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1.
Mol Pain ; 18: 17448069221087583, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35240891

RESUMEN

Knee osteoarthritis (KOA) is a highly prevalent, chronic joint disorder, and it is a typical disease which can develop chronic pain. Our previous study has proved that endocannabinoid (2-AG)-CB1R-GABA-5-HT pathway is involved in electroacupuncture (EA) mediated inhibition of chronic pain. However, it is still unclear which among the 5-HT receptor subtype is involved in EA evoked 5-HT mediated inhibition of chronic pain in the dorsal spinal cord. 5-HT2A is a G protein-coupled receptor and it is involved in 5-HT descending pain modulation system. We found that EA treatment at frequency of 2 Hz +1 mA significantly increased the expression of 5-HT2A receptor in the dorsal spinal cord and intrathecal injection of 5-HT2A receptor antagonist or agonist reversed or mimicked the analgesic effect of EA in each case respectively. Intrathecal injection of a selective GABAA receptor antagonist Bicuculline also reversed the EA effect on pain hypersensitivity. Additionally, EA treatment reversed the reduced expression of GABAA receptor and KCC2 in the dorsal spinal cord of KOA mice. Furthermore, we demonstrated that intrathecal 5-HT2A receptor antagonist/agonist reversed or mimicked the effect of EA up-regulate of KCC2 expression, respectively. Similarly, intrathecal injection of PLC and PKC inhibitors prevented both anti-allodynic effect and up-regulation of KCC2 expression by EA treatment. Our data suggest that EA treatment up-regulated KCC2 expression through activating 5-HT2A-Gq-PLC-PKC pathway and enhanced the inhibitory function of GABAA receptor, thereby inhibiting chronic pain in a mouse model of KOA.


Asunto(s)
Dolor Crónico , Electroacupuntura , Osteoartritis de la Rodilla , Simportadores , Animales , Dolor Crónico/metabolismo , Dolor Crónico/terapia , Ratones , Osteoartritis de la Rodilla/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de GABA-A/metabolismo , Serotonina/metabolismo , Médula Espinal/metabolismo , Simportadores/metabolismo
2.
Neurochem Res ; 46(3): 504-512, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33387191

RESUMEN

Electro-acupuncture (EA) has been used for clinic analgesia for many years. However, its mechanisms are not fully understood. We recently reported that AXL, a tyrosine kinase receptor, contributes to the peripheral mechanism of neuropathic pain. We here aim to figure out the significance of EA on neuropathic pain mediated by AXL in dorsal root ganglion (DRG). Spinal nerve ligation (SNL) was used as a neuropathic pain model. EA was applied at ''Huantiao'' (GB-30) and ''Yanglingquan'' (GB-34) acupoints for 30 min daily from day 7 to day 10 after SNL. EA not only gradually attenuated SNL-induced mechanical allodynia, but also suppressed the expression of phosphorylated AXL (p-AXL) and AXL in injured DRGs of SNL rats examined by western blotting and immunofluorescence. Moreover, intrathecal injection of the subthreshold dose of AXL inhibitor TP0903, significantly prolonged the analgesic time of single EA treatment and enhanced the analgesic effect of repeated EA treatments, suggesting a synergic effect of EA and AXL inhibitor. These results indicate that AXL signaling underlies EA analgesia and combination of AXL inhibitor and EA might be a new strategy for clinic analgesia on neuropathic pain.


Asunto(s)
Analgésicos/uso terapéutico , Electroacupuntura , Neuralgia/tratamiento farmacológico , Neuralgia/terapia , Pirimidinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/metabolismo , Sulfonamidas/uso terapéutico , Animales , Ganglios Espinales/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/terapia , Ligadura , Masculino , Ratas Sprague-Dawley , Nervios Espinales/cirugía
3.
Mol Pain ; 13: 1744806917719804, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28714351

RESUMEN

Background Paclitaxel is commonly used as a cancer chemotherapy drug that frequently causes peripheral neuropathic pain. Inflammasome is a multiprotein complex consisting of Nod-like receptor proteins (NLRPs), apoptosis-associated speck-like protein, and caspase-1, which functions to switch on the inflammatory process and the release of interleukin-1ß. Growing evidences have supported that peripheral interleukin-1ß is critical in enhancing paclitaxel-induced neuropathic pain. However, whether activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain is still unclear. Results Paclitaxel induced mechanical allodynia of rats from day 3 and worsened gradually till 3 weeks after injection. Paclitaxel resulted in expression of NLRP3 and activated fragments of caspase-1 and interleukin-1ß in L4-6 dorsal root ganglia and sciatic nerve three weeks after injection, indicating activation of NLRP3 inflammasome. The expression of NLRP3 was located in CD68-labeled macrophages infiltrating in L4-6 dorsal root ganglia and sciatic nerve, and paclitaxel increased the expression of NLRP3 in macrophage. Moreover, the paclitaxel elicited mitochondria damage, which became swollen and enlarged in macrophages and axons of sciatic nerve three weeks after injection. In vitro, paclitaxel increased the number of damaged mitochondria and mitochondrial reactive oxygen species production in the rat alveolar macrophage cell line NR8383. The administration of a non-specific reactive oxygen species scavenger, phenyl-N-tert-butylnitrone, markedly alleviated mechanical allodynia and inhibited the activation of NLRP3 inflammasome in L4-6 dorsal root ganglia and sciatic nerve of the paclitaxel-induced neuropathic pain model. Conclusions Paclitaxel induced mechanical allodynia and activation of NLRP3 inflammasome in infiltrated macrophages of L4-6 dorsal root ganglia and sciatic nerve. Paclitaxel elicited mitochondria damage and reactive oxygen species production may result in activation of NLRP3 inflammasome in peripheral nerve, which contributes to paclitaxel-induced neuropathic pain.


Asunto(s)
Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neuralgia/inducido químicamente , Neuralgia/metabolismo , Paclitaxel/efectos adversos , Nervios Periféricos/metabolismo , Animales , Caspasa 1/genética , Caspasa 1/metabolismo , Línea Celular , Óxidos N-Cíclicos/farmacología , Óxidos N-Cíclicos/uso terapéutico , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/patología , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Macrófagos/ultraestructura , Masculino , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Neuralgia/patología , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Nervio Ciático/metabolismo , Nervio Ciático/patología , Nervio Ciático/ultraestructura
4.
Mol Pain ; 13: 1744806917719169, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28714350

RESUMEN

Background Calpain is a calcium-dependent cysteine protease, and inhibition of calpain by pre-treatment with MDL28170 attenuated the rat mechanical allodynia in a variety of pain models. Postherpetic neuralgia (Shingles) is a neuropathic pain conditioned with the presence of profound mechanical allodynia. Systemic injection of resiniferatoxin can reproduce the clinical symptoms of postherpetic neuralgia. In this study, we determined to study whether activation of calpain contributes to cleave the myelin basic protein of dorsal root and is involved in resiniferatoxin-induced mechanical allodynia of postherpetic neuralgia animal model. Results Resiniferatoxin up-regulated the expression and activation of µ-calpain in dorsal root. The expression of µ-calpain was located in Schwann cell of dorsal root, and resiniferatoxin increased the expression of µ-calpain in Schwann cell in L4-L6 dorsal root at six weeks after injection. Resiniferatoxin also induced myelin basic protein degradation in L4-L6 dorsal root at six weeks after injection. Moreover, intraperitoneal injection of calpain inhibitor MDL28170 prevented the degradation of myelin basic protein and then reduced the sprouting of myelinated afferent fibers into spinal lamina II, thus relieving resiniferatoxin-induced mechanical allodynia. Conclusions Up-regulation and activation of µ-calpain located in Schwann cell may be the mechanism underlying resiniferatoxin-mediated proteolysis of myelin basic protein in dorsal root. Calpain inhibitor MDL28170 prevents resiniferatoxin-induced sprouting of myelinated afferent fibers and mechanical allodynia through inhibition of degradation of the myelin basic protein in dorsal root. Our results indicate that inhibition of pathological µ-calpain activation may present an interesting novel drug target in the treatment of postherpetic neuralgia.


Asunto(s)
Calpaína/metabolismo , Ganglios Espinales/enzimología , Ganglios Espinales/patología , Hiperalgesia/enzimología , Hiperalgesia/patología , Animales , Biomarcadores/metabolismo , Dipéptidos/farmacología , Diterpenos/administración & dosificación , Activación Enzimática/efectos de los fármacos , Vértebras Lumbares/patología , Masculino , Proteína Básica de Mielina/metabolismo , Vaina de Mielina/metabolismo , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/metabolismo , Isoformas de Proteínas/metabolismo , Proteolisis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Células de Schwann/efectos de los fármacos , Células de Schwann/enzimología , Regulación hacia Arriba/efectos de los fármacos
5.
Mol Neurobiol ; 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38963532

RESUMEN

The comorbidity of anxiety and depression frequently occurs in patients with neuropathic pain. The ventrolateral orbital cortex (VLO) plays a critical role in mediating neuropathic pain and anxiodepression in rodents. Previous studies suggested that 5-HT6 receptors in the VLO are involved in neuropathic pain. Strong evidence supports a close link between 5-HT6 receptors and affective disorders such as depression and anxiety disorders. However, it remains unclear whether the 5-HT6 receptors in the VLO are involved in neuropathic pain-induced anxiodepression. Using a rat neuropathic pain model of spared nerve injury (SNI), we demonstrated that rats exhibited significant anxiodepression-like behaviors and the expression of VLO 5-HT6 receptors obviously decreased four weeks after SNI surgery. Microinjection of the 5-HT6 receptor agonist EMD-386088 into the VLO or overexpression of VLO 5-HT6 receptors alleviated anxiodepression-like behaviors. These effects were blocked by pre-microinjection of a selective 5-HT6 receptor antagonist (SB-258585) or inhibitors of AC (SQ-22536), PKA (H89), and MEK1/2 (U0126) respectively. Meanwhile, the expression of p-ERK, p-CREB, and BDNF in the VLO decreased four weeks after SNI surgery. Furthermore, administration of EMD-386088 upregulated the expression of BDNF, p-ERK, and p-CREB in the VLO of SNI rats, which were reversed by pre-injection of SB-258585. These findings suggest that activating 5-HT6 receptors in the VLO has anti-anxiodepressive effects in rats with neuropathic pain via activating AC-cAMP-PKA-MERK-CREB-BDNF signaling pathway. Accordingly, 5-HT6 receptor in the VLO could be a potential target for the treatment of the comorbidity of neuropathic pain and anxiodepression.

6.
Neuropharmacology ; 245: 109830, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38160874

RESUMEN

The ventrolateral orbital cortex (VLO) is identified as an integral component of the endogenous analgesic system comprising a spinal cord - thalamic nucleus submedius - VLO - periaqueductal gray (PAG) - spinal cord loop. The present study investigates the effects of 5-HT5A receptor activation in the VLO on allodynia induced by spared nerve injury and formalin-evoked flinching behavior and spinal c-Fos expression in male SD rats, and further examines whether GABAergic modulation is involved in the effects evoked by VLO 5-HT5A receptor activation. We found an upregulation of 5-HT5A receptor expression in the VLO during neuropathic and inflammatory pain states. Microinjection of the non-selective 5-HT5A receptor agonist 5-CT into the VLO dose dependently alleviated allodynia, and flinching behavior and spinal c-Fos expression, which were blocked by the selective 5-HT5A receptor antagonist SB-699551. Moreover, application of the GABAA receptor antagonist bicuculline in the VLO augmented the analgesic effects induced by 5-CT in neuropathic and inflammatory pain states, whereas the GABAA receptor agonist muscimol attenuated these analgesic effects. Additionally, the 5-HT5A receptors were found to be colocalized with GABAergic neurons in the VLO. These results provide new evidence for the involvement of central 5-HT5A receptors in the VLO in modulation of neuropathic and inflammatory pain and support the hypothesis that activation of 5-HT5A receptors may inhibit the inhibitory effect of GABAergic interneurons on output neurons projecting to the PAG (GABAergic disinhibitory mechanisms), consequently activating the brainstem descending inhibitory system that depresses nociceptive transmission at the spinal cord level.


Asunto(s)
Hiperalgesia , Enfermedades del Sistema Nervioso Periférico , Ratas , Masculino , Animales , Hiperalgesia/metabolismo , Serotonina/metabolismo , Ratas Sprague-Dawley , Receptores de GABA-A/metabolismo , Dimensión del Dolor , Dolor/tratamiento farmacológico , Dolor/metabolismo , Analgésicos/farmacología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Corteza Prefrontal
7.
Front Neurosci ; 15: 733779, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34602973

RESUMEN

Knee osteoarthritis (KOA) is a common and disabling condition characterized by attacks of pain around the joints, and it is a typical disease that develops chronic pain. Previous studies have proved that 5-HT1, 5-HT2, and 5-HT3 receptors in the spinal cord are involved in electroacupuncture (EA) analgesia. The 5-HT7 receptor plays antinociceptive role in the spinal cord. However, it is unclear whether the 5-HT7 receptor is involved in EA analgesia. The 5-HT7 receptor is a stimulatory G-protein (Gs)-coupled receptor that activates adenylyl cyclase (AC) to stimulate cyclic adenosine monophosphate (cAMP) formation, which in turn activates protein kinase A (PKA). In the present study, we found that EA significantly increased the tactile threshold and the expression of the 5-HT7 receptor in the dorsal spinal cord. Intrathecal injection of 5-HT7 receptor agonist AS-19 mimicked the analgesic effect of EA, while a selective 5-HT7 receptor antagonist reversed this effect. Moreover, intrathecal injection of AC and PKA antagonists prior to EA intervention prevented its anti-allodynic effect. In addition, GABAA receptor antagonist bicuculline administered (intrathecal, i.t.) prior to EA intervention blocked the EA effect on pain hypersensitivity. Our data suggest that the spinal 5-HT7 receptor activates GABAergic neurons through the Gs-cAMP-PKA pathway and participates in EA-mediated inhibition of chronic pain in a mouse model of KOA.

8.
Front Behav Neurosci ; 13: 239, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31680895

RESUMEN

Tourette syndrome (TS), a developmental neurobehavioral disorder, is characterized by involuntary behavioral stereotypies. Clinical studies have confirmed the positive effect of acupuncture on treating TS, but the underlying mechanisms are not fully understood. In the present study, we used behavioral tests, Western blotting, double-immunofluorescence labeling, and fluorescence spectrophotometry to investigate whether acupuncture performed at acupoints "Baihui" (GV20) and "Yintang" (GV29) affected behavioral stereotypies and regulated the dopamine (DA) system in three different brain regions in Balb/c mice injected with 3,3'-iminodipropionitrile (IDPN) as a model for TS. We found that acupuncture alleviated behavioral stereotypies, down-regulated the expression of D1R and D2R in the striatum (STR) and substantia nigra pars compacta (SNpc), and decreased the concentration of DA in the STR, SNpc, and prefrontal cortex (PFC) as well. Moreover, acupuncture reduced the expression of tyrosine hydroxylase (TH) in the SNpc. Conclusively, acupuncture ameliorated behavioral stereotypies by regulating the DA system in the STR, SNpc, and PFC. Our findings provide novel evidence for the therapeutic effect of acupuncture on TS.

9.
Arthritis Res Ther ; 21(1): 120, 2019 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-31088511

RESUMEN

BACKGROUND: Conditioned pain modulation (CPM) is impaired in people with chronic pain such as knee osteoarthritis (KOA). The purpose of this randomized, controlled clinical trial was to investigate whether strong electroacupuncture (EA) was more effective on chronic pain by strengthening the CPM function than weak EA or sham EA in patients with KOA. METHODS: In this multicenter, three-arm parallel, single-blind randomized controlled trial, 301 patients with KOA were randomly assigned. Patients were randomized into three groups based on EA current intensity: strong EA (> 2 mA), weak EA (< 0.5 mA), and sham EA (non-acupoint). Treatments consisted of five sessions per week, for 2 weeks. Primary outcome measures were visual analog scale (VAS), CPM function, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Three hundred one patients with KOA were randomly assigned, among which 271 (90.0%) completed the study (mean age 63.93 years old). One week of EA had a clinically important improvement in VAS and WOMAC but not in CPM function. After 2 weeks treatment, EA improved VAS, CPM, and WOMAC compared with baseline. Compared with sham EA, weak EA (3.8; 95% CI 3.45, 4.15; P < .01) and strong EA (13.54; 95% CI 13.23, 13.85; P < .01) were better in improving CPM function. Compared with weak EA, strong EA was better in enhancing CPM function (9.73; 95% CI 9.44, 10.02; P < .01), as well as in reducing VAS and total WOMAC score. CONCLUSION: EA should be administered for at least 2 weeks to exert a clinically important effect on improving CPM function of KOA patients. Strong EA is better than weak or sham EA in alleviating pain intensity and inhibiting chronic pain. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry ( ChiCTR-ICR-14005411 ), registered on 31 October 2014.


Asunto(s)
Electroacupuntura/métodos , Osteoartritis de la Rodilla/terapia , Anciano , Dolor Crónico/etiología , Dolor Crónico/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
10.
J Pain Res ; 12: 1259-1268, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31118749

RESUMEN

Purpose: We determined whether electroacupuncture (EA) reduces Netrin-1-induced myelinated primary afferent nerve fiber sprouting in the spinal cord and pain hypersensitivity associated with postherpetic neuralgia (PHN) through activation of µ-opioid receptors. Methods: PHN was induced by systemic injection of resiniferatoxin (RTX) in rats. Thirty-six days after RTX injection, a µ-opioid receptor antagonist, beta-funaltrexamine (ß-FNA) or a κ-opioid receptor antagonist, nor Binaltorphimine (nor-BNI), was injected intrathecally 30 mins before EA, once every other day for 4 times. Mechanical allodynia was tested with von Frey filaments. The protein expression level of Netrin-1 and its receptors (DCC and UNC5H2) were quantified by using western blotting. The myelinated primary afferent nerve fiber sprouting was mapped with the transganglionic tracer cholera toxin B-subunit (CTB). Results: Treatment with 2 Hz EA at "Huantiao" (GB30) and "Yanglingquan" (GB34) decreased the mechanical allodynia at 22 days and the myelinated primary afferent nerve fiber preternatural sprouting into the lamina II of the spinal dorsal horn at 42 days after RTX injection. Also, treatment with 2 Hz EA reduced the protein levels of DCC and Netrin-1 and promoted the expression of UNC5H2 in the spinal dorsal horn 42 days after RTX injection. Furthermore, the µ-opioid receptor antagonist ß-FNA, but not the κ-opioid receptor antagonist nor-BNI, reversed the effect of EA on neuropathic pain caused by RTX. In addition, morphine inhibited the Netrin-1 protein level induced by RTX in SH-SY5Y cells. Conclusions: Through activation of µ-opioid receptors, treatment with EA reduces the expression level of DCC and Netrin-1 and changes a growth-permissive environment in spinal dorsal horn into an inhibitory environment by increasing UNC5H2, thus decreasing RTX-caused primary afferent nerve sprouting in the spinal dorsal horn and neuropathic pain.

11.
Zhen Ci Yan Jiu ; 43(4): 203-8, 2018 Apr 25.
Artículo en Zh | MEDLINE | ID: mdl-29888571

RESUMEN

OBJECTIVE: To observe the effect of different frequencies of electroacupuncture (EA) stimulation on pain threshold (PT) and expression of vascular endothelial growth factor (VEGF) in dorsal horns (DHs) of the lumbar spinal cord in resiniferatoxin (RTX)-induced post-herpetic neuralgia (PHN) rats, so as to reveal its mechanism in alleviating PHN. METHODS: Male SD rats were randomized into control, model, 2 Hz-EA, 15 Hz-EA, 100 Hz-EA and sham EA groups (n=16 in each). The PHN model was induced by a single intraperitoneal injection of RTX (250 µg/kg), and rats of the control group received intraperitoneal injection of the same dose of vehicle (10% Tween 80, 10% alcohol and 0.9% NaCl). Rats of EA treatment groups received EA stimulation (2 Hz, 15 Hz or 100 Hz, 1 mA) at the left "Huantiao" (GB 30) and "Yanglingquan" (GB 34) for 30 min, once every other day for 35 days, starting from 1 week after RTX injection. For sham control, acupuncture needles were inserted ipsilaterally into GB 30 and GB 34 for 30 min without electrical stimulation or manual needle manipulation. The mechanical allodynia was quantified with Von Frey filaments. The expression of mRNA and protein of VEGF in the DHs of lumbar spinal cord 4-6 segments (sampled under light microscope) was detected by quantitative polymerase chain reaction (qPCR) and Western blot, respectively. RESULTS: A single RTX injection gradually induced tactile allodynia (significant reduction of the mechanical PT) within 3 weeks relevant to the control group (P<0.01). EA applied to GB 30 and GB 34 at 2 Hz and 15 Hz, but not 100 Hz, significantly decreased the tactile allodynia after the treatment (2 Hz from 2 weeks on and 15 Hz from 3 weeks on) in RTX-treated rats (P<0.05). RTX administration increased the mRNA and protein expression of VEGF in the lumbar spinal cord compared with the control group (P<0. 05). Moreover, 2 Hz, but not 15 Hz and 100 Hz EA significantly reduced VEGF mRNA and protein expression(P<0.05). The expression of both VEGF mRNA and protein was negatively correlated with mechanical PT in RTX-induced PHN rats. CONCLUSION: EA at 2 Hz can significantly reduce VEGF expression in the lumbar spinal cord DHs of PHN rats, which is possibly in part related to its effect in alleviating the mechanical allodynia. Our study suggests that 2 Hz EA is the best stimulation frequency for relieving PHN.


Asunto(s)
Electroacupuntura , Neuralgia Posherpética , Neuralgia , Analgésicos , Animales , Masculino , Neuralgia Posherpética/terapia , Ratas , Ratas Sprague-Dawley , Asta Dorsal de la Médula Espinal , Factor A de Crecimiento Endotelial Vascular
12.
J Pain Res ; 11: 2797-2808, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30510442

RESUMEN

PURPOSE: Knee osteoarthritis (KOA) is a highly prevalent, chronic joint disorder, with chronic pain as its typical symptom. Although studies have shown that an activated peripheral CB2 receptor can reduce acute pain, whether the CB2 receptor is involved in electroacupuncture (EA) inhibiting chronic pain and the involved mechanism remains unclear. The aim of this study was to investigate whether EA may strengthen peripheral CB2 receptor-inhibited chronic pain in a mouse model of KOA. MATERIALS AND METHODS: KOA was induced by intra-articular injection of monosodium iodoacetate (MIA) into the left knee joint of mice. Thermal hyperalgesia was tested with the hot plate test, and mechanical allodynia was quantified using von Frey filaments. The expression of CB2 receptor and IL-1ß were quantified by using immunofluorescence labeling. RESULTS: EA treatment at 2 Hz+1 mA significantly increased the expression of CB2 receptor in fibroblasts and decreased the expression of IL-1ß in the menisci compared with that in the KOA group. However, EA had no effect on the expression of IL-1ß in CB2-/- mice. At 2 Hz+1 mA, EA significantly increased mechanical threshold, thermal latency, and weight borne after KOA modeling. However, knockout of the CB2 receptor blocked these effects of EA. After 2 Hz+1 mA treatment, EA significantly reduced the Osteoarthritis Research Society International (OARSI) score after KOA modeling. However, EA had no significant effect on the OARSI score in CB2-/- mice. CONCLUSION: EA reduced the expression of IL-1ß by activating the CB2 receptor, thus inhibiting the chronic pain in the mouse model of KOA.

13.
Front Mol Neurosci ; 11: 112, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29681797

RESUMEN

Knee osteoarthritis (KOA) is a highly prevalent, chronic joint disorder, which can lead to chronic pain. Although electroacupuncture (EA) is effective in relieving chronic pain in the clinic, the involved mechanisms remain unclear. Reduced diffuse noxius inhibitory controls (DNIC) function is associated with chronic pain and may be related to the action of endocannabinoids. In the present study, we determined whether EA may potentiate cannabinoid receptor-mediated descending inhibitory control and inhibit chronic pain in a mouse model of KOA. We found that the optimized parameters of EA inhibiting chronic pain were the low frequency and high intensity (2 Hz + 1 mA). EA reversed the reduced expression of CB1 receptors and the 2-arachidonoylglycerol (2-AG) level in the midbrain in chronic pain. Microinjection of the CB1 receptor antagonist AM251 into the ventrolateral periaqueductal gray (vlPAG) can reversed the EA effect on pain hypersensitivity and DNIC function. In addition, CB1 receptors on GABAergic but not glutamatergic neurons are involved in the EA effect on DNIC function and descending inhibitory control of 5-HT in the medulla, thus inhibiting chronic pain. Our data suggest that endocannabinoid (2-AG)-CB1R-GABA-5-HT may be a novel signaling pathway involved in the effect of EA improving DNIC function and inhibiting chronic pain.

14.
Zhongguo Zhen Jiu ; 36(8): 845-850, 2016 Aug 12.
Artículo en Zh | MEDLINE | ID: mdl-29231572

RESUMEN

OBJECTIVE: To explore the anti-inflammatory and analgesia mechanism of electroacupuncture (EA) device of point injection (PI) on rats of inflammatory pain. METHODS: 48 Sprague Dawley (SD) rats were randomly assigned into a control group, a model group, an EA+PI group, an EA device of PI (EAPI) group, an EA group and a PI group, eight rats in each one. The rats in the control group were subcutaneously injected with 50 µL of liquid paraffin oil solvent into the dorsum of left hindpaw, while rats in the remaining groups were treated with 50 µL of complete freund's adjuvant (CFA) at identical location to induce the model of inflammatory pain. After model establishment, the rats in the EA+PI group, EAPI group, EA group and PI group were treated with EA+PI,EA device of PI, EA and PI, respectively, once every other day (the 2nd day, 4th day and 6th day). Each treatment was given for 30 min. The mechanical withdrawal threshold, thermal withdrawal threshold and foot swelling before and 1 d to 6 d after model establishment were observed; the western blotting method was applied to measure IL-1ß expression in inflammatory tissue of skin. RESULTS: After model establishment, compared with the control group, the mechanical withdrawal threshold and thermal withdrawal threshold were reduced (all P<0.05) and the foot swelling was increased in the rest groups (all P<0.05). After treatment, the mechanical withdrawal threshold and thermal withdrawal threshold in the EAPI group were significantly increased compared with those in the EA+PI group, EA group and PI group (all P<0.05), but the foot swelling was reduced (all P<0.05). The IL-1ß expression in the model group was higher than that in the control group (P<0.05); after treatment, the IL-1ß expression in the EAPI group was lower than that in the model group, EA group and PI group (all P<0.05), but no significantly different from that in the EA+PI group (P>0.05). CONCLUSIONS: The efficacy of EA device of PI on inflammatory pain is superior to EA combined with PI, EA alone and PI alone, which is suitable for further popularization and application.


Asunto(s)
Analgesia por Acupuntura/instrumentación , Electroacupuntura/instrumentación , Manejo del Dolor/instrumentación , Umbral del Dolor , Analgesia por Acupuntura/métodos , Adyuvantes Inmunológicos/administración & dosificación , Animales , Adyuvante de Freund/administración & dosificación , Humanos , Aceites/administración & dosificación , Dolor , Manejo del Dolor/métodos , Parafina/administración & dosificación , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley
15.
Mol Neurobiol ; 53(8): 5640-51, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-26482371

RESUMEN

Netrin-1 is a neuronal guidance molecule implicated in the development of spinal cord neurons and cortical neurons. In the adult spinal cord, UNC5H (repulsive receptor of netrin-1), but not deleted in colorectal cancer (DCC) (attractive receptor of netrin-1), constitutes a major mode of netrin-1 signal transduction, which may be involved in axon repulsion and inhibits neurite outgrowth. Abnormal sprouting of myelinated afferent fibers in the spinal dorsal horn can cause mechanical allodynia associated with postherpetic neuralgia (PHN, Shingles) and other neuropathic pains. However, whether netrin-1 participates in sprouting of myelinated afferent fibers and mechanical allodynia remains unknown. In an ultropotent TRPV1 agonist resiniferatoxin (RTX)-induced PHN-like model, RTX treatment for 6 weeks increased netrin-1 expression in dorsal horn neurons, including NK-1-positive projection neurons. In human neuroblastoma SH-SY5Y cells, we found that TRPV1 antagonist capsazepine antagonized RTX-induced upregulation of netrin-1. After RTX treatment, UNC5H2 expression was gradually decreased, whereas DCC expression was significantly increased. Silencing netrin-1 in the spinal dorsal horn significantly attenuated RTX-induced mechanical allodynia and sprouting of myelinated fibers into the spinal lamina II. Our results suggest that RTX treatment upregulates netrin-1 expression through activation of TRPV1 receptors and change UNC5H2-rich spinal dorsal horn into a growth-permissive environment by increasing DCC expression, thus enhancing the sprouting of myelinated afferent nerves. Netrin-1 may be targeted for reducing primary afferent sprouting and mechanical allodynia in PHN and other neuropathic pain conditions.


Asunto(s)
Vaina de Mielina/metabolismo , Netrina-1/metabolismo , Neuralgia/metabolismo , Neurogénesis , Neuronas Aferentes/metabolismo , Animales , Biomarcadores/metabolismo , Línea Celular Tumoral , Receptor DCC/metabolismo , Diterpenos/toxicidad , Regulación hacia Abajo/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Hiperalgesia/metabolismo , Hiperalgesia/patología , Lentivirus/metabolismo , Masculino , Vaina de Mielina/efectos de los fármacos , Netrina-1/genética , Neurogénesis/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/patología , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas Sprague-Dawley , Receptores de Superficie Celular/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patología , Regulación hacia Arriba/efectos de los fármacos
16.
Mol Neurobiol ; 53(6): 3616-3625, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-26108183

RESUMEN

Activation of cannabinoid receptor-2 (CB2) results in ß-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception. However, the underlying mechanism is still unknown. The CB2 receptor is generally thought to couple to Gi/o to inhibit cAMP production, which cannot explain the peripheral stimulatory effects of CB2 receptor activation. In this study, we found that in a keratinocyte cell line, the Gßγ subunits from Gi/o, but not Gαs, were involved in CB2 receptor activation-induced ß-endorphin release. Inhibition of MAPK kinase, but not PLC, abolished CB2 receptor activation-induced ß-endorphin release. Also, CB2 receptor activation significantly increased intracellular Ca(2+). Treatment with BAPTA-AM or thapsigargin blocked CB2 receptor activation-induced ß-endorphin release. Using a rat model of inflammatory pain, we showed that the MAPK kinase inhibitor PD98059 abolished the peripheral effect of the CB2 receptor agonist on nociception. We thus present a novel mechanism of CB2 receptor activation-induced ß-endorphin release through Gi/o-Gßγ-MAPK-Ca(2+) signaling pathway. Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists.


Asunto(s)
Receptor Cannabinoide CB2/metabolismo , Transducción de Señal , betaendorfina/metabolismo , Analgésicos/farmacología , Animales , Calcio/metabolismo , Cannabinoides/farmacología , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Humanos , Masculino , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Nociceptores/metabolismo , Proopiomelanocortina/metabolismo , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/agonistas , Transducción de Señal/efectos de los fármacos , Fosfolipasas de Tipo C/metabolismo
17.
Artículo en Inglés | MEDLINE | ID: mdl-26167190

RESUMEN

Background. Nocturnal enuresis (NE) is recognized as a widespread health problem in young children and adolescents. Clinical researches about acupuncture therapy for nocturnal enuresis are increasing, while systematic reviews assessing the efficacy of acupuncture therapy are still lacking. Objective. This study aims to assess the effectiveness of acupuncture therapy for nocturnal enuresis. Materials and Methods. A comprehensive literature search of 8 databases was performed up to June 2014; randomized controlled trials which compared acupuncture therapy and placebo treatment or pharmacological therapy were identified. A meta-analysis was conducted. Results. This review included 21 RCTs and a total of 1590 subjects. The overall methodological qualities were low. The results of meta-analysis showed that acupuncture therapy was more effective for clinical efficacy when compared with placebo or pharmacological treatment. Adverse events associated with acupuncture therapy were not documented. Conclusion. Based on the findings of this study, we cautiously suggest that acupuncture therapy could improve the clinical efficacy. However, the beneficial effect of acupuncture might be overstated due to low methodological qualities. Rigorous high quality RCTs are urgently needed.

18.
Artículo en Inglés | MEDLINE | ID: mdl-26064156

RESUMEN

Background. Itch (pruritus) is a sensitive state that provokes the desire to scratch. It is not only a common symptom of skin diseases but it also occurs in some systemic diseases. Clinical studies on the efficacy of the acupuncture therapy in alleviating itch are increasing, while systematic reviews assessing the efficacy of acupuncture therapy are still lacking. Objective. This systematic review aims to assess the effectiveness of acupuncture therapy for itch. Materials and Methods. A comprehensive literature search of eight databases was performed up to June 2014, and randomized controlled trials which compared acupuncture therapy and placebo acupuncture or no treatment group were identified. Accordingly, a meta-analysis was conducted. Results. This review included three articles of randomized controlled trials (RCTs) from a total of 2530 articles. The results of Meta-analysis showed that acupuncture therapy was effective to alleviate itch compared with placebo acupuncture and no treatment group. Conclusion. Based on the findings of this systematic review, we cautiously suggest that acupuncture therapy could improve the clinical efficacy of itch. However, this conclusion needs more studies on various ethnic samples to confirm our final conclusion.

19.
Trials ; 16: 131, 2015 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-25873092

RESUMEN

BACKGROUND: Previous studies have shown that electroacupuncture (EA) has a significant effect on acute pain, but it has not solved the clinical problem of the chronification of acute pain. Diffuse noxious inhibitory controls (DNIC) function as a reliable indicator to predict the risk of chronic pain events. DNIC function in knee osteoarthritis (KOA) patients has been demonstrated to gradually decrease during the development of chronic pain. The purpose of this study is to conduct a randomized, controlled clinical trial to determine if EA can repair impaired DNIC function and thus prevent chronification of the acute pain of KOA. METHODS/DESIGN: This is a multicenter, single blind, randomized, controlled, three-arm, large-scale clinical trial. A total of 450 KOA patients will be randomly assigned to three groups. The strong EA group will receive EA with high-intensity current (2 mA < current < 5 mA) at the ipsilateral 'Neixiyan' (EX-LE5), 'Dubi'(ST35), 'Liangqiu'(ST34) and 'Xuehai' (SP10). The weak EA group will receive EA with low-intensity current (0 mA < current < 0.5 mA) on the same acupoints. The sham EA group will receive EA with low-intensity current (0 mA < current < 0.5 mA) with fine needles inserted superficially into the sites 2 cm lateral to the above acupoints. The patients will be treated with EA once a day, 30 minutes per session, in 5 sessions per week, for 2 weeks. In order to determine the best stage of KOA for effective EA intervention, patients within the treatment groups also will be divided into four stages. The primary outcomes are Visual Analog Scale (VAS), DNIC function and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Clinical assessments will be evaluated at baseline (before treatment) and after 5 to 10 sessions of treatment. DISCUSSION: This trial will be helpful in identifying whether strong EA is more effective than weak EA in reversing chronification of acute pain through repairing the impaired DNIC function and in screening for the best stage of KOA for effective EA intervention. TRIAL REGISTRATION: Chinese Clinical Trial Registry Number: ChiCTR-ICR-14005411. The date of registration is 31 October 2014.


Asunto(s)
Dolor Agudo/terapia , Protocolos Clínicos , Electroacupuntura , Osteoartritis de la Rodilla/terapia , Humanos , Evaluación de Resultado en la Atención de Salud , Tamaño de la Muestra , Método Simple Ciego
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