=1.987,=0.122)and p38(=1.260,=0.375)in the spinal dorsal horn between DS group and DV group.The serum concentrations of ox-LDL and IL-1β in DV group were(41.86 ± 13.40)ng/ml and(108.16 ± 25.88)pg/ml,respectively,which were significantly higher than those in NV group [(24.66 ± 7.87)ng/ml(=3.606,=0.003)and(49.32 ± 28.35)pg/ml(=5.079,=0.000)] and DS group [(18.81 ± 5.62)ng/ml (=4.833, =0.000)and(32.73 ± 11.73)pg/ml(=6.510, =0.000)].Conclusions Simvastatin can relieve the mechanical allodynia of diabetic rats possibly by inhibiting the activation of RAGE/AKT and the phosphorylation of JNK in the spinal dorsal horn.Simvastatin can also decrease the serum concentrations of ox-LDL and IL-1β in diabetic rats,which may contribute to the relief of systematic inflammation.
Animals ; Diabetes Mellitus, Experimental ; complications ; Hyperalgesia ; Inflammation ; drug therapy ; Interleukin-1beta ; blood ; Lipoproteins, LDL ; blood ; Neuralgia ; drug therapy ; Proto-Oncogene Proteins c-akt ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptor for Advanced Glycation End Products ; metabolism ; Simvastatin ; pharmacology

Objective To observe the changes of brain function in patients with trigeminal neuralgia after administration of flurbiprofen axetil by using the resting-state functional magnetic resonance imaging(fMRI)and based on the amplitude of low-frequency fluctuation(ALFF). Methods Resting fMRI data of 20 patients with trigeminal neuralgia before and after treatment with flurbiprofen axetil were collected by 1.5T magnetic resonance imaging system.The resting fMRI data were pretreated by Statistical Parametric Mapping and DPABI(a toolbox for Data Processing and Analysis for Brain Imaging)software,and the difference of low-frequency oscillation amplitude of brain spontaneous activity before and after treatment with flurbiprofen axetil was analyzed by ALFF. Results The Visual Analogue Scale of pain intensity after flurbiprofen axetil injection was significantly lower than that before administration,and the pain relieved significantly(P=0.000).The ALFF values of right dorsolateral prefrontal lobe,bilateral medial prefrontal lobe,and right middle cingulate gyrus in patients treated with flurbiprofen axetil at rest were significantly lower than those before administration(P=0.000). Conclusions The analgesic effect of flurbiprofen axetil is exerted on the central system.This agent can inhibit the abnormal brain function caused by chronic pain stimulation and thus reduce pain.However,the specific mechanism needs further investigations.
Brain ; drug effects ; Brain Mapping ; Flurbiprofen ; analogs & derivatives ; pharmacology ; Humans ; Magnetic Resonance Imaging ; Trigeminal Neuralgia ; drug therapy

Background: Nucleoside reverse transcriptase inhibitors (NRTIs) are the earliest and most commonly used anti-human immunodeficiency virus drugs and play an important role in high active antiretroviral therapy. However, NRTI drug therapy can cause peripheral neuropathic pain. In this study, we aimed to investigate the mechanisms of rapamycin on the pain sensitization of model mice by in vivo experiments to explore the effect of mammalian target of rapamycin (mTOR) in the pathogenesis of neuropathic pain caused by NRTIs. Methods: Male Kun Ming (KM) mice weighing 20-22 g were divided into control, 2 mg/kg rapamycin, 12 mg/kg stavudine, and CMC-Na groups. Drugs were orally administered to mice for 42 consecutive days. The von Frey filament detection and thermal pain tests were conducted on day 7, 14, 21, 28, 35, and 42 after drug administration. After the last behavioral tests, immunohistochemistry and western blotting assay were used for the measurement of mTOR and other biomarkers. Multivariate analysis of variance was used. Results: The beneficial effects of rapamycin on neuropathic pain were attributed to a reduction in mammalian target of rapamycin sensitive complex 1 (mTORC1)-positive cells (70.80 ± 2.41 vs. 112.30 ± 5.66, F = 34.36, P < 0.01) and mTORC1 activity in the mouse spinal cord. Mechanistic studies revealed that Protein Kinase B (Akt)/mTOR signaling pathway blockade with rapamycin prevented the phosphorylation of mTORC1 in stavudine-intoxicated mice (0.72 ± 0.04 vs. 0.86 ± 0.03, F = 4.24, P = 0.045), as well as decreased the expression of phospho-p70S6K (0.47 ± 0.01 vs. 0.68 ± 0.03, F = 6.01, P = 0.022) and phospho-4EBP1 (0.90 ± 0.04 vs. 0.94 ± 0.06, F = 0.28, P = 0.646). Conclusions Taken together, these results suggest that stavudine elevates the expression and activity of mTORC1 in the spinal cord through activating the Akt/mTOR signaling pathway. The data also provide evidence that rapamycin might be useful for the treatment of peripheral neuropathic pain.
Animals ; HIV Infections ; drug therapy ; Humans ; Male ; Mice ; Neuralgia ; Phosphatidylinositol 3-Kinase ; drug effects ; Phosphatidylinositols ; Proto-Oncogene Proteins c-akt ; Reverse Transcriptase Inhibitors ; pharmacology ; Sirolimus ; TOR Serine-Threonine Kinases ; drug effects

The voltage-gated Na channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7-expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.
Animals ; Antibodies, Monoclonal ; therapeutic use ; Biotin ; metabolism ; Cells, Cultured ; Disease Models, Animal ; Female ; Ganglia, Spinal ; cytology ; HEK293 Cells ; Humans ; Hybridomas ; chemistry ; Hyperalgesia ; drug therapy ; Male ; Mice ; Mice, Inbred C57BL ; NAV1.5 Voltage-Gated Sodium Channel ; metabolism ; NAV1.7 Voltage-Gated Sodium Channel ; chemistry ; immunology ; metabolism ; Neuralgia ; drug therapy ; metabolism ; Protein Binding ; drug effects ; Recombinant Proteins ; biosynthesis ; therapeutic use ; Sensory Receptor Cells ; drug effects ; physiology