Dietary phytate induces subclinical mechanical allodynia in mice

Neuropathic pain is a condition with varying origins, including reduced dietary micronutrient intake. Phytate is a polyphosphate found in seeds and grains that can act as an antinutrient due to the ability of sequester essential divalent metals. Here we tested whether moderate dietary phytate intake could alter nociceptive pain. We subjected weaning mice to a chow supplemented with 1% phytate for eight weeks. Body weight gain, glycemic responses, food ingestion, water ingestion, and liver and adipose tissue weights were not altered compared to controls. We observed a decreased mechanical allodynia threshold in the intervention group, although there were no changes in heat- or cold-induced pain. Animals consuming phytate showed reduced spinal cord tumor necrosis factor (TNF), indicating altered inflammatory process. These data provide evidence for a subclinical induction of mechanical allodynia that is independent of phytate consumption in animals with otherwise normal phenotypic pattern.

Comparative study of cold hyperalgesia and mechanical allodynia in two animal models of neuropathic pain: different etiologies and distinct pathophysiological mechanisms

Abstract Neuropathic pain (NP) affects more than 8% of the global population. The proposed action of the transient receptor potential ankyrin 1 (TRPA1) as a mechanosensor and the characterization of the transient receptor potential melastatin 8 (TRPM8) as a cold thermosensor raises the question of whether these receptors are implicated in NP. Our study aimed to evaluate the involvement of TRPA1 and TRPM8 in cold and mechanical signal transduction to obtain a comparative view in rat models of streptozotocin-induced diabetes (STZ) and chronic constriction injury of the sciatic nerve (CCI). The electronic von Frey test showed that STZ rats presented mechanical allodynia that was first evidenced on the 14th day after diabetes confirmation, and four days after CCI. This phenomenon was reduced by the intraplantar (ipl) administration of a TRPA1 receptor antagonist (HC-030031; 40 µL/300 µg/paw) in both NP models. Only CCI rats displayed cold hyperalgesia based on the cold plate test. The pharmacological blocking of TRPA1 through the injection of the antagonist attenuated cold hyperalgesia in this NP model. STZ animals showed a reduction in the number of flinches induced by the intraplantar injection of mustard oil (MO; TRPA1 agonist; 0.1%/50 µL/paw), or intraplantar injection of menthol (MT; TRPM8 agonist; 0.5% and 1%/50 µL/paw). The response induced by the ipl administration of MT (1%/50 µL/paw) was significantly different between the CCI and SHAM groups. Together, these data suggest a different pattern in nociceptive behavior associated with different models of NP, suggesting a variant involvement of TRPA1 and TRPM8 in both conditions

Alleviation of neuropathic pain by trazodone in rats

Abstract Neuropathic pain is generally characterised by an abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a stimulus that does not normally provoke pain (allodynia). The present study was designed to investigate the effect of trazodone (5mg/kg and 10mg/kg) on peripheral neuropathic pain induced by partial sciatic nerve ligation in rats. Mechanical hyperalgesia, cold allodynia and thermal hyperalgesia were assessed by performing the pinprick, acetone, and hot plate tests, respectively. Biochemically, lipid peroxidation level and total calcium levels were measured. However, trazodone administration (5 and 10 mg/ kg i.p.) for 21days significantly diminished partial sciatic nerve ligation-induced neuropathic pain along with areduction in oxidative stress and calcium levels. The results of the present study suggest that trazodone is effective in attenuating partial sciatic nerve ligation-inducedpainful neuropathic states, which may be attributed to decreased oxidative stress and calcium levels.

Neuroprotective role of Tinospora cordifolia extract in streptozotocin induced neuropathic pain

Abstract Diabetic Neuropathy (DN) is one of the prevailing micro vascular complications of diabetes which can be characterized by neuropathic pain. Streptozotocin (STZ) induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy. STZ injection leads to neurotoxicity of peripheral nerves that leads to development of Peripheral Diabetic Neuropathy in rat model. The present study was aimed at exploring the protective role of Tinospora cordifolia extract in STZ induced neurotoxicity and evaluating mechanisms responsible for attenuating neuropathic pain. Neuropathic pain markers like hyperalgesia, allodynia and motor deficits were assessed before STZ injection and after the treatment with 250 mg/kg and 500 mg/kg dose of Tinospora cordifolia. Oxidative stress markers, NGF expression in sciatic nerve were observed after seven weeks treatment. Our results demonstrated that seven weeks treatment with Tinospora cordifolia leaf extract significantly relieved thermal hyperalgesia and allodynia by increasing the antioxidant enzyme levels, decreasing the lipid peroxidation and by increasing the Nerve growth factor (NGF) expression in diabetic rat sciatic nerves. Our findings highlighted the beneficial effects of oral administration of Tinospora cordifolia extract in attenuating diabetic neuropathic pain, possibly through a strong antioxidant activity and by inducing NGF m RNA in sciatic nerves.

The profile of dexamethasone combined with transcranial direct current stimulation in rats submitted to an arthritis model / O perfil da dexametasona combinada com estimulação transcraniana por corrente contínua em ratos submetidos a um modelo de artrite

ABSTRACT BACKGROUND AND OBJECTIVES: To pursue safer and more effective treatments for rheumatoid arthritis, the effect of dexamethasone treatment (DEX, 0.25mg/kg) combined with transcranial direct current stimulation (tDCS) in the behavior and neurochemical parameters of arthritic rats was evaluated. METHODS: Thirty-six Wistar rats were divided into four groups: control+DEX (CTRL+DEX), arthritis+DEX (RA+DEX), arthritis+DEX+sham-tDCS (RA+DEX+sham-tDCS) and arthritis+DEX+tDCS (RA+DEX+tDCS). The arthritic model (RA) was induced by complete Freund's adjuvant (CFA) paw administration. Paw edema and mechanical allodynia were assessed by plethysmometer and von Frey apparatus, respectively. Fourteen days after the CFA injection, rats received the treatment for eight days (DEX and/or tDCS). Behavioral parameters were measured with the Open-Field test. ELISA was used to evaluate hippocampal and spinal cord tumor necrosis factor (TNF-α) levels, cerebral cortex and brainstem BDNF levels. RESULTS: In pre-treatment measurements, arthritic rats presented an increase in joint swelling and mechanical allodynia when compared to the control group, confirming chronic pain establishment. A slight antinociceptive effect of dexamethasone combined with tDCS in the pain model was observed. The pain model significantly induced an increase in the grooming behavior and a reduction in the spinal cord and hippocampal TNF-α levels; these effects were reverted in the sham- and active-tDCS-treated rats. However, no effects of DEX or tDCS were observed in the BDNF levels in the cerebral cortex and brainstem. CONCLUSION: Despite the small effect observed, tDCS treatment cannot be discarded as a non-pharmacological adjuvant technique for inflammatory chronic pain treatment.

RESUMO JUSTIFICATIVA E OBJETIVOS: Para investigar métodos mais seguros e eficazes para o manejo da artrite reumatoide, avaliou-se o efeito do tratamento com dexametasona (DEX, 0,25mg/kg) combinado com estimulação transcraniana por corrente contínua (ETCC) sobre parâmetros comportamentais e bioquímicos de ratos submetidos a um modelo de artrite reumatoide. MÉTODOS: Trinta e seis ratos Wistar foram alocados em 4 grupos: controle+DEX (CTRL+DEX), artrite+DEX (AR+DEX), artrite+DEX+sham-ETCC (AR+DEX+sham-ETCC) e artrite+DEX+ETCC (AR+DEX+ETCC). O modelo de artrite foi induzido pela administração de complete Freund's adjuvant (CFA) na pata. Edema na pata e a alodínia mecânica foram avaliadas por pletismômetro e teste de von Frey, respectivamente. 14 dias após injeção de CFA, ratos foram tratados por 8 dias (DEX e/ou ETCC). Atividade locomotora foi avaliada pelo teste do campo aberto. TNF-alfa (hipocampo e medula espinal) e BDNF (córtex e tronco) foram mensurados por ELISA. RESULTADOS: Nas medições pré-tratamento, ratos com artrite exibiram aumento de o inchaço articular e alodínia mecânica comparados ao grupo controle, confirmando o estabelecimento de modelo de dor crônica. Também se observou discreto efeito antinociceptivo da dexametasona combinada com ETCC no modelo de artrite. O modelo de dor induziu um aumento no comportamento de grooming e reduziu os níveis de TNF-alfa no hipocampo; estes efeitos foram revertidos nos grupos sham- e ETCC ativo. Entretanto, não foram observados efeitos da DEX ou ETCC nos níveis de BDNF no córtex cerebral ou no tronco encefálico. CONCLUSÃO: Apesar dos discretos efeitos observados, não se pode descartar a ETCC como uma abordagem terapêutica não farmacológica para o manejo da dor crônica inflamatória na artrite reumatoide.

Indomethacin attenuates mechanical allodynia during the organization but not the maintenance of the peripheral neuropathic pain induced by nervus ischiadicus chronic constriction injury

The neurochemical mechanisms underlying neuropathic pain (NP) are related to peripheral and central sensitization caused by the release of inflammatory mediators in the peripheral damaged tissue and ectopic discharges from the injured nerve, leading to a hyperexcitable state of spinal dorsal horn neurons. The aim of this work was to clarify the role played by cyclooxygenase (COX) in the lesioned peripheral nerve in the development and maintenance of NP by evaluating at which moment the non-steroidal anti-inflammatory drug indomethacin, a non-selective COX inhibitor, attenuated mechanical allodynia after placing one loose ligature around the nervus ischiadicus, an adaptation of Bennett and Xie's model in rodents. NP was induced in male Wistar rats by subjecting them to chronic constriction injury (CCI) of the nervus ischiadicus, placing one loose ligature around the peripheral nerve, and a sham surgery (without CCI) was used as control. Indomethacin (2 mg/kg) or vehicle was intraperitoneally and acutely administered in each group of rats and at different time windows (1, 2, 4, 7, 14, 21, and 28 days) after the CCI or sham surgical procedures, followed by von Frey's test for 30 min. The data showed that indomethacin decreased the mechanical allodynia threshold of rats on the first, second, and fourth days after CCI (P<0.05). These findings suggested that inflammatory mechanisms are involved in the induction of NP and that COX-1 and COX-2 are involved in the induction but not in the maintenance of NP.

Spinal P2X7R contributes to streptozotocin-induced mechanical allodynia in mice / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Painful diabetic neuropathy (PDN) is a diabetes mellitus complication. Unfortunately, the mechanisms underlying PDN are still poorly understood. Adenosine triphosphate (ATP)-gated P2X7 receptor (P2X7R) plays a pivotal role in non-diabetic neuropathic pain, but little is known about its effects on streptozotocin (STZ)-induced peripheral neuropathy. Here, we explored whether spinal cord P2X7R was correlated with the generation of mechanical allodynia (MA) in STZ-induced type 1 diabetic neuropathy in mice. MA was assessed by measuring paw withdrawal thresholds and western blotting. Immunohistochemistry was applied to analyze the protein expression levels and localization of P2X7R. STZ-induced mice expressed increased P2X7R in the dorsal horn of the lumbar spinal cord during MA. Mice injected intrathecally with a selective antagonist of P2X7R and P2X7R knockout (KO) mice both presented attenuated progression of MA. Double-immunofluorescent labeling demonstrated that P2X7R-positive cells were mostly co-expressed with Iba1 (a microglia marker). Our results suggest that P2X7R plays an important role in the development of MA and could be used as a cellular target for treating PDN.

Research progress on the role and mechanism of Wnt signaling pathway in neuropathic pain / 药学学报

Neuropathic pain (NP), as a kind of chronic pain syndrome, seriously endangers the quality of life of patients, and the pathogenesis is complex, clinical treatment is limited, and it is easy to relapse. More and more reports have found that Wnt signaling pathway is closely related to the occurrence and development of neuropathic pain. Therefore, further study of the Wnt signaling pathway may provide useful ideas for exploring the pathogenesis of NP and discovering effective treatment methods. This article reviews the role and mechanism of Wnt signaling pathway in neuropathic pain.

Botulinum toxin treatment for intractable allodynia in a patient with complex regional pain syndrome: A case report

@#The right hand of a 58-year-old female was compressed by a compression machine and subsequently began to show pain. She was diagnosed with complex regional pain syndrome type 2 according to the Budapest criteria. Conventional therapy was ineffective for her allodynia. After subcutaneous injection of botulinum toxin, the subject’s allodynia substantially improved. Subcutaneous injection of botulinum toxin could effectively treat patients with complex regional pain syndrome and intractable allodynia. Clinical studies with larger sample sizes are needed to evaluate the efficacy of and selection of patients for botulinum toxin treatment of complex regional pain syndrome.

Kir2.1 Channel Regulation of Glycinergic Transmission Selectively Contributes to Dynamic Mechanical Allodynia in a Mouse Model of Spared Nerve Injury / 神经科学通报·英文版

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABA receptor antagonist, induced only punctate, but not dynamic, allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents (gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration or acute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively. In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.

Glial Cell Line-derived Neurotrophic Factor-overexpressing Human Neural Stem/Progenitor Cells Enhance Therapeutic Efficiency in Rat with Traumatic Spinal Cord Injury

Spinal cord injury (SCI) causes axonal damage and demyelination, neural cell death, and comprehensive tissue loss, resulting in devastating neurological dysfunction. Neural stem/progenitor cell (NSPCs) transplantation provides therapeutic benefits for neural repair in SCI, and glial cell line-derived neurotrophic factor (GDNF) has been uncovered to have capability of stimulating axonal regeneration and remyelination after SCI. In this study, to evaluate whether GDNF would augment therapeutic effects of NSPCs for SCI, GDNF-encoding or mock adenoviral vector-transduced human NSPCs (GDNF-or Mock-hNSPCs) were transplanted into the injured thoracic spinal cords of rats at 7 days after SCI. Grafted GDNF-hNSPCs showed robust engraftment, long-term survival, an extensive distribution, and increased differentiation into neurons and oligodendroglial cells. Compared with Mock-hNSPC- and vehicle-injected groups, transplantation of GDNF-hNSPCs significantly reduced lesion volume and glial scar formation, promoted neurite outgrowth, axonal regeneration and myelination, increased Schwann cell migration that contributed to the myelin repair, and improved locomotor recovery. In addition, tract tracing demonstrated that transplantation of GDNF-hNSPCs reduced significantly axonal dieback of the dorsal corticospinal tract (dCST), and increased the levels of dCST collaterals, propriospinal neurons (PSNs), and contacts between dCST collaterals and PSNs in the cervical enlargement over that of the controls. Finally grafted GDNF-hNSPCs substantially reversed the increased expression of voltage-gated sodium channels and neuropeptide Y, and elevated expression of GABA in the injured spinal cord, which are involved in the attenuation of neuropathic pain after SCI. These findings suggest that implantation of GDNF-hNSPCs enhances therapeutic efficiency of hNSPCs-based cell therapy for SCI.

Dolor En Síndrome De Guillain Barré: Una Manifestación Subestimada / Pain In Guillain Barré Syndrome: An Underestimated Manifestation

RESUMEN El Síndrome de Guillain-Barré es una polineuropatía desmielinizante aguda que se presenta clínicamente con debilidad muscular y trastornos autonómicos de forma típica, mientras que los síntomas sensitivos suelen pasar desapercibidos. Se describe la historia clínica de un paciente masculino con cuadriparesia fláccida aguda y trastornos sensitivos tipo parestesias y alodinia que dificultaron el diagnóstico durante su abordaje inicial. Luego del abordaje diagnóstico completo se confirmó la presencia del Síndrome de Guillain-Barré. Pese a que los síntomas sensitivos dificultaron el diagnóstico durante el ingreso, es importante destacar que el dolor es una manifestación frecuente de este trastorno, siendo subestimado en numerosos pacientes.

ABSTRACT Guillain-Barré syndrome is an acute demyelinating polyneuropathy that presents clinically with muscular weakness and autonomic disorders in its typical form, while the sensory symptoms usually go unnoticed. We describe the clinical history of a male patient with acute flaccid quadriparesis and sensory disorders such as paresthesia and allodynia that hinder diagnosis within the initial approach. Complete diagnostic work up confirmed the presence of Guillain-Barré syndrome. Although the sensory symptoms confused the diagnosis during admission, it is important to highlight that pain is a frequent manifestation of this disorder, being underestimated in many patients.

Cold Allodynia after C2 Root Resection in Sprague-Dawley Rats

OBJECTIVE: The purpose of this study was to evaluate pain-related behaviors after bilateral C2 root resection and change in pain patterns in the suboccipital region in rats.METHODS: Male Sprague-Dawley rats were randomly assigned to three groups (n=25/group); näive, sham, and C2 resection. Three, 7, 10, and 14 days after surgery, cold allodynia was assessed using 20 μL of 99.7% acetone. c-Fos and c-Jun were immunohistochemically stained to evaluate activation of dorsal horn gray matter in C2 segments of the spinal cord 2 hours, 1 day, 7 days, and 14 days after surgery.RESULTS: Three days after surgery, the response to acetone in the sham group was significantly greater than in the näive group, and this significant difference between the näive and sham groups was maintained throughout the experimental period (p < 0.05 at 3, 7, 10, and 14 days). Seven, 10, and 14 days after surgery, the C2 root resection group exhibited a significantly greater response to acetone than the näive group (p < 0.05), and both the sham and C2 resection groups exhibited significantly greater responses to acetone compared with 3 days after surgery. No significant difference in cold allodynia was observed between the sham and C2 root resection groups throughout the experimental period. Two hours after surgery, both the sham and C2 root resection groups exhibited significant increases in c-Fos- and c-Jun-positive neurons compared with the naive group (p=0.0021 and p=0.0358 for the sham group, and p=0.0135 and p=0.014 for the C2 root resection group, respectively). One day after surgery, both the sham and C2 root resection groups exhibited significant decreases in c-Fos -positive neurons compared with two hours after surgery (p=0.0169 and p=0.0123, respectively), and these significant decreases in c-Fos immunoreactivity were maintained in both the sham and C2 root resection groups 7 and 14 days after surgery. The sham and C2 root resection groups presented a tendency toward a decrease in c-Jun-positive neurons 1, 7, and 14 days after surgery, but the decrease did not reach statistical significance.CONCLUSION: We found no significant difference in cold allodynia and the early expression of c-Fos and c-Jun between the sham and C2 resection groups. Our results may support the routine resection of the C2 nerve root for posterior C1–2 fusion, but, further studies are needed.

Effect of exchange protein directly activated by cyclic adenosine monophosphate 1 on mechanical pain of diabetic rats / 中华内分泌代谢杂志

Objective To investigate effect of exchange protein directly activated by cyclic adenosine monophosphate 1 on mechanical pain in diabetic rats.Methods Male SD rats were randomly divided into CON group and STZ group. CON group were further randomly divided into CONshRNA group,and CONEpac1shRNA group. STZ group induced diabetic mechanical pain (DMA) model were randomly divided into DMA shRNA group, DMA Epac1shRNA group,DMANS group,and DMA 8-pCPT group. The Epac1shRNA lentivirus vector is used to inhibit the expression of Epac1, and the shRNA lentivirus vector is negative control, and 8-pCPT is the activator of Epac1. Group CONshRNA and group DMAshRNA were given intrathecal injection of control shRNA lentivirus vector. Group CONEpac1shRNA and group DMAEpac1shRNA were injected with Epac1shRNA lentivirus carrier, DMANS group was injected into the plantar saline,and 8-pCPT in group DMA8-pCPT was injected into the foot. The changes of hind paw retraction threshold(PWT) were observed and the expression of guanine nucleotide transforming factor 1(Epac1) mRNA was detected by Real Time-PCR and Western blot in rat dorsal root ganglion(DRG) And protein expression changes.Results Compared with CON rats,the mechanical pain threshold of STZ rats decreased (P=0.035). Compared with saline group,the pain of injection Epac1 activator 8-pCPT group was prolonged(2h, P=0.012;4h,P=0.020). The expression of Epac1 mRNA and protein was significantly higher in the DMA group than in the CON group(both P<0.01). Intrathecal injection of shRNA reduced the expression of Epac1 mRNA and protein(P<0.01,P=0.020),and the PWT of the DMA group was significantly lower than that of the CON group (P=0.006).Conclusion Epac1 expression in diabetic rats with increased pain,and down-regulation of Epac1 may relieve pain.

Cold Allodynia after C2 Root Resection in Sprague-Dawley Rats

OBJECTIVE: The purpose of this study was to evaluate pain-related behaviors after bilateral C2 root resection and change in pain patterns in the suboccipital region in rats. METHODS: Male Sprague-Dawley rats were randomly assigned to three groups (n=25/group); näive, sham, and C2 resection. Three, 7, 10, and 14 days after surgery, cold allodynia was assessed using 20 μL of 99.7% acetone. c-Fos and c-Jun were immunohistochemically stained to evaluate activation of dorsal horn gray matter in C2 segments of the spinal cord 2 hours, 1 day, 7 days, and 14 days after surgery.

Application of three artemisinin derivatives in neuropathic pain: evaluating co-curation of nociceptive and emotional syndromes in spinal cord ligation mice / 中国中药杂志

In this study, on aspects of the nociceptive, anxiety and depressive syndromes in neuropathic pain (NP), the effects of dihydroartemisinine (DHA), artesunate (ART) and artemether (ARTN) (40 mg·kg⁻¹) were analyzed in the spinal cord ligation (SNL) mice. Clinical equivalent dose of the first-line drug for NP, pregabalin (PGB, 25 mg·kg⁻¹) and amitriptyline (ARP, 20 mg·kg⁻¹), were used as positive controls. General, from day 7 to 14, significant remissions of the nociceptive, anxiety and depressive behaviors were achieved by DHA, ART and ARTN separately. Moreover, on day 14, on aspects of the nociceptive behaviors, analyzed 1.5 h after the gavage administration, no significant difference between the shamed mice and mice administrated with DHA, ART and ARTN was detected; analyzed 3 h after the gavage, significant decreases of pain thresholds in ARTN, but not in DHA nor ART group, were detected as compared with thresholds measured 1.5 h; analyzed 24 h after gavage, pain thresholds in DHA, ART and ARTN were still higher than PGB, in spite of the significant decreases as compared to Sham group. On aspects of the anxiety and depressive behaviors, no significant difference was detected between the shamed mice and mice administrated with DHA nor ART. However, differences still remained between the shamed ones and ones administrated with ARTN. Preliminarily, the effects of DHA, ART and ARTN were consolidated in SNL mice. On aspects of the duration of analgesic effects and the control of negative emotion, ART and ARTN were proven more favorable than ARTN.

Proteomic Analysis of the Hippocampus in Mouse Models of Trigeminal Neuralgia and Inescapable Shock-Induced Depression / 神经科学通报·英文版

To investigate the behavioral and biomolecular similarity between neuralgia and depression, a trigeminal neuralgia (TN) mouse model was established by constriction of the infraorbital nerve (CION) to mimic clinical trigeminal neuropathic pain. A mouse learned helplessness (LH) model was developed to investigate inescapable foot-shock-induced psychiatric disorders like depression in humans. Mass spectrometry was used to assess changes in the biomolecules and signaling pathways in the hippocampus from TN or LH mice. TN mice developed not only significant mechanical allodynia but also depressive-like behaviors (mainly behavioral despair) at 2 weeks after CION, similar to LH mice. MS analysis demonstrated common and distinctive protein changes in the hippocampus between groups. Many protein function families (such as cell-to-cell signaling and interaction, and cell assembly and organization,) and signaling pathways (e.g., the Huntington's disease pathway) were involved in chronic neuralgia and depression. Together, these results demonstrated that the LH and TN models both develop depressive-like behaviors, and revealed the involvement of many psychiatric disorder-related biomolecules/pathways in the pathogenesis of TN and LH.

Involvement of NF-κB and the CX3CR1 Signaling Network in Mechanical Allodynia Induced by Tetanic Sciatic Stimulation / 神经科学通报·英文版

Tetanic stimulation of the sciatic nerve (TSS) triggers long-term potentiation in the dorsal horn of the spinal cord and long-lasting pain hypersensitivity. CX3CL1-CX3CR1 signaling is an important pathway in neuronal-microglial activation. Nuclear factor κB (NF-κB) is a key signal transduction molecule that regulates neuroinflammation and neuropathic pain. Here, we set out to determine whether and how NF-κB and CX3CR1 are involved in the mechanism underlying the pathological changes induced by TSS. After unilateral TSS, significant bilateral mechanical allodynia was induced, as assessed by the von Frey test. The expression of phosphorylated NF-κB (pNF-κB) and CX3CR1 was significantly up-regulated in the bilateral dorsal horn. Immunofluorescence staining demonstrated that pNF-κB and NeuN co-existed, implying that the NF-κB pathway is predominantly activated in neurons following TSS. Administration of either the NF-κB inhibitor ammonium pyrrolidine dithiocarbamate or a CX3CR1-neutralizing antibody blocked the development and maintenance of neuropathic pain. In addition, blockade of NF-κB down-regulated the expression of CX3CL1-CX3CR1 signaling, and conversely the CX3CR1-neutralizing antibody also down-regulated pNF-κB. These findings suggest an involvement of NF-κB and the CX3CR1 signaling network in the development and maintenance of TSS-induced mechanical allodynia. Our work suggests the potential clinical application of NF-κB inhibitors or CX3CR1-neutralizing antibodies in treating pathological pain.

Regulation of Pain and Itch by TRP Channels / 神经科学通报·英文版

Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily (TRPV1, TRPV3, and TRPV4), and finally members of the melastatin group (TRPM2, TRPM3, and TRPM8). Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory compounds targeting specific pain/itch-TRPs so that physiological protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1-modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accomplished via simple dosing strategies, and also by incorporating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.

Allopregnanolone suppresses mechanical allodynia and internalization of neurokinin-1 receptors at the spinal dorsal horn in a rat postoperative pain model

BACKGROUND: To identify a new strategy for postoperative pain management, we investigated the analgesic effects of allopregnanolone (Allo) in an incisional pain model, and also assessed its effects on the activities of the primary afferent fibers at the dorsal horn. METHODS: In experiment 1, 45 rats were assigned to Control, Allo small-dose (0.16 mg/kg), and Allo large-dose (1.6 mg/kg) groups (n = 15 in each). The weight bearing and mechanical withdrawal thresholds of the hind limb were measured before and at 2, 24, 48, and 168 h after Brennan's surgery. In experiment 2, 16 rats were assigned to Control and Allo (0.16 mg/kg) groups (n = 8 in each). The degree of spontaneous pain was measured using the grimace scale after the surgery. Activities of the primary afferent fibers in the spinal cord (L6) were evaluated using immunohistochemical staining. RESULTS: In experiment 1, the withdrawal threshold of the Allo small-dose group was significantly higher than that of the Control group at 2 h after surgery. Intergroup differences in weight bearing were not significant. In experiment 2, intergroup differences in the grimace scale scores were not significant. Substance P release in the Allo (0.16 mg/kg) group was significantly lower than that in the Control group. CONCLUSIONS: Systemic administration of Allo inhibited mechanical allodynia and activities of the primary afferent fibers at the dorsal horn in a rat postoperative pain model. Allo was proposed as a candidate for postoperative pain management.