Photobiomodulation mitigates Bothrops jararacussu venom-induced damage in myoblast cells by enhancing myogenic factors and reducing cytokine production.

BACKGROUND: Photobiomodulation has exhibited promise in mitigating the local effects induced by Bothrops snakebite envenoming; however, the mechanisms underlying this protection are not yet fully understood. Herein, the effectiveness of photobiomodulation effects on regenerative response of C2C12 myoblast cells following exposure to Bothrops jararacussu venom (BjsuV), as well as the mechanisms involved was investigated. METHODOLOGY/PRINCIPAL FINDINGS: C2C12 myoblast cells were exposed to BjsuV (12.5 µg/mL) and irradiated once for 10 seconds with laser light of 660 nm (14.08 mW; 0.04 cm2; 352 mW/cm2) or 780 nm (17.6 mW; 0.04 cm2; 440 mW/ cm2) to provide energy densities of 3.52 and 4.4 J/cm2, and total energies of 0.1408 and 0.176 J, respectively. Cell migration was assessed through a wound-healing assay. The expression of MAPK p38-α, NF-Кß, Myf5, Pax-7, MyoD, and myogenin proteins were assessed by western blotting analysis. In addition, interleukin IL1-ß, IL-6, TNF-alfa and IL-10 levels were measured in the supernatant by ELISA. The PBM applied to C2C12 cells exposed to BjsuV promoted cell migration, increase the expression of myogenic factors (Pax7, MyF5, MyoD and myogenin), reduced the levels of proinflammatory cytokines, IL1-ß, IL-6, TNF-alfa, and increased the levels of anti-inflammatory cytokine IL-10. In addition, PBM downregulates the expression of NF-kB, and had no effect on p38 MAKP. CONCLUSION/SIGNIFICANCE: These data demonstrated that protection of the muscle cell by PBM seems to be related to the increase of myogenic factors as well as the modulation of inflammatory mediators. PBM therapy may offer a new therapeutic strategy to address the local effects of snakebite envenoming by promoting muscle regeneration and reducing the inflammatory process.

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.

Structural analysis of TrkA mutations in patients with congenital insensitivity to pain reveals PLCγ as an analgesic drug target.

Chronic pain is a major health issue, and the search for new analgesics has become increasingly important because of the addictive properties and unwanted side effects of opioids. To explore potentially new drug targets, we investigated mutations in the NTRK1 gene found in individuals with congenital insensitivity to pain with anhidrosis (CIPA). NTRK1 encodes tropomyosin receptor kinase A (TrkA), the receptor for nerve growth factor (NGF) and that contributes to nociception. Molecular modeling and biochemical analysis identified mutations that decreased the interaction between TrkA and one of its substrates and signaling effectors, phospholipase Cγ (PLCγ). We developed a cell-permeable phosphopeptide derived from TrkA (TAT-pQYP) that bound the Src homology domain 2 (SH2) of PLCγ. In HEK-293T cells, TAT-pQYP inhibited the binding of heterologously expressed TrkA to PLCγ and decreased NGF-induced, TrkA-mediated PLCγ activation and signaling. In mice, intraplantar administration of TAT-pQYP decreased mechanical sensitivity in an inflammatory pain model, suggesting that targeting this interaction may be analgesic. The findings demonstrate a strategy to identify new targets for pain relief by analyzing the signaling pathways that are perturbed in CIPA.

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.

Interactions between cannabinoid and opioid receptors in a mouse model of diabetic neuropathy.

ABSTRACT: Diabetic neuropathy, often associated with diabetes mellitus, is a painful condition with no known effective treatment except glycemic control. Studies with neuropathic pain models report alterations in cannabinoid and opioid receptor expression levels; receptors whose activation induces analgesia. We examined whether interactions between CB1R and opioid receptors could be targeted for the treatment of diabetic neuropathy. For this, we generated antibodies that selectively recognize native CB1R-MOR and CB1R-DOR heteromers using a subtractive immunization strategy. We assessed the levels of CB1R, MOR, DOR, and interacting complexes using a model of streptozotocin-induced diabetic neuropathy and detected increased levels of CB1R, MOR, DOR, and CB1R-MOR complexes compared with those in controls. An examination of G-protein signaling revealed that activity induced by the MOR, but not the DOR agonist, was potentiated by low nanomolar doses of CB1R ligands, including antagonists, suggesting an allosteric modulation of MOR signaling by CB1R ligands within CB1R-MOR complexes. Because the peptide endocannabinoid, hemopressin, caused a significant potentiation of MOR activity, we examined its effect on mechanical allodynia and found that it blocked allodynia in wild-type mice and mice with diabetic neuropathy lacking DOR (but have CB1R-MOR complexes). However, hemopressin does not alter the levels of CB1R-MOR complexes in diabetic mice lacking DOR but increases the levels of CB1R-DOR complexes in diabetic mice lacking MOR. Together, these results suggest the involvement of CB1R-MOR and CB1R-DOR complexes in diabetic neuropathy and that hemopressin could be developed as a potential therapeutic for the treatment of this painful condition.

Translational aspects of deep brain stimulation for chronic pain.

The use of deep brain stimulation (DBS) for the treatment of chronic pain was one of the first applications of this technique in functional neurosurgery. Established brain targets in the clinic include the periaqueductal (PAG)/periventricular gray matter (PVG) and sensory thalamic nuclei. More recently, the anterior cingulum (ACC) and the ventral striatum/anterior limb of the internal capsule (VS/ALIC) have been investigated for the treatment of emotional components of pain. In the clinic, most studies showed a response in 20%-70% of patients. In various applications of DBS, animal models either provided the rationale for the development of clinical trials or were utilized as a tool to study potential mechanisms of stimulation responses. Despite the complex nature of pain and the fact that animal models cannot reliably reflect the subjective nature of this condition, multiple preparations have emerged over the years. Overall, DBS was shown to produce an antinociceptive effect in rodents when delivered to targets known to induce analgesic effects in humans, suggesting a good predictive validity. Compared to the relatively high number of clinical trials in the field, however, the number of animal studies has been somewhat limited. Additional investigation using modern neuroscience techniques could unravel the mechanisms and neurocircuitry involved in the analgesic effects of DBS and help to optimize this therapy.

Posterior-superior insular deep transcranial magnetic stimulation alleviates peripheral neuropathic pain - A pilot double-blind, randomized cross-over study.

OBJECTIVES: Peripheral neuropathic pain (pNeP) is prevalent, and current treatments, including drugs and motor cortex repetitive transcranial magnetic stimulation (rTMS) leave a substantial proportion of patients with suboptimal pain relief. METHODS: We explored the intensity and short-term duration of the analgesic effects produced in pNeP patients by 5 days of neuronavigated deep rTMS targeting the posterior superior insula (PSI) with a double-cone coil in a sham-controlled randomized cross-over trial. RESULTS: Thirty-one pNeP patients received induction series of five active or sham consecutive sessions of daily deep-rTMS to the PSI in a randomized sequence, with a washout period of at least 21 days between series. The primary outcome [number of responders (>50% pain intensity reduction from baseline in a numerical rating scale ranging from 0 to 10)] was significantly higher after real (58.1%) compared to sham (19.4%) stimulation (p = 0.002). The number needed to treat was 2.6, and the effect size was 0.97 [95% CI (0.6; 1.3)]. One week after the 5th stimulation day, pain scores were no longer different between groups, and no difference in neuropathic pain characteristics and interference with daily living were present. No major side effects occurred, and milder adverse events (i.e., short-lived headaches after stimulation) were reported in both groups. Blinding was effective, and analgesic effects were not affected by sequence of the stimulation series (active-first or sham-first), age, sex or pain duration of participants. DISCUSSION: PSI deep-rTMS was safe in refractory pNeP and was able to provide significant pain intensity reduction after a five-day induction series of treatments. Post-hoc assessment of neuronavigation targeting confirmed deep-rTMS was delivered within the boundaries of the PSI in all participants. CONCLUSION: PSI deep-rTMS provided significant pain relief during 5-day induction sessions compared to sham stimulation.

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.

Electrical stimulation of the posterior insula induces mechanical analgesia in a rodent model of neuropathic pain by modulating GABAergic signaling and activity in the pain circuitry.

The insula has emerged as a critical target for electrical stimulation since it influences pathological pain states. We investigated the effects of repetitive electrical stimulation of the insular cortex (ESI) on mechanical nociception, and general locomotor activity in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. We also studied neuroplastic changes in central pain areas and the involvement of GABAergic signaling on ESI effects. CCI rats had electrodes implanted in the left agranular posterior insular cortex (pIC), and mechanical sensitivity was evaluated before and after one or five daily consecutive ESIs (15 min each, 60 Hz, 210 µs, 1 V). Five ESIs (repetitive ESI) induced sustained mechanical antinociception from the first to the last behavioral assessment without interfering with locomotor activity. A marked increase in Fos immunoreactivity in pIC and a decrease in the anterior and mid-cingulate cortex, periaqueductal gray and hippocampus were noticed after five ESIs. The intrathecal administration of the GABAA receptor antagonist bicuculline methiodide reversed the stimulation-induced antinociception after five ESIs. ESI increased GAD65 levels in pIC but did not interfere with GABA, glutamate or glycine levels. No changes in GFAP immunoreactivity were found in this work. Altogether, the results indicate the efficacy of repetitive ESI for the treatment of experimental neuropathic pain and suggest a potential influence of pIC in regulating pain pathways partially through modulating GABAergic signaling.

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.

Hemopressin as a breakthrough for the cannabinoid field.

Hemopressin (PVNFKFLSH in rats, and PVNFKLLSH in humans and mice), a fragment derived from the α-chain of hemoglobin, was the first peptide described to have type 1 cannabinoid receptor activity. While hemopressin was shown to have inverse agonist/antagonistic activity, extended forms of hemopressin (i.e. RVD-hemopressin, also called pepcan-12) exhibit type 1 and type 2 cannabinoid receptor agonistic/allosteric activity, and recent studies suggest that they can activate intracellular mitochondrial cannabinoid receptors. Therefore, hemopressin and hemopressin-related peptides could have location-specific and biased pharmacological action, which would increase the possibilities for fine-tunning and broadening cannabinoid receptor signal transduction. Consistent with this, hemopressins were shown to play a role in a number of physiological processes including antinociceptive and anti-inflammatory activity, regulation of food intake, learning and memory. The shortest active hemopressin fragment, NFKF, delays the first seizure induced by pilocarpine, and prevents neurodegeneration in an experimental model of autoimmune encephalomyelitis. These functions of hemopressins could be due to engagement of both cannabinoid and non-cannabinoid receptor systems. Self-assembled nanofibrils of hemopressin have pH-sensitive switchable surface-active properties, and show potential as inflammation and cancer targeted drug-delivery systems. Upon disruption of the self-assembled hemopressin nanofibril emulsion, the intrinsic analgesic and anti-inflammatory properties of hemopressin could help bolster the therapeutic effect of anti-inflammatory or anti-cancer formulations. In this article, we briefly review the molecular and behavioral pharmacological properties of hemopressins, and summarize studies on the intricate and unique mode of generation and binding of these peptides to cannabinoid receptors. Thus, the review provides a window into the current status of hemopressins in expanding the repertoire of signaling and activity by the endocannabinoid system, in addition to their new potential for pharmaceutic formulations.

Electrical stimulation of the posterior insula induces mechanical analgesia in a rodent model of neuropathic pain by modulating GABAergic signaling and activity in the pain circuitry

The insula has emerged as a critical target for electrical stimulation since it influences pathological pain states. We investigated the effects of repetitive electrical stimulation of the insular cortex (ESI) on mechanical nociception, and general locomotor activity in rats subjected to chronic constriction injury (CCI) of the sciatic nerve. We also studied neuroplastic changes in central pain areas and the involvement of GABAergic signaling on ESI effects. CCI rats had electrodes implanted in the left agranular posterior insular cortex (pIC), and mechanical sensitivity was evaluated before and after one or five daily consecutive ESIs (15 min each, 60 Hz, 210 μs, 1 V). Five ESIs (repetitive ESI) induced sustained mechanical antinociception from the first to the last behavioral assessment without interfering with locomotor activity. A marked increase in Fos immunoreactivity in pIC and a decrease in the anterior and mid-cingulate cortex, periaqueductal gray and hippocampus were noticed after five ESIs. The intrathecal administration of the GABAA receptor antagonist bicuculline methiodide reversed the stimulation-induced antinociception after five ESIs. ESI increased GAD65 levels in pIC but did not interfere with GABA, glutamate or glycine levels. No changes in GFAP immunoreactivity were found in this work. Altogether, the results indicate the efficacy of repetitive ESI for the treatment of experimental neuropathic pain and suggest a potential influence of pIC in regulating pain pathways partially through modulating GABAergic signaling.

Hemopressin as a breakthrough for the cannabinoid field

Hemopressin (PVNFKFLSH in rats, and PVNFKLLSH in humans and mice), a fragment derived from the α-chain of hemoglobin, was the first peptide described to have type 1 cannabinoid receptor activity. While hemopressin was shown to have inverse agonist/antagonistic activity, extended forms of hemopressin (i.e. RVD-hemopressin, also called pepcan-12) exhibit type 1 and type 2 cannabinoid receptor agonistic/allosteric activity, and recent studies suggest that they can activate intracellular mitochondrial cannabinoid receptors. Therefore, hemopressin and hemopressin-related peptides could have location-specific and biased pharmacological action, which would increase the possibilities for fine-tunning and broadening cannabinoid receptor signal transduction. Consistent with this, hemopressins were shown to play a role in a number of physiological processes including antinociceptive and anti-inflammatory activity, regulation of food intake, learning and memory. The shortest active hemopressin fragment, NFKF, delays the first seizure induced by pilocarpine, and prevents neurodegeneration in an experimental model of autoimmune encephalomyelitis. These functions of hemopressins could be due to engagement of both cannabinoid and non-cannabinoid receptor systems. Self-assembled nanofibrils of hemopressin have pH-sensitive switchable surface-active properties, and show potential as inflammation and cancer targeted drug-delivery systems. Upon disruption of the self-assembled hemopressin nanofibril emulsion, the intrinsic analgesic and anti-inflammatory properties of hemopressin could help bolster the therapeutic effect of anti-inflammatory or anti-cancer formulations. In this article, we briefly review the molecular and behavioral pharmacological properties of hemopressins, and summarize studies on the intricate and unique mode of generation and binding of these peptides to cannabinoid receptors. Thus, the review provides a window into the current status of hemopressins in expanding the repertoire of signaling and activity by the endocannabinoid system, in addition to their new potential for pharmaceutic formulations.