Electroacupuncture attenuates neuropathic pain via suppressing BIP-IRE-1α-mediated endoplasmic reticulum stress in the anterior cingulate cortex.

Studies have suggested that endoplasmic reticulum stress (ERS) is involved in neurological dysfunction and that electroacupuncture (EA) attenuates neuropathic pain (NP) via undefined pathways. However, the role of ERS in the anterior cingulate cortex (ACC) in NP and the effect of EA on ERS in the ACC have not yet been investigated. In this study, an NP model was established by chronic constriction injury (CCI) of the left sciatic nerve in rats, and mechanical and cold tests were used to evaluate behavioral hyperalgesia. The protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that glucose-regulated protein 78 (BIP) and inositol-requiring enzyme 1α (IRE-1α) were co-localized in neurons in the ACC. After CCI, BIP, IRE-1α, and phosphorylation of IRE-1α were upregulated in the ACC. Intra-ACC administration of 4-PBA and Kira-6 attenuated pain hypersensitivity and downregulated phosphorylation of IRE-1α, while intraperitoneal injection of 4-PBA attenuated hyperalgesia and inhibited the activation of P38 and JNK in ACC. In contrast, ERS activation by intraperitoneal injection of tunicamycin induced behavioral hyperalgesia in naive rats. Furthermore, EA attenuated pain hypersensitivity and inhibited the CCI-induced overexpression of BIP and pIRE-1α. Taken together, these results demonstrate that EA attenuates NP by suppressing BIP- and IRE-1α-mediated ERS in the ACC. Our study presents novel evidence that ERS in the ACC is implicated in the development of NP and provides insights into the molecular mechanisms involved in the analgesic effect of EA.

The deep and the deeper: Spinal cord and deep brain stimulation for neuropathic pain.

Neuropathic pain occurs in people experiencing lesion or disease affecting the somatosensorial system. It is present in 7 % of the general population and may not fully respond to first- and second-line treatments in up to 40 % of cases. Neuromodulation approaches are often proposed for those not tolerating or not responding to usual pharmacological management. These approaches can be delivered surgically (invasively) or non-invasively. Invasive neuromodulation techniques were the first to be employed in neuropathic pain. Among them is spinal cord stimulation (SCS), which consists of the implantation of epidural electrodes over the spinal cord. It is recommended in some guidelines for peripheral neuropathic pain. While recent studies have called into question its efficacy, others have provided promising data, driven by advances in techniques, battery capabilities, programming algorithms and software developments. Deep brain stimulation (DBS) is another well-stablished neuromodulation therapy routinely used for movement disorders; however, its role in pain management remains limited to specific research centers. This is not only due to variable results in the literature contesting its efficacy, but also because several different brain targets have been explored in small trials, compromising comparisons between these studies. Structures such as the periaqueductal grey, posterior thalamus, anterior cingulate cortex, ventral striatum/anterior limb of the internal capsule and the insula are the main targets described to date in literature. SCS and DBS present diverse rationales for use, mechanistic backgrounds, and varying levels of support from experimental studies. The present review aims to present their methodological details, main mechanisms of action for analgesia and their place in the current body of evidence in the management of patients with neuropathic pain, as well their particularities, effectiveness, safety and limitations.

Motor cortical stimulation for the treatment of trigeminal neuropathic pain secondary to an arteriovenous malformation. A case report.

INTRODUCTION: Trigeminal neuropathic pain (TNP) is a syndrome of severe, disabling, constant facial pain arising from the trigeminal nerve or ganglion. Arteriovenous malformations (AVM) are a rare cause of TNP. The limited choices of intervention of TNP include peripheral nerve stimulation, trigeminal nucleotomy and motor cortex stimulation. CASE REPORT: We present a 56-year-old man who suffered from trigeminal neuropathic pain secondary to nerve compression due to a giant posterior fossa AVM. The pain was refractory to drug treatment. From all the therapeutic options available we declined the microvascular decompression of the trigeminal nerve due to the presence of the giant AVM, or stereotactic radiosurgery because of the AVM´s diffuse nidus. After a multidisciplinary discussion we proposed a minimally invasive, safe and reversible treatment: Motor Cortical Stimulation (MCS). We placed a 16-pole epidural electrode on the right precentral gyrus. The patient had satisfactory pain control with some supplemental medication. No complications or side effects such as seizures, sensory disturbances or infections were presented. DISCUSSION: The limited choices of intervention of TNP include peripheral nerve stimulation, trigeminal nucleotomy and MCS. Henssen et al performed a systematic review where they investigated the effectiveness of MCS and discovered that this is significantly different among different chronic neuropathic orofacial pain disorders. A visual analogue scale (VAS) measured median pain relief of 66.5% was found. CONCLUSION: MCS should be one more tool to consider in highly selected cases, when other treatments are unfeasible.

Introducción: El dolor neuropático trigeminal (DNT) es un síndrome de dolor facial intenso, incapacitante y constante que surge del nervio o ganglio del trigémino. Las malformaciones arteriovenosas (MAV) son una causa rara de DNT. Las opciones terapéuticas de DNT incluyen la estimulación de los nervios periféricos, la nucleotomía del trigémino y la estimulación cortical motora. Caso clínico: Presentamos el caso de un varón de 56 años con dolor neuropático trigeminal secundario a compresión nerviosa por una MAV gigante de fosa posterior. El dolor era refractario al tratamiento farmacológico. De todas las opciones terapéuticas disponibles, desestimamos la descompresión microvascular del nervio trigémino por la presencia de la MAV gigante, o la radiocirugía estereotáctica, por ser difuso el nido de la MAV. Tras una discusión multidisciplinar propusimos un tratamiento mínimamente invasivo, seguro y reversible: Estimulación cortical motora (ECM). Colocamos un electrodo epidural en el giro precentral derecho. El paciente tuvo un control satisfactorio del dolor con medicación suplementaria. No presentó complicaciones ni efectos secundarios como convulsiones, alteraciones sensoriales o infecciones. Discusión: Las opciones limitadas de intervención de DNT incluyen estimulación nerviosa periférica, nucleotomía trigeminal y ECM. Henssen et al realizaron una revisión sistemática donde investigaron la efectividad de MCS y descubrieron que esto es significativamente diferente entre los diferentes trastornos de dolor orofacial neuropático crónico. Se encontró un promedio de alivio del dolor medida por una escala analógica visual del 66,5%. Conclusión: La ECM debería ser una herramienta más a considerar en casos estrictamente seleccionados donde otros tratamientos no son viables.

Effect of electrical and chemical (activation versus inactivation) stimulation of the infralimbic division of the medial prefrontal cortex in rats with chronic neuropathic pain.

Neuropathic pain (NP) represents a complex disorder with sensory, cognitive, and emotional symptoms. The medial prefrontal cortex (mPFC) takes critical regulatory roles and may change functionally and morphologically during chronic NP. There needs to be a complete understanding of the neurophysiological and psychopharmacological bases of the NP phenomenon. This study aimed to investigate the participation of the infralimbic division (IFL) of the mPFC in chronic NP, as well as the role of the N-methyl-D-aspartic acid receptor (NMDAr) in the elaboration of chronic NP. Male Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve or Sham-procedure ("false operated"). Electrical neurostimulation of the IFL/mPFC was performed by low-frequency stimuli (20 µA, 100 Hz) applied for 15 s by deep brain stimulation (DBS) device 21 days after CCI. Either cobalt chloride (CoCl2 at 1.0 mM/200 nL), NMDAr agonist (at 0.25, 1.0, and 2.0 nmol/200 nL) or physiological saline (200 nL) was administered into the IFL/mPFC. CoCl2 administration in the IFL cortex did not alter either mechanical or cold allodynia. DBS stimulation of the IFL cortex decreased mechanical allodynia in CCI rats. Chemical stimulation of the IFL cortex by an NMDA agonist (at 2.0 nmol) decreased mechanical allodynia. NMDA at any dose (0.25, 1.0, and 2.0 nmol) reduced the flicking/licking duration in the cold test. These findings suggest that the IFL/mPFC and the NMDAr of the neocortex are involved in attenuating chronic NP in rats.

The glossopharyngeal nerve (IX cranial nerve pair): anatomical considerations and neuralgia: literature review / O nervo glossofaringeo (IX par de nervo craniano): considerações anatômicas e neuralgia: revisão da literatura

The glossopharyngeal nerve (IX cranial nerve) is a mixed nerve, with both motor and sensory function. This relates to the tongue and pharynx. Glossopharyngeal neuralgia is a rare nervous neuropathy, with poristic, lancinating and paritary crises, usually unilateral. The aim of the study was to review the literature on glossopharyngeal neuralgia of the nerve (IX cranial nerve), highlighting the anatomical aspects of this nerve and the possible causes and complications of neuralgia as well as forms of treatment. A literature review was carried out in the international Pubmed database. The literature review included 72 articles from 2015 to 2021. The keywords used were: "anatomy of glossopharyngeal neuralgia". Of the 72 articles, 7 were used for this literature review. Uncommon as nervous/glossophingeal etiologies and pathologies are neurological abnormalities/neurovarises and pathologies are neurovascular/neurovariseal lesions. Pharmacological treatment approaches mentioned in the literature were therapy with antiepileptics and antidepressants such as carbamazepine and gabapentin; a microvascular decompression; and gamma knife radiosurgery(AU)

O nervo glossofaríngeo (IX par de nervo craniano) é um nervo misto, contendo função tanto motora como sensitiva. Este nervo relaciona-se com a língua e com a faringe. A neuralgia do nervo glossofaríngeo é uma neurapatia rara, sendo caracterizada por crises dolorosas, lancinantes e paroxísticas, geralmente unilaterais. O objetivo do estudo foi realizar uma revisão de literatura sobre a neuralgia do nervo glossofaríngeo (IX par de nervo craniano), destacando os aspectos anatômicos deste nervo e as possíveis causas e complicações da neuralgia bem como formas de tratamento. Foi realizada uma revisão da literatura na base de dados internacional Pubmed. A revisão da literatura incluiu 72 artigos no período de 2015 a 2021. As palavras-chave utilizadas foram: "anatomia da neuralgia do glossofaríngeo". Dos 72 artigos, 7 foram utilizados para esta revisão de literatura. Verificouse que a neuralgia do nervo glossofaríngeo é incomum e as etiologias mais encontradas foram compressão neurovascular/variações vasculares, patologias e traumas. As abordagens dos tratamentos mencionadas na literatura foram a terapia farmacológica da área com antiepilépticos e antidepressivos, como carbamazepina e gabapentina; a descompressão microvascular; e radiocirurgia com faca gama(AU)

Evolving techniques for reducing phantom limb pain.

At least two million people in the United States of America live with lost limbs, and the number is expected to double by 2050, although the incidence of amputations is significantly greater in other parts of the world. Within days to weeks of the amputation, up to 90% of these individuals develop neuropathic pain, presenting as phantom limb pain (PLP). The pain level increases significantly within one year and remains chronic and severe for about 10%. Amputation-induced changes are considered to underlie the causation of PLP. Techniques applied to the central nervous system (CNS) and peripheral nervous system (PNS) are designed to reverse amputation-induced changes, thereby reducing/eliminating PLP. The primary treatment for PLP is the administration of pharmacological agents, some of which are considered but provide no more than short-term pain relief. Alternative techniques are also discussed, which provide only short-term pain relief. Changes induced by various cells and the factors they release are required to change neurons and their environment to reduce/eliminate PLP. It is concluded that novel techniques that utilize autologous platelet-rich plasma (PRP) may provide long-term PLP reduction/elimination.

Electroacupuncture inhibits dendritic spine remodeling through the srGAP3-Rac1 signaling pathway in rats with SNL.

Previous studies have shown that peripheral nerve injury can lead to abnormal dendritic spine remodeling in spinal dorsal horn neurons. Inhibition of abnormal dendritic spine remodeling can relieve neuropathic pain. Electroacupuncture (EA) has a beneficial effect on the treatment of neuropathic pain, but the specific mechanism remains unclear. Evidence has shown that slit-robo GTPase activating protein 3 (srGAP3) and Rho GTPase (Rac1) play very important roles in dendritic spine remodeling. Here, we used srGAP3 siRNA and Rac1 activator CN04 to confirm the relationship between SrGAP3 and Rac1 and their roles in improving neuropathic pain with EA. Spinal nerve ligation (SNL) was used as the experimental model, and thermal withdrawal latency (TWL), mechanical withdrawal threshold (MWT), Western blotting, immunohistochemistry and Golgi-Cox staining were used to examine changes in behavioral performance, protein expression and dendritic spines. More dendritic spines and higher expression levels of srGAP3 were found in the initial phase of neuropathic pain. During the maintenance phase, dendritic spines were more mature, which was consistent with lower expression levels of srGAP3 and higher expression levels of Rac1-GTP. EA during the maintenance phase reduced the density and maturity of dendritic spines of rats with SNL, increased the levels of srGAP3 and reduced the levels of Rac1-GTP, while srGAP3 siRNA and CN04 reversed the therapeutic effects of EA. These results suggest that dendritic spines have different manifestations in different stages of neuropathic pain and that EA may inhibit the abnormal dendritic spine remodeling by regulating the srGAP3/Rac1 signaling pathway to alleviate neuropathic pain.

Systemic and Peripheral Mechanisms of Cortical Stimulation-Induced Analgesia and Refractoriness in a Rat Model of Neuropathic Pain.

Epidural motor cortex stimulation (MCS) is an effective treatment for refractory neuropathic pain; however, some individuals are unresponsive. In this study, we correlated the effectiveness of MCS and refractoriness with the expression of cytokines, neurotrophins, and nociceptive mediators in the dorsal root ganglion (DRG), sciatic nerve, and plasma of rats with sciatic neuropathy. MCS inhibited hyperalgesia and allodynia in two-thirds of the animals (responsive group), and one-third did not respond (refractory group). Chronic constriction injury (CCI) increased IL-1ß in the nerve and DRG, inhibited IL-4, IL-10, and IL-17A in the nerve, decreased ß-endorphin, and enhanced substance P in the plasma, compared to the control. Responsive animals showed decreased NGF and increased IL-6 in the nerve, accompanied by restoration of local IL-10 and IL-17A and systemic ß-endorphin. Refractory animals showed increased TNF-α and decreased IFNγ in the nerve, along with decreased TNF-α and IL-17A in the DRG, maintaining low levels of systemic ß-endorphin. Our findings suggest that the effectiveness of MCS depends on local control of inflammatory and neurotrophic changes, accompanied by recovery of the opioidergic system observed in neuropathic conditions. So, understanding the refractoriness to MCS may guide an improvement in the efficacy of the technique, thus benefiting patients with persistent neuropathic pain.

Transcranial direct current stimulation effects in the pain threshold and in oxidative stress parameters of neuropathic pain rats.

Transcranial direct current stimulation (tDCS) can modulate cortical excitability and relieve neuropathic pain (NP), but the role of several biomarkers in this process is not well understood. This study aimed to analyze the effects of tDCS on biochemical parameters in rats with neuropathic pain (NP) induced by chronic constriction injury (CCI) of the right sciatic nerve. Eighty-eight male 60-day-old Wistar rats were divided into nine groups: control (C), control-electrode off (CEoff), control-tDCS (C-tDCS), sham-lesion (SL), sham-lesion electrode off (SLEoff), sham-lesion (SL-tDCS), lesion (L), lesion electrode off (LEoff), and lesion-tDCS (L-tDCS). After NP establishment, 20-minute bimodal tDCS for 8 consecutive days was applied to the rats. Fourteen days after the induction of NP, rats developed mechanical hyperalgesia with a decreased threshold, and at the end of treatment, an increase in the pain threshold was observed in NP rats. In addition, NP rats had increased levels of reactive species (RS) in the prefrontal cortex, while superoxide dismutase (SOD) activity was decreased in NP rats. In the spinal cord, nitrite levels and glutathione-S-transferase (GST) activity decreased in the L-tDCS group, and it was observed that increased levels in total sulfhydryl content for neuropathic pain rats were reversed by tDCS. In serum analyses, the neuropathic pain model increased the levels of RS and thiobarbituric acid-reactive substances (TBARS) and decreased the activity of butyrylcholinesterase (BuChE). In conclusion, bimodal tDCS increased total sulfhydryl content in the spinal cord of rats with neuropathic pain, positively modulating this parameter.

Electroacupuncture inhibits dendritic spine remodeling through the srGAP3-Rac1 signaling pathway in rats with SNL

Previous studies have shown that peripheral nerve injury can lead to abnormal dendritic spine remodeling in spinal dorsal horn neurons. Inhibition of abnormal dendritic spine remodeling can relieve neuropathic pain. Electroacupuncture (EA) has a beneficial effect on the treatment of neuropathic pain, but the specific mechanism remains unclear. Evidence has shown that slit-robo GTPase activating protein 3 (srGAP3) and Rho GTPase (Rac1) play very important roles in dendritic spine remodeling. Here, we used srGAP3 siRNA and Rac1 activator CN04 to confirm the relationship between SrGAP3 and Rac1 and their roles in improving neuropathic pain with EA. Spinal nerve ligation (SNL) was used as the experimental model, and thermal withdrawal latency (TWL), mechanical withdrawal threshold (MWT), Western blotting, immunohistochemistry and Golgi-Cox staining were used to examine changes in behavioral performance, protein expression and dendritic spines. More dendritic spines and higher expression levels of srGAP3 were found in the initial phase of neuropathic pain. During the maintenance phase, dendritic spines were more mature, which was consistent with lower expression levels of srGAP3 and higher expression levels of Rac1-GTP. EA during the maintenance phase reduced the density and maturity of dendritic spines of rats with SNL, increased the levels of srGAP3 and reduced the levels of Rac1-GTP, while srGAP3 siRNA and CN04 reversed the therapeutic effects of EA. These results suggest that dendritic spines have different manifestations in different stages of neuropathic pain and that EA may inhibit the abnormal dendritic spine remodeling by regulating the srGAP3/Rac1 signaling pathway to alleviate neuropathic pain.

New updates on transcranial magnetic stimulation in chronic pain.

PURPOSE OF REVIEW: Chronic pain is the most prevalent symptomatic disease worldwide. Nonpharmacological interventions, such as noninvasive neuromodulation (NIN), have gained scientific evidence to support their use as an add-on strategy to pharmacological pain management. The most studied NIN technique is repetitive transcranial magnetic stimulation (rTMS). This review aims to identify the current indications for rTMS in the treatment of chronic pain and its new perspectives. RECENT FINDINGS: High-frequency rTMS delivered to the primary motor cortex (M1) is currently a treatment strategy with the most literature support for decreased pain intensity and alleviation of associated symptoms in peripheral neuropathic pain, fibromyalgia and migraine. It has been shown that stimulation sessions are well tolerated and tolerable, and the effects of daily stimulation sessions can be prolonged by spaced maintenance stimulation sessions. Despite its efficacy, some individuals will not respond to rTMS targeted to M1. Lines of research are currently being developed to improve rTMS efficacy either by exploring new therapeutic targets, using novel stimulation parameters or more comprehensively profiling patients who are likely to respond to this treatment modality. SUMMARY: Noninvasive brain stimulation for chronic TMS pain is a well tolerated and reasonable add-on treatment approach for pain syndromes such as neuropathic pain, migraine and fibromyalgia. Strategies to improve its efficacy are an active field of research.

Analgesia with 5' extracellular nucleotidase-mediated electroacupuncture for neuropathic pain.

BACKGROUND: Acupuncture is a treatment for neuropathic pain, but its mechanism remains unclear. Previous studies showed that analgesia was induced in rats with neuropathic pain when their spinal cord adenosine content increased after electroacupuncture (EA); however, the mechanism behind this electroacupuncture-induced increase has not been clarified. OBJECTIVE: This study aimed to determine the role that ecto-5'-nucleotidase plays in EA-induced analgesia for neuropathic pain. METHODS: We performed electroacupuncture at the Zusanli acupoint on the seventh day after establishing a rat model of neuropathic pain induced through chronic constriction injuries. We observed the mechanical withdrawal threshold and thermal pain threshold and detected the expression of ecto-5'-nucleotidase in the spinal cord using Western blot. Chronic constriction injury rat models were intraperitoneally injected with α,ß-methyleneadenosine 5'-diphosphate, an ecto-5'-nucleotidase inhibitor, 30 min before electroacupuncture. The adenosine content of the spinal cord was detected using high-performance liquid chromatography. Lastly, the adenosine A1 receptor agonist N6-cyclopentyladenosine was intrathecally injected into the lumbar swelling of the rats, and the mechanical withdrawal and thermal pain thresholds were reevaluated. RESULTS: Analgesia and increased ecto-5'-nucleotidase expression and adenosine content in the spinal cord were observed 1 h after electroacupuncture. α,ß-methyleneadenosine 5'-diphosphate was able to inhibit upregulation of adenosine content and electroacupuncture-induced analgesia. After administration of N6-cyclopentyladenosine, electroacupuncture-induced analgesia was restored. CONCLUSIONS: Our results suggest that electroacupuncture at Zusanli can produce analgesia in chronic constriction injury rat models, possibly via the increased ecto-5'-nucleotidase expression induced through electroacupuncture, thus leading to increased adenosine expression in the spinal cord.

Non-invasive insular stimulation for peripheral neuropathic pain: Influence of target or symptom?

OBJECTIVES: The posterior-superior insula (PSI) has been shown to be a safe and potentially effective target for neuromodulation in peripheral neuropathic pain (PNP) in humans and animal models. However, it remains unknown whether there is a measurable responder profile to PSI stimulation. Two factors were hypothesized to influence the response of repetitive transcranial magnetic stimulation (rTMS) of the PSI: differences in rTMS target (discrete subregions of the PSI) or PNP phenotype. METHODS: This is a secondary analysis from a randomized, double-blind, sham-controlled, cross-over trial assessing PSI-rTMS in PNP (N = 31, 5 days rTMS) (10.1016/j.neucli.2021.06.003). Active PSI-rTMS true responders (>50% pain reduction from baseline after active but not after sham series of treatment) were compared with not true responders, to determine whether they differed with respect to 1) rTMS neuro-navigational target coordinates, and/or 2) specific neuropathic pain symptom inventory (NPSI) clusters (pinpointed pain, evoked pain, and deep pain) at baseline. RESULTS: Mean rTMS target coordinates did not differ between true (n = 45.1%) and not true responders (p = 0.436 for X, p = 0.120 for Y, and p = 0.116 for Z). The Euclidian distance between true and not true responders was 4.04 mm. When comparing differences in responders between NPSI clusters, no participant within the evoked pain cluster was a true responder (p = 0.024). CONCLUSION: Response to PSI-rTMS may depend on pain cluster subtype rather than on differences in targeting within the PSI.

Neural management plus advice to stay active on clinical measures and sciatic neurodynamic for patients with chronic sciatica: Study protocol for a controlled randomised clinical trial.

Advice to stay active is the primary management strategy for sciatica. Other conservative treatments such as neural management techniques may also contribute to sciatica recovery, but currently, the effects have not been robustly assessed. Thus, the aim of this study is to compare the effects of adding neural management to advice to stay active versus advice to stay active alone in improving pain intensity and functional limitation. Secondarily, to compare the effects of the experimental intervention in the sciatic neurodynamic, pain modulation, and psychosocial factors. A parallel-group, controlled, examiner-blinded superiority clinical trial randomised at a 1:1 allocation will be conducted in 210 participants with chronic sciatica. Patients will be recruited from outpatient physiotherapy clinics and community advertisements. The experimental group will receive neural mobilisation techniques and soft tissue mobilisation techniques for 30 minutes per session, 10 weekly sessions, plus advice to stay active on their activities of daily living, information on physical activity, imaging tests, and sciatica for 5 biweekly sessions lasting 25-30 minutes. The control group will receive advice to stay active only. The re-evaluation will be performed out after 5 weeks, 10 weeks, and 26 weeks after randomisation and primary endpoints will be pain intensity and functional limitation at 10 weeks. Secondary outcomes will include neuropathic symptoms, sciatic neurodynamic, pain modulation, and psychosocial factors. Adverse events and patient satisfaction will be assessed. Ethical approval has been granted from an Institutional Human Research Ethics Committee. Trial registration: Trial was prospectively registered in the Brazilian Registry of Clinical Trials (number: RBR-3db643c).

Infralimbic medial prefrontal cortex alters electroacupuncture effect in animals with neuropathic chronic pain.

INTRODUCTION: Morphological reorganization in the neural networks of the medial prefrontal cortex (mPFC) may be involved in the development of chronic neuropathic pain (NP). OBJECTIVES: We investigated whether inactivation and neurostimulation of the infralimbic division (IFL) of the mPFC alter electroacupuncture-induced analgesia (EIA) at 2 Hz and 2/100 Hz in animals with chronic NP. METHODS: Wistar rats were submitted to chronic constrictor injury of the ischiadicus nerve (CCI). Von Frey and acetone tests were performed to evaluate mechanical or cold allodynia. Animals were submitted to electroacupuncture (EA) at 2 Hz and 2/100 Hz for 20 min. After EA, the IFL cortex synaptic contacts were inactivated by cobalt chloride (200 nL of 1.0 mM CoCl2). Neurostimulation of the IFL cortex was also performed at 20 µA for 15 s, after EA, using a deep brain stimulation device. RESULTS: EA at 2 Hz and 2/100 Hz attenuated mechanical or cold allodynia in CCI rats. Microinjection of CoCl2 into the IFL division of the mPFC blocked the EA effect. EA at 2 Hz and 2/100 Hz, in association with neurostimulation of the IFL cortex, attenuated mechanical and thermal allodynia. CONCLUSION: EA induces antinociception in CCI rats. The analgesia was potentiated in association with neurostimulation in the IFL division of the mPFC.

Effects of rTMS and tDCS on neuropathic pain after brachial plexus injury: a randomized placebo-controlled pilot study.

Neuropathic pain after brachial plexus injury (NPBPI) is a highly disabling clinical condition and is increasingly prevalent due to increased motorcycle accidents. Currently, no randomized controlled trials have evaluated the effectiveness of non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS) in patients suffering from NPBPI. In this study, we directly compare the efficacy of 10-Hz rTMS and anodal 2 mA tDCS techniques applied over the motor cortex (5 daily consecutive sessions) in 20 patients with NPBPI, allocated into 2 parallel groups (active or sham). The order of the sessions was randomised for each of these treatment groups according to a crossover design and separated by a 30-day interval. Scores for "continuous" and "paroxysmal" pain (primary outcome) were tabulated after the last stimulation day and 30 days after. Secondary outcomes included the improvement in multidimensional aspects of pain, anxiety state and quality of life from a qualitative and quantitative approach. Active rTMS and tDCS were both superior to sham in reducing continuous (p < 0.001) and paroxysmal (p = 0.002; p = 0.02) pain as well as in multidimensional aspects of pain (p = 0.001; p = 0.002) and anxiety state (p = < 0.001; p = 0.005). Our results suggest rTMS and tDCS are able to treat NPBPI with little distinction in pain and anxiety state, which may promote the use of tDCS in brachial plexus injury pain management, as it constitutes an easier and more available technique.Clinical Trial Registration: http://www.ensaiosclinicos.gov.br/, RBR-5xnjbc - Sep 3, 2018.

Comparative effect of dense-and-disperse versus non-repetitive and non-sequential frequencies in electroacupuncture-induced analgesia in a rodent model of peripheral neuropathic pain.

BACKGROUND: Neuropathic pain (NP) is a complex disease that remains challenging to treat. Low-frequency dense-and-disperse (DD) electroacupuncture (EA) has been used as adjuvant therapy for neuropathic pain; however, its analgesic effect decreases as stimulation time increases, or when it is repeatedly used. We hypothesized that a new frequency parameter could improve the effectiveness of EA, and aimed to compare the efficacy and duration of the analgesic effect between classic DD-EA and non-repetitive and non-sequential frequency (random frequency (RF)-EA) in neuropathic rats. Furthermore, the effect of RF-EA at local traditional acupuncture point locations versus auricular vagus nerve stimulation (aVNS) was evaluated. METHODS: Male Wistar rats with peripheral neuropathy were subjected to a single session of DD-EA or RF-EA for 20 or 40 min at ST36 + GB34. An additional group of rats was treated with RF-EA for 20 min using aVNS at the appropriate ear point locations. Paw pressure test, von Frey filaments and spontaneous pain scores were evaluated. Sham-operated rats were used as controls. RESULTS: In all, 20 min of RF-EA reversed hyperalgesia (for 24 h) and allodynia (for 8 h), showing a longer analgesic effect than DD-EA. Both RF-EA and DD-EA induced partial inhibition of spontaneous pain for 8 h. Forty minutes of DD-EA did not interfere with the NP phenomena; however, RF-EA induced significant long-term analgesia. aVNS induced an analgesic effect similar to local stimulation. CONCLUSION: This pilot study shows that RF-EA at both local traditional acupuncture point and auriculotherapy point locations induces long-lasting analgesia in neuropathic rats, and more effectively so than classical DD-EA.

Assessment of neuropathic pain in leprosy patients with relapse or treatment failure by infrared thermography: A cross-sectional study.

BACKGROUND: Neuropathic pain (NP) is one of the main complications of leprosy, and its management is challenging. Infrared thermography (IRT) has been shown to be effective in the evaluation of peripheral autonomic function resulting from microcirculation flow changes in painful syndromes. This study used IRT to map the skin temperature on the hands and feet of leprosy patients with NP. METHODOLOGY/PRINCIPAL FINDINGS: This cross-sectional study included 20 controls and 55 leprosy patients, distributed into 29 with NP (PWP) and 26 without NP (PNP). Thermal images of the hands and feet were captured with infrared camera and clinical evaluations were performed. Electroneuromyography (ENMG) was used as a complementary neurological exam. Instruments used for the NP diagnosis were visual analog pain scale (VAS), Douleur Neuropathic en 4 questions (DN4), and simplified neurological assessment protocol. The prevalence of NP was 52.7%. Pain intensity showed that 93.1% of patients with NP had moderate/severe pain. The most frequent DN4 items in individuals with NP were numbness (86.2%), tingling (86.2%) and electric shocks (82.7%). Reactional episodes type 1 were statistically significant in the PWP group. Approximately 81.3% of patients showed a predominance of multiple mononeuropathy in ENMG, 79.6% had sensory loss, and 81.4% showed some degree of disability. The average temperature in the patients' hands and feet was slightly lower than in the controls, but without a significant difference. Compared to controls, all patients showed significant temperature asymmetry in almost all points assessed on the hands, except for two palmar points and one dorsal point. In the feet, there was significant asymmetry in all points, indicating a greater involvement of the lower limbs. CONCLUSION: IRT confirmed the asymmetric pattern of leprosy neuropathy, indicating a change in the function of the autonomic nervous system, and proving to be a useful method in the approach of pain.