Phenotypical characterization of exteroceptive sensation and pain symptoms on diabetic patients.

BACKGROUD: Diabetic neuropathy (DN) is one of the most common complications of diabetes, affecting about half of individuals with the disease. Among the various symptoms of DN, the development of chronic pain stands out and manifests as exacerbated responses to sensorial stimuli. The conventional clinical treatments used for general neuropathy and associated painful symptoms, still brings uncomplete and unsatisfactory pain relief. Patients with neuropathic pain syndromes are heterogeneous. They present with a variety of sensory symptoms and pain qualities which difficult the correct diagnosis of sensory comorbidities and consequently, the appropriate chronic pain management. AIMS: Herein, we aimed to demonstrate the existence of different sensory profiles on diabetic patients by investigating epidemiological and clinical data on the symptomatology of a group of patients with DN. METHODS: This is a longitudinal and observational study, with a sample of 57 volunteers diagnosed with diabetes from outpatient day clinic of Hospital Universitário of the University of São Paulo-Brazil. After being invited and signed the Informed Consent Form (ICF), patients were submitted to clinical evaluation and filled out pain and quality of life questionnaires. They also performed quantitative sensory test (QST) and underwent skin biopsy for correlation with cutaneous neuropathology. RESULTS: Data demonstrate that 70% of the studied sample presented some type of pain, manifesting in a neuropathic or nociceptive way, what has a negative impact on the life of patients with DM. We also demonstrated a positive association between pain and anxiety and depression, in addition to pain catastrophic thoughts. Three distinct profiles were identified in the sample, separated according to the symptoms of pain: (i) subjects without pain; (ii) with mild or moderate pain; (iii) subjects with severe pain. We also identified through skin biopsy that diabetic patients presented advanced sensory impairment, as a consequence of the degeneration of the myelinated and unmyelinated peripheral fibers. This study characterized the painful symptoms and exteroceptive sensation profile in these diabetic patients, associated to a considerable level of sensory degeneration, indicating, and reinforcing the importance of the long-term clinical monitoring of individuals diagnosed with DM, regarding their symptom profiles and exteroceptive sensitivity.

Effect of photobiomodulation on neuropathic pain of diabetic origin: a narrative review of the literature.

To update the literature on the effectiveness of photobiomodulation (PBM) therapy in relieving pain in patients with diabetic peripheral neuropathy (DPN) compared to the effects of post-intervention, control/placebo groups, and other therapies. Search on the following databases: PORTAL PERIODICOS CAPES, PUBMED, GOOGLE ACADEMIC/SCHOLAR, SCOPUS, SCIELO, CENTRAL, and MEDLINE. Manual search: 1) manually capture the references of relevant articles originally selected to be included in the eligible studies. Two independent researchers performed the screening and selection of studies, methods assessment, and data extraction with unblinded authors and impressions. Subsequently, the full text of the originally selected studies was screened. The screening form registered the criteria for excluding literature from the full-text screening. The screening resulted in a total of 1692 citations. Out of these, 1402 citations were examined for titles and abstracts, followed by the removal of duplicated studies; therefore, 68 articles remained for full-text evaluation. 54 articles were excluded after full-text screening. Fourteen articles met the selection criteria, hence being selected and included in this narrative review. PBM showed to be a promising modality in relieving painful symptoms in DPN, especially when implemented in combination with other therapies, by improving the quality of life of diabetic patients.

Inhibitory insula-ACC projections modulate affective but not sensory aspects of neuropathic pain.

The insula and anterior cingulate cortex (ACC) are brain regions that undergo structural and functional reorganization in neuropathic pain states. Here, we aimed to study inhibitory parvalbumin positive (PV+) posterior insula (pIC) to posterior ACC (pACC) projections, and to evaluate the effects of direct optogenetic manipulation of such projections on mechanical nociception and spontaneous ongoing pain in mice with Spared Nerve Injury (SNI). CTB488 tract-tracing in male PVCrexAi9 mice revealed a small proportion of PV+ projections from the pIC to the pACC. Electrophysiological analysis confirmed the existence of synaptic inputs into the pACC by pIC GABAergic cells. Optogenetic stimulation of these pathways did not change mechanical nociception, but induced conditioned place preference behavior responses. Our results suggest the presence of inhibitory projections between the pIC and the pACC which are able to selectively modulate affective aspects of neuropathic pain.

Dry needling in the treatment of myofascial trigger points and painful shoulder dysfunctions: narrative review of the literature / Agulhamento a seco no tratamento de pontos-gatilho miofasciais e disfunções dolorosas do ombro: revisão narrativa da literatura

ABSTRACT BACKGROUND AND OBJECTIVES: Shoulder painful dysfunctions comprises one of the most common musculoskeletal disorders that requires specialized assistance. Dry Needling (DN) became an adjuvant approach with increased use in clinical practice to treat this type of condition. The present study discusses the literature related to DN in the treatment of myofascial trigger points (MTPs), shoulder dysfunctions and associated pain. METHODS: A narrative review through search of articles from 2010 to 2022 written in Portuguese, English or Spanish was performed in Latin American and Caribbean Literature on Health Sciences (LILACS), Health Information from the National Library of Medicine (Medline), Web of Science and the Scientific Electronic Library Online (Scielo) databases using the keywords: <"Dry Needling">; <"Agulhamento a Seco">; <"Myofascial Trigger Points">; <"Pontos-Gatilhos Miofasciais">; <"Shoulder Dysfunctions">; <"Disfunções do ombro">. The qualitative analysis was performed determining the level of evidence for DN treatment of MTPs, shoulder dysfunctions and pain. RESULTS: A total of 45 citations were found, 22 citations were excluded because they did not meet the selection criteria. The 23 remaining citations were examined for titles and abstracts and duplicate studies were removed. Finally, 10 articles met the selection criteria and were included in the present review. No articles were excluded after full-text screening. The analysis showed poor advances and knowledge regarding the application of DN for the treatment of pain, painful and general shoulder dysfunctions and MTPs, with few evidence regarding treatment effectiveness, patient's pain scores data, mechanisms of action and statistical analysis. CONCLUSION: There is still a lack of concrete scientific evidence to assess DN effectiveness in modulating pain in patients with MTPs shoulder. More systematic reviews and meta-analyses together with experimental and clinical searches must be conducted to provide stronger evidence of this modality to relief painful symptoms in the shoulder, as well as a treatment of MTPs and general shoulder disorders.

RESUMO JUSTIFICATIVA E OBJETIVOS: As disfunções dolorosas de ombro constituem uma das disfunções musculoesqueléticas mais comuns que requerem assistência especializada. O agulhamento a seco (AS) tornou-se uma abordagem adjuvante com uso crescente na prática clínica para tratar esse tipo de condição. O objetivo deste estudo foi rever na literatura aspectos relacionados ao AS no tratamento de pontos-gatilho miofasciais (PGMs), disfunções do ombro e dores associadas. MÉTODOS: Foi realizada uma revisão narrativa através da busca de artigos de 2010 a 2022 escritos em português, inglês ou espanhol, na Literatura Latino-Americana e do Caribe nos bancos de dado Ciências da Saúde (LILACS), Informações em Saúde da Biblioteca Nacional de Medicina (Medline), Web of Science e Scientific Electronic Library Online (Scielo) utilizando as palavras-chave <"Dry Needling">; <"Agulhamento a Seco">; <"Myofascial Trigger Points">; <"Pontos-Gatilhos Miofasciais">; <" Disfunções do ombro">. A análise qualitativa foi realizada determinando o nível de evidência para tratamento de AS para o tratamento de PGMs, disfunções do ombro e dor. RESULTADOS: Um total de 45 citações foram encontradas, 22 citações foram excluídas porque não atenderam aos critérios de seleção. As 23 citações restantes foram examinadas para títulos e resumos e estudos duplicados foram removidos. Finalmente, 10 artigos atenderam aos critérios de seleção e foram incluídos na presente revisão. Nenhum artigo foi excluído após a triagem de texto completo. A análise mostrou poucos avanço e conhecimento sobre a aplicação de AS para o tratamento da dor, disfunções dolorosas e gerais do ombro e PGMs, com poucas evidências sobre a eficácia do tratamento, dados dos escores de dor do paciente, mecanismos de ação e análise estatística. CONCLUSÃO: Ainda faltam evidências científicas concretas para avaliar a eficácia do AS na modulação da dor em pacientes com PGMs no ombro. Mais revisões sistemáticas e meta-análises associadas a pesquisas experimentais e clínicas devem ser realizadas para fornecer evidências dessa modalidade promissora para alívio de sintomas dolorosos no ombro, bem como tratamento de PGMs e distúrbios gerais do ombro.

Time perception and pain: Can a temporal illusion reduce the intensity of pain?

It is commonly known-and previous studies have indicated-that time appears to last longer during unpleasant situations. This study examined whether a reciprocal statement can be made-that is, whether changes in the perception of time can influence our judgment (or rating) of a negative event. We used a temporal illusion method (Pomares et al. Pain 152, 230-234, 2011) to induce distortions in the perception of time. Two stimuli were presented for a constant time: a full clock, which stayed on the screen until its clock hand completed a full rotation (360°); and a short clock, in which the clock hand moved just three-quarters of the way (270°), thus suggesting a reduced interval duration. However, both stimuli were shown for the same amount of time. We specifically investigated (a) whether we could induce a temporal illusion with this simple visual manipulation, and (b) whether this illusion could change participants' ratings of a painful stimulus. In Experiment I (n = 22), to answer (a) above, participants were asked to reproduce the duration in which the different clocks were presented. In Experiment II (n = 30), a painful thermal stimulation was applied on participants' hands while the clocks were shown. Participants were asked to rate the perceived intensity of their pain, and to reproduce its duration. Results showed that, for both experiments, participants reproduced a longer interval after watching the full clock compared with the short clock, confirming that the clock manipulation was able to induce a temporal illusion. Furthermore, the second experiment showed that participants rated the thermal stimuli as less painful when delivered with the short clock than with the full clock. These findings suggest that temporal distortions can modulate the experience of pain.

Effects of specific hypnotic suggestions on mechanical and thermal sensitivity of healthy volunteers: randomized and double-blind study / Efeito de sugestões hipnóticas específicas sobre a nocicepção mecânica e térmica em voluntários saudáveis: estudo randomizado e duplo-cego

ABSTRACT BACKGROUND AND OBJECTIVES: Hypnotic suggestions for hypoalgesia or analgesia are efficient for relieving different pain conditions, presenting few or no side effects. However, little is known about its direct effect on the modulation of peripheral nociception. The goal of this study was to evaluate the mechanical and thermal response after specific hypnotic suggestions in healthy volunteers. METHODS: This is a randomized double-blinded controlled trial that aimed to evaluate both mechanical and thermal nociception after specific hypnotic suggestions in healthy volunteers. For this, twenty-seven participants were enrolled, according to the following eligibility criteria: age between 18-65 years and absence of pain complaints or psychological disorders. After signed Free Informed Consent Term (FICT) the participants were divided by a computer-generated randomization in three groups: sham group (no induction of hypnosis), hypnosis-induced pain group and hypnosis-induced analgesia group. Susceptibility to hypnosis was assessed through the Waterloo-Stanford Group C (WSGC) scale of hypnotic susceptibility and outcomes included evaluation of questionnaires (Hospital Anxiety and Depression Scale and Short Form Brief Pain Inventory) as well as the examination of mechanical and thermal nociception through the Quantitative Sensory Testing (QST), a tool widely used to investigate somatosensory sensitivity by assessing functions of small A-δ and C nerve sensory fibers, before and after specific hypnotic suggestion for pain and analgesia made by a qualified hypnotherapist. RESULTS: Data demonstrated that specific hypnotic suggestions induced significant changes in mechanical and thermal sensitivity. The pain group revealed an increase in mechanical hyperalgesia and allodynia, while the analgesia group increased pain thresholds to thermal stimulations, being conditioned to withstand temperature changes after hypnosis, demonstrating a modulatory effect for both pain and analgesia sensations in healthy volunteers. CONCLUSION: The evidence presented in this study supports the use of the hypnosis technique as an auxiliary tool in clinical practice. HIGHLIGHTS Specific hypnotic suggestions can modulate peripheral nociception in healthy subjects. Data show a modulatory effect for both pain and analgesia sensations. Hypnosis can be considered a feasible technique for the clinical pain management.

RESUMO JUSTIFICATIVA E OBJETIVOS: Sugestões hipnóticas de hipoalgesia ou analgesia são eficientes para aliviar diferentes quadros álgicos, apresentando poucos ou nenhum efeito colateral. No entanto, pouco se sabe sobre seu efeito direto na modulação da nocicepção periférica. O objetivo deste estudo foi avaliar a resposta mecânica e térmica após sugestões hipnóticas específicas em voluntários saudáveis. MÉTODOS: Este é um estudo randomizado e duplo-cego que visou avaliar a nocicepção mecânica e térmica após sugestões hipnóticas específicas em voluntários saudáveis. Para isso, vinte e sete participantes foram selecionados, de acordo com os seguintes critérios de elegibilidade: idade entre 18 e 65 anos e ausência de distúrbios psicológicos e de queixas de dor. Após a assinatura do Termo de Consentimento Livre e Esclarecido (TCLE), os participantes foram divididos por randomização gerada por computador em três grupos: grupo sham (sem indução de hipnose), grupo dor induzida por hipnose e grupo analgesia induzida por hipnose. A suscetibilidade à hipnose foi avaliada através da escala Waterloo-Stanford Group C (WSGC) de suscetibilidade hipnótica e os resultados incluíram a avaliação de questionários (Escala Hospitalar de Ansiedade e Depressão e Inventário Breve de Dor), bem como o exame de nocicepção mecânica e térmica através do Teste Sensorial Quantitativo (QST), uma ferramenta amplamente utilizada para investigar a sensibilidade somatossensorial por meio da avaliação das funções das fibras sensoriais finas dos nervos A-δ e C, antes e após sugestão hipnótica específica para dor e analgesia aplicada por um hipnoterapeuta qualificado. RESULTADOS: Os dados mostraram que as sugestões hipnóticas específicas induziram mudanças significativas na sensibilidade mecânica e térmica dos indivíduos. O grupo dor revelou aumento da hiperalgesia mecânica e da alodinia, enquanto o grupo analgesia aumentou os limiares de dor por estímulos térmicos, sendo condicionado a suportar mudanças de temperatura após a hipnose, demonstrando efeito modulador tanto para as sensações de dor quanto de analgesia em voluntários saudáveis. CONCLUSÃO: As evidências apresentadas neste estudo sustentam o uso da técnica de hipnose como ferramenta auxiliar na prática clínica. DESTAQUES Sugestões hipnóticas específicas podem modular a nocicepção periférica em sujeitos saudáveis. Os dados mostram um efeito modulador tanto para as sensações de dor quanto de analgesia. A hipnose pode ser considerada uma técnica viável para o manejo clínico da dor.

Electrical stimulation of the posterior insular cortex induces opioid and cannabinoid-dependent antinociception and regulates glial cells in the spinal cord / A estimulação elétrica do córtex insular posterior induz antinocicepção opioide e canabinoide dependente e regula células da glia na medula espinal

ABSTRACT BACKGROUND AND OBJECTIVES: Half of neuropathic pain patients still end up failing clinical treatments. Electrical stimulation of the posterior insular cortex (ESI) modulates sensory and nociceptive circuits. This study evaluated the effects of a range of frequencies of ESI proposed to improve neuropathic pain. METHODS: Male Sprague Dawley rats, 280-340 g, submitted to the chronic constriction of the right sciatic nerve were tested for mechanical sensitivity using the paw pressure and von Frey flaments tests, and for thermal sensitivity using the hot plate test. The rats were submitted to ESI 10, 60 or 100 Hz (one, five or seven ESI, 15 min, 210 µs, 1V), applied to the posterior insular cortex, and were evaluated in the tests before and after ESI, or in follow-up of 48, 72 and 168h. The open field evaluated general activity after ESI 5. The involvment of opioid and cannabinoid testes were evaluated through treatment with naloxone and SR1416A - antagonist and inverse agonist/antagonist of the receptors, respectively, after ESI 5, while activation of astrocytes, marked by glial fibrillary acid protein (GFAP), and of microglia, marked by IBA-1 (glial marker), in the spinal cord evaluated by immunohistochemistry. RESULTS: Data demonstrate that 10, 60, and 100 Hz ESIs modulate mechanical and thermal sensitivity. ESI 5 increased immunoreactivity of GFAP in the spinal cord, without altering IBA-1 (glial marker). Naloxone and SR141716A reversed the antinociception of 60 Hz ESI 5. 60 Hz ESI 7 induced antinociception up to 72h. CONCLUSION: 60 Hz ESI induces opioid and cannabinoid-dependent antinociception and regulates glia. HIGHLIGHTS 60 Hz-delivered ESI was the best analgesic protocol for the insular stimulation. Data showed a prolonged analgesic effect up to 72h after repetitive ESI. ESI regulates glia activation in pain modulatory system.

RESUMO JUSTIFICATIVA E OBJETIVOS: Metade dos pacientes com dor neuropática são refratários aos tratamentos. A estimulação elétrica do córtex insular (EECI) posterior modula circuitos sensoriais e nociceptivos. Assim, este estudo avaliou os efeitos de uma faixa de frequências de EECI como tratamento em modelo animal de dor neuropática. MÉTODOS: Ratos machos, Sprague Dawley, 280-340 g, submetidos a cirurgia para indução de constrição crônica (ICC) do nervo isquiático direito, foram avaliados em relação à sensibilidade mecânica com a utilização do teste de pressão de pata e de flamentos de von Frey, e sensibilidade térmica usando o teste de placa quente. Os ratos foram submetidos a EECI de 10, 60 ou 100 Hz (uma, cinco ou sete EECI, 15 min, 210 µs, 1V), aplicada ao córtex insular posterior esquerdo, e avaliados nos testes antes e após EECI, ou em follow up de 48, 72 e 168 horas. Por meio do teste de campo aberto, avaliou-se a atividade geral após a EECI5. O envolvimento de receptores opioides e canabinoides foi avaliado por meio da administração de naloxona e SR141716A - antagonista e agonista/antagonista inverso dos receptores, respectivamente - após a EECI 5, enquanto a ativação de astrócitos - marcada por proteína ácida fibrilar glial (GFAP), e de micróglia - marcada por IBA-1 - na medula espinal foi avaliada por imuno-histoquímica. RESULTADOS: Os dados mostraram que EECI em 10, 60 e 100 Hz modulam a sensibilidade mecânica e térmica dos animais. A EECI 5 aumentou a imunorreatividade de GFAP na medula espinhal, sem alterar IBA-1 (marcador glial). Naloxona e SR141716A reverteram a antinocicepção produzida por EECI 5 de 60 Hz. EECI 7 de 60 Hz induziu antinocicepção por até 72 horas. CONCLUSÃO: A EECI 60 Hz produz antinocicepção dependente de opioides e canabinoides e regula a glia. DESTAQUES A EECI de 60 Hz foi o melhor protocolo analgésico para nossa estimulação insular. Os dados mostram um efeito analgésico prolongado de até 72h após repetidas EECI. A EECI regula a ativação da glia no sistema modulatório da dor.

Pain in Covid Era.

The COVID19 pandemic has impacted the lives and health of persons worldwide and although majority of COVID19 patients present with respiratory symptoms, pain emerges as an important feature of COVID19 infection. About 15-20% of patients progress to a severe condition that requires hospitalization. Although the disease was initially reported as a respiratory syndrome, other systems such as cardiovascular, renal, and nervous systems may be affected in the acute stages, increasing the need for continuous support to treat multiple sequelae caused by the disease. Due to the severity of the disease, damages found after discharge should also be considered. Providing multidisciplinary interventions promoting physical and psychological recovery in the first stages of hospitalization can minimize these damages. Cognitive, physical and psychological dysfunction reported by COVID19 patients after discharge can have profound effects on quality of life. Pain is usually part of this dysfunction, but it is still poorly understood how it affects survivors of COVID19 infections. There is limited information about the clinical characteristics, treatment and outcome of maintenance of pain in COVID19 patients. The purpose of this narrative review is to provide an overview of the implications of COVID19 on acute and chronic pain states.

Involvement of substance P, osteopontin and satellite glial cells on photobiomodulation-induced antinociceptive effect in an experimental model of dentin hypersensitivity.

The aim of this work was to investigate the involvement of substance P (SP), osteopontin (OPN), and satellite glial cells (SGC) on photobiomodulation-induced (PBM) antinociceptive effect in an experimental model of dentin hypersensitivity (DH). Rats ingested isotonic drink (ID, pH 2.87) for 45 consecutive days and after this period received PBM irradiation at λ660 nm or λ808 nm (1 J, 3.5 J/cm2, 100 mW, 10 s, 0.028 cm2, continuous wave, 3 consecutive daily sessions), and were evaluated for nociceptive behavior 24, 48, 72 h, and 14 days after laser treatments. ID ingestion induced an increase on thermal sensitivity of DH characteristics in rats that was completely reversed by PBM treatment at both 660 and 808 nm. Immunohistochemical analysis revealed increased SP expression at both dentin-pulp complex (DPC) and trigeminal ganglia (TG) of DH-rats which did not occur in PBM groups by PBM treatment. Also, the increase of glial fibrillary acidic protein (GFAP) observed in the TG of DH-rats was also reversed by PBM treatment. Finally, PBM at both 660 and 808 nm increased OPN expression in the dentin-pulp complex of DH-rats after 14 days of PBM treatment. All in all, this data demonstrates that PBM reverses nociception in a DH experimental model by inhibiting neurogenic inflammation and inducing a regenerative response.

Photobiomodulation increases cell viability via AKT activation in an in vitro model of diabetes induced by glucose neurotoxicity.

Peripheral neuropathy (PN) is a serious complication of diabetes mellitus (DM) and is known to be resistant to conventional treatment. Photobiomodulation (PBM) is demonstrated to be effective in treating PN and in protecting nerve fiber damage. To better understand the mechanisms underlying the regenerative effects of PBM on diabetic neuropathy, we conducted a study in an in vitro model of diabetes induced by glucose neurotoxicity. Neuro 2A cells (1 × 104 cells/ well; N2A) were cultured in Minimum Essential Medium (MEM) supplemented with high glucose concentrations (100 mM) for 48 h and after the incubation period were submitted to either one or three consecutive applications of PBM, once a day (low-level InGaAlP, continuous wave mode, 660 nm, 30 mW, 1.6 J/cm2, 15 s, per well). Cell viability was measured by MTT method, neurotoxicity by LDH release, neurite outgrowth was evaluated through morphometric analysis, and AKT/ERK protein expression levels were assessed by western blotting. Results demonstrate that PBM increased N2A viability as well as induced neurogenesis observed by the increase in neurite outgrowth being this effect modulated by AKT activation. Data obtained herein reinforce the regenerative potential of PBM in the treatment of PN and strongly suggests that phototherapy should be considered adjuvant in the treatment of diabetes.

Photobiomodulation-induced analgesia in experimental temporomandibular disorder involves central inhibition of fractalkine.

Temporomandibular disorder (TMD) is a collective term that encompasses a set of clinical problems that affect the masticatory muscles, the temporomandibular joint, and associated structures. Despite their high clinical prevalence, the mechanisms of chronic craniofacial muscle pain are not yet well understood. Treatments for TMD pain relief and control should be minimally invasive, reversible, and conservative. Photobiomodulation (PBM) is a promising option once it is known to inhibit inflammatory response and to relief painful symptoms. Herein, the effects of PBM (660 nm, 30 mW, 16 J/cm2, 0.2 cm2, 15 s in a continuous frequency) on the pain sensitivity of rats submitted to an experimental model of TMD induced by CFA was evaluated. Experimental TMD was induced in rats by the injection of complete Freund's adjuvant (CFA) injection into the masseter muscle. Nociceptive behavior was evaluated by electronic von Frey before CFA and after 1 h, 3 h, 6 h, and 24 h and 7, 14, and 21 days after PBM treatment. Inflammatory infiltrate was evaluated by histology of the masseter muscle and fractalkine expression was evaluated by immunohistochemistry of the trigeminal ganglia. PBM reversed the mechanical hypersensitivity of the animals by inhibiting the local inflammatory response, observed by the decrease of the inflammatory infiltrate in the masseter muscle of rats and by a central inhibition of fractalkine observed in the trigeminal ganglion. These data provide new insights into the mechanisms involved in the effects of photobiomodulation therapy emphasizing its therapeutic potential in the treatment of TMD.

Characterization of traumatic spinal cord injury model in relation to neuropathic pain in the rat.

Purpose/aim: Neuropathic pain following spinal cord injury (SCI) has a tremendous impact on patient's quality of life, and frequently is the most limiting aspect of the disease. In view of the severity of this condition and the absence of effective treatments, the establishment of a reliable animal model that reproduces neuropathic pain after injury is crucial for a better understanding of the pathophysiology and for the development of new therapeutic strategies. Thus, the objective of the present study was to standardize the traumatic SCI model in relation to neuropathic pain. MATERIALS AND METHODS: Wistar rats were submitted to SCI of mild intensity (pendulum height 12.5 mm) or moderate intensity (pendulum height 25 mm) using the New York University Impactor equipment. Behavioural assessment was performed during 8 weeks. Thereafter, spinal cords were processed for immunohistochemistry. RESULTS: The animals of the moderate injury group in comparison with mild injury had a greater motor function deficit, worse mechanical allodynia, and latter bladder recovery; moreover, histological analysis revealed more extensive lesions with lower neuronal population. CONCLUSIONS: Our study suggests that moderate SCI causes a progressive and long-lasting painful condition (at least 8 weeks), in addition to motor impairment, and thus represents a reliable animal model for the study of chronic neuropathic pain after SCI.

Light emitting diode (LED) therapy reduces local pathological changes induced by Bothrops asper snake venom.

The therapeutic effect of the Light Emitting Diode (LED) treatment in two wavelengths (635 or 945 nm) was evaluated in the local pathological alterations induced by Bothrops asper snake venom. Mice received irradiation of infrared LED (120 mW, 945 nm) or red LED (110 mW, 635 nm) applied immediately, 1 and 2 h after venom injection. LED treatment reduced edema formation in the plantar region and gastrocnemius muscle and significantly reduced neutrophil migration and hyperalgesia after the venom injection. Also, both infrared LED and red LED treatment significantly reduced myonecrosis, as revealed by muscle CK and plasma CK levels. Histological analysis corroborated the reduction in the extent of venom-induced myonecrosis. In conclusion, our data demonstrates that PBM with LED light in both red and infrared wavelengths, when applied after envenomation in mice, reduces the extent of myotoxicity, edema, inflammatory infiltrate and hyperalgesia, suggesting that photobiomodulation is a potential therapeutic approach that should be further investigated for the treatment of local effects of Bothrops snakebite.

Electrical stimulation of the insular cortex as a novel target for the relief of refractory pain: An experimental approach in rodents.

Cortical electrical stimulation (CES) has shown to be an effective therapeutic alternative for neuropathic pain refractory to pharmacological treatment. The primary motor cortex(M1) was the main cortical target used in the vast majority of both invasive and non-invasive studies. Despite positive results M1-based approaches still fail to relieve pain in a significant proportion of individuals. It has been advocated that the direct stimulation of cortical areas directly implicated in the central integration of pain could increase the efficacy of analgesic brain stimulation. Here, we evaluated the behavioral effects of electrical stimulation of the insular cortex (ESI) on pain sensitivity in an experimental rat model of peripheral neuropathy, and have described the pathways involved. Animals underwent chronic constriction of the sciatic nerve in the right hind limb and had concentric electrodes implanted in the posterior dysranular insular cortex. Mechanical nociception responses were evaluated before and at the end of a 15-min session of ESI (60Hz, 210µs, 1V). ESI reversed mechanical hypersensitivity in the paw contralateral to the brain hemisphere stimulated, without inducing motor impairment in the open-field test. Pharmacological blockade of µ-opioid (MOR) or type 1-cannabinoid receptors (CB1R) abolished ESI-induced antinociceptive effects. Evaluation of CB1R and MOR spatial expression demonstrated differential modulation of CB1R and MOR in the periaqueductal gray matter (PAG) of ESI-treated rats in sub-areas involved in pain processing/modulation. These results indicate that ESI induces antinociception by functionally modulating opioid and cannabinoid systems in the PAG pain circuitry in rats with experimentally induced neuropathic pain.

Analgesic Effect of Photobiomodulation on Bothrops Moojeni Venom-Induced Hyperalgesia: A Mechanism Dependent on Neuronal Inhibition, Cytokines and Kinin Receptors Modulation.

BACKGROUND: Envenoming induced by Bothrops snakebites is characterized by drastic local tissue damage that involves an intense inflammatory reaction and local hyperalgesia which are not neutralized by conventional antivenom treatment. Herein, the effectiveness of photobiomodulation to reduce inflammatory hyperalgesia induced by Bothrops moojeni venom (Bmv), as well as the mechanisms involved was investigated. METHODOLOGY/PRINCIPAL FINDINGS: Bmv (1 µg) was injected through the intraplantar route in the right hind paw of mice. Mechanical hyperalgesia and allodynia were evaluated by von Frey filaments at different time points after venom injection. Low level laser therapy (LLLT) was applied at the site of Bmv injection at wavelength of red 685 nm with energy density of 2.2 J/cm2 at 30 min and 3 h after venom inoculation. Neuronal activation in the dorsal horn spinal cord was determined by immunohistochemistry of Fos protein and the mRNA expression of IL-6, TNF-α, IL-10, B1 and B2 kinin receptors were evaluated by Real time-PCR 6 h after venom injection. Photobiomodulation reversed Bmv-induced mechanical hyperalgesia and allodynia and decreased Fos expression, induced by Bmv as well as the mRNA levels of IL-6, TNF-α and B1 and B2 kinin receptors. Finally, an increase on IL-10, was observed following LLLT. CONCLUSION/SIGNIFICANCE: These data demonstrate that LLLT interferes with mechanisms involved in nociception and hyperalgesia and modulates Bmv-induced nociceptive signal. The use of photobiomodulation in reducing local pain induced by Bothropic venoms should be considered as a novel therapeutic tool for the treatment of local symptoms induced after bothropic snakebites.

Oligopeptidases B from Trypanossoma cruzi and Trypanossoma brucei inhibit inflammatory pain in mice by targeting serotoninergic receptors.

In the present study, the antinociceptive profile of oligopeptidases B from Trypanosoma cruzi (OPTc) and Trypanosoma brucei (OPTb) were examined in mice evaluated by the acetic acid-induced writhing test. Both OPTc and OPTb injected intraperitoneally attenuated the writhing numbers in the acetic acid-induced writhing test. This effect was not dependent on the enzymatic activity, but the enzyme structure was important for this purpose. Intraperitoneal pretreatment with methysergide (5-HT serotonergic receptor antagonist) attenuated antinociceptive effect induced by both OPTc and OPTb in the writhing test. However, naloxone (opioid receptor antagonist) or yohimbine (α2-adrenergic receptor antagonist) did not affect antinociception induced by both oligopeptidases. Our results suggest that OPTc and OPTb show antinociceptive property in the writhing test. Furthermore, this antinociceptive effect may be mediated by serotonergic receptor but not opioidergic or α2-adrenergic receptors.

Analgesic properties of S100A9 C-terminal domain: a mechanism dependent on calcium channel inhibition.

Calcium-binding protein S100A9 and its C-terminus peptide (mS100A9p) are anti-inflammatory and induce antinociception in rodents. We investigated the mechanisms involved in this effect, and whether they depend or not on the anti-inflammatory properties of mS100A9p. In mice, mS100A9p inhibited thermal and mechanical hyperalgesia and allodynia induced by either carrageenan or formalin, without interfering with paw edema. mS100A9p also inhibited myeloperoxidase activity (MPO), a marker of granulocyte infiltration, induced by carrageenan, but increased MPO after formalin intraplantar injection. The in vivo analgesic properties of mS100A9p were independent of opioid receptor activation. Calcium flux into dorsal root ganglia neurons induced by KCl was inhibited by mS100A9p, suggesting that this protein is able to inhibit signaling, in sensory neurons. The inhibitory effects of mS100A9p on primary afferent signaling were neither due to intracellular calcium store inhibition nor to calcium chelating properties. However, mS100A9p was able to inhibit calcium currents carried by transiently expressed N-type, but not L-type calcium channels, as demonstrated both by gene transfection techniques and electrophysiology. These data demonstrate that mS100A9p interferes with mechanisms involved in nociception, hyperalgesia and calcium signaling in sensory neurons, modulating primary afferent nociceptive signal by inhibiting activation of N-type voltage operated calcium channels.

Functional mapping of the motor cortex of the rat using transdural electrical stimulation.

Motor cortex stimulation oriented by functional cortical mapping is used mainly for treating otherwise intractable neurological disorders, however, its mechanism of action remains elusive. Herein, we present a new method for functional mapping of the rat motor cortex using non-invasive transdural electrical stimulation. This method allows a non-invasive mapping of the surface of the neocortex providing a differentiation of representative motor areas. This study may facilitate further investigation about the mechanisms mediating the effects of electrical stimulation, possibly benefiting patients who do not respond to this neuromodulation therapy.

Antinociception induced by epidural motor cortex stimulation in naive conscious rats is mediated by the opioid system.

Epidural motor cortex stimulation (MCS) has been used for treating patients with neuropathic pain resistant to other therapeutic approaches. Experimental evidence suggests that the motor cortex is also involved in the modulation of normal nociceptive response, but the underlying mechanisms of pain control have not been clarified yet. The aim of this study was to investigate the effects of epidural electrical MCS on the nociceptive threshold of naive rats. Electrodes were placed on epidural motor cortex, over the hind paw area, according to the functional mapping accomplished in this study. Nociceptive threshold and general activity were evaluated under 15-min electrical stimulating sessions. When rats were evaluated by the paw pressure test, MCS induced selective antinociception in the paw contralateral to the stimulated cortex, but no changes were noticed in the ipsilateral paw. When the nociceptive test was repeated 15 min after cessation of electrical stimulation, the nociceptive threshold returned to basal levels. On the other hand, no changes in the nociceptive threshold were observed in rats evaluated by the tail-flick test. Additionally, no behavioral or motor impairment were noticed in the course of stimulation session at the open-field test. Stimulation of posterior parietal or somatosensory cortices did not elicit any changes in the general activity or nociceptive response. Opioid receptors blockade by naloxone abolished the increase in nociceptive threshold induced by MCS. Data shown herein demonstrate that epidural electrical MCS elicits a substantial and selective antinociceptive effect, which is mediated by opioids.