Avaliação do efeito da administração aguda pregabalina na ativação do córtex somatosensitivo e motor esquerdo de fibromialgicas por meio da espectroscopia infravermelha funcional (fNIRS)

A Fibromialgia (FM) é uma síndrome que se caracteriza por dor crônica difusa, fadiga, transtornos do sono e alterações de humor. Embora sua fisiopatologia não esteja totalmente elucidada, o processo neurobiológico parece envolver alterações do córtex sensitivo e motor e de suas conexões com estruturas subcorticais que constituem a neuromatriz da dor, assim como alterações neuropáticas periféricas. Sabe-se que o aumento do cálcio intracelular acima de certo limiar, pode ser parte do processo dependente de atividade que leva à sensibilização central, por aumento do influxo de cálcio por meio de canais NMDA, AMPA, canais dependentes de voltagem, e por liberação de reservas intracelular microssomais. A sensibilização central pode ser também interpretada como um processo de plasticidade mal-adaptativa que sustenta circuitos da dor e de seus correlatos. Por tanto, o córtex sensitivo e motor tem sido alvo diagnóstico e terapêutico para o estudo e tratamento da dor crônica. Dentre as múltiplas estratégias farmacológicas tem sido preconizado o uso da pregabalina, aprovado pela Food and Drug Administration (FDA) dos EUA para uso no tratamento de fibromialgia em 2007. A pregabalina age inibindo os canais de cálcio pré sinápticos dependentes de voltagem por se ligar à proteína auxiliar alfa-2-delta. In vitro, este fármaco reduz a liberação de neurotransmissores cálcio-dependentes incluindo glutamato, norepinefrina, calcitonina e substância P, estes neurotransmissores têm sido associados à sensibilização do sistema nervoso. Portanto, considerando o potencial neuromodulador da pregabalina baseado no seu mecanismo de ação, é um fármaco atrativo para avaliar o papel da modulação do córtex sensitivo e motor na fisiopatolgia da FM. No entanto, para que se avance no conhecimento do efeito dos fármacos na função encefálica, necessitamos utilizar recursos de neuroimagem que sejam exequíveis em contextos diversos, e que permitam mensurar o efeito dos fármacos dinamicamente. Dentre os recursos de imagem existe a Functional Near Infrared Spectroscopy (fNIRS) que permite avaliar ativação cortical por meio da mudança no consumo local de oxigênio que acompanha o disparo neuronal regional, mensurado pelas mudanças na concetração da oxi- e desoxi-hemoglobina. Com estas considerações, hipotetizamos que a modulação farmacológica induzida pela pregabalina poderia ser mensurada, clinicamente por meio de testes psicofísicos da dor (que avaliam vias nociceptivas associadas a termoreceptores e barorreceptores) e à nível de neuroimagem por meio do fNIRS. Por se tratar de um mesmo sistema com potencial de ser avaliado de forma virtualmente simultânea, hipotetizamos também que existirá uma associação entre as modulações clínicas (testes psicofísicos) e neurológicas (fNIRS do córtex sensitivo e motor primários). Desta forma, neste estudo avaliou-se o efeito de pregabalina (150 mg) em dose única em fibromiálgicas e controles saudáveis. Em ambos os grupos a pregabalina foi comparada ao placebo, num desenho de estudo randomizado, duplo-cego, cruzado. Avaliou-se o efeito das intervenções, intra e inter-grupos, na ativação cortical de maneira indireta, pela concetração da oxi-hemoglobina durante testes psicofísicos da dor por meio meio do Quantitative Sensory Testing (QST) e algometria de pressão, que foram comparados com a ativação cortical durante uma tarefa motora de percussão dos dedos da mão (left hand finger tapping). Foram estudadas mulheres com idade entre 18 e 65 anos, 17 fibromiálgicas e 10 controles saudáveis. Os parâmetros do QST foram avaliados uma hora após dose única de 150 mg de pregabalina. Resultados: Na linha de base, as fibromiálgicas apresentaram alterações no QST sugestivas de lesão de fibras finas: o limiar de detecção de calor (HDT, do inglês Heat Detection Threshold) foi maior que nas controles (35,53 ºC ± 3,22 vs. 33,33 ºC ± 0,85; p<0,05), enquanto o limiar de dor por pressão (PPT, do inglês Pain Pressure Threshold) foi menor (2,44 kg/cm2 ± 1,08 vs. 4,32 kg/cm2 ± 1,45; P<0,01). Não foram observadas diferenças nos outros componentes do QST, nem mudanças com a pregabalina. Quando comparados com as saudáveis, nas fibromiálgicas o HDT, limiar de dor por calor (HPT) e a tolerância ao calor (HT) evocaram activação nos giros frontal médio, precentral e póscentral, porém, de menor amplitude do que as controles. Depois da administração da pregabalina, aumentou a ativação em responsta ao HDT, mas não teve correlação com o valor do limiar. Já o HPT mostrou se correlacionar de forma inversa com a ativação nos giros frontal superior (rs=-0,552, p=0,033) e precentral (rs=-0,545, p=0,036) na linha de base e após pregabalina (rs=-0,52, p=0,047). A HT também apresentou uma correlação inversa com os giros frontal superior (rs=-0,645, p=0,032) e precentral (rs=-0,655, p=0,029), mas neste caso, esta correlação desapareceu após ter recebido pregabalina. A ativação cortical pelo PPT não detectou diferenças entre fibromiálgicas e controles. Conclusões: O perfil nos testes psicofísicos nas pacientes apresenta correlação com sua ativação cortical. As alterações nos testes sugerem alterações de fibras finas nociceptivas, o que é explicado por um componente de neuropatia periférica, que na fibromialgia é acompanhado por diminuição da ativação em áreas sensitivas e motoras, e aumento da ativação em áreas associadas com processamento cognitivo da dor, cuja atividade foi elevada com a pregabalina. Quando comparadas às controles, nas fibromiálgicas a HT recrutou mais áreas associada ao processamento cognitivo da dor, o que fortalece a hipótese a favor da existência do componente de sensibilização central na fibromialgia. Desta forma, estes achados reforçam a provável coexistência de alterações periféricas e centrais na fisiopatologia da fibromialgia.Fibromyalgia is a syndrome characterized by presenting chronic diffuse pain, fatigue, mood and sleep disturbances. Although its pathophysiology has not been totally elucidated yet, the neurobiological processes seems to involve funciontal alterations of the sensorimotor cortex and its conections with subcortical structures (related to the pain neuronal matrix), and also, with quantitative and qualitative alterations in fine sensitive fibers from the peripheral nervous system. It is known that increased intracellular calcium above certain threshold might be part of a process activity-dependant that leads to central sensitization, due to elevated calcium influx through NMDA and AMPA channels, as well as voltage-dependent channels, and also due to relase of intracellular microsomal reserves. Central sensitization can also be interpreted as a maladaptive plasticity that sustains pain circuits and its correlated. Thus, the sensorimotor cortex has been a diagnostic and therapeutic target for the study and treatment of chronic pain. Among the multiple pharmacological strategies, the use of pregabalin has been recommended and approved by the Food and Drug Administration (FDA) of the United States of America for treatment of patients with fibromyalgia since 2007. Pregabalin acts by inhibiting voltage-dependant pre-synaptic calcium channels by binding to the auxiliary protein alfa-2-delta. In vitro, this drug reduces the liberation of neurottransmissors that depend on calcium, and that include glutamate, norepinephrine, calcitonin and P-substance. All the latter mentioned neurotransmitters are associated with the central nervou system sensitization. Thus, considering its potential as neuronal modulation, taking into accout tis mechanisms of action, the pregabalin is an appealing drug to study the role of the modulation fo the sensorimotor cortex in the pathophysiology of fibromyalgia. Nevertheless, to incrase the knowledge about the effect of drugs on the cortical function, we need to use feasible neuroimaging resources able to be applied in diverse contexts, and that allow to measure the effect of the drugs in real time. Among the neuroimaging resources, there is the Functional Near Infrared Spectroscopy (fNIRS), which allows to assess cortical activation estimating the uptake of regional oxygen, that accompanies local neuronal firing. The fNIRS measures changes in the concentration of oxy and desoxy hemoglobin. Given these considerations, we hypothezise that the pharmacological modulation induced by pregabalin could be measured, clinically through psychophysical pain testing, and at the neuroimaging level using fNIRS. Given that it is about the same system with the potential to be assessed in complementary and virtually simultaneous ways, we also hypothesize that there still could exist an association between the clinical modulation (psychophysical tests) and cortical sensorimotor activation (assessed by fNIRS). In this way, this study appraised the effect of a single dose of pregabalin (150 mg) in the cortical activation and psicophysical pain testing in fibromyalgic and in healthy subjects. In both groups, pregabalin was compared to placebo, in a randomized, double-blinded, cross-over trial design. We assessed the effect of pregabalin, within and between-groups, on the cortical activity in an indirect way via the changes in oxy-hemoglobin upon heat and pressure stimuliation inside a protocol of QST, and also compared the psychophysical pain tests results with the performance during a Left Hand Fingertapping Task. We studied women aging 18 to 65, 17 of them with fibromyalgia and 10 healthy controls. QST parameters were assessed one hour after a single dose of 150 mg of pregabalin. Results: At baseline, patients with fibromyalgia presented QST alterations suggestive of fine nerve fibers lesion: baseline HDT was higher in fibromyalgia (35.53±3.22 vs. 33.33±0.85, P<0.05), while PPT was lower (2.44±1.08 vs. 4.32±1.45, P<0.01) than healthy volunteers, but did not change with pregabalin. When compared to healthy subjects, HDT, HPT, and HT evoked smaller activation in the middle frontal, pre- and post-central gyri in fibromyalgia, that increased after pregabalin (only for HDT-induced activation), but that was not correlated to the HDT. HPT was inversely correlated to the activation in the superior frontal (rs=-0.552, p=0.033) and precentral gyri (rs=-0.545, p=0.036), remaining unchanged after pregabalin (rs=-0.52, p=0.047). HT was inversely correlated to the middle frontal (rs=-0.645, p=0.032) and precentral gyri activation (rs=-0.655, p=0.029), but was no longer correlated after pregabalin. PPT cortical activation did not differ between fibromyalgia and healthy volunteers. Conclusions: The psychophysical pain testing profile in fibromyalgia has a cortical correlate. Alterations in tests for small fibers support its probable peripheral neuropathic component, and was accompanied by decreased activation in sensorimotor areas but increased in pain-related cognitive processing cortexes, and whose activity is increased by pregabalin. Also, upon HT fibromyalgia patients recruited more areas related to pain cognitive processing, which could favor the hypothesis of a component of central sensitization in fibromyalgia, and which was poorly modulated by pregabalin. Taken together, these findings support the co-existence of both, peripheral and central alterations in fibromyalgia

Caffeine teratogenicity in rats: morphological characterization and hypothesized mechanisms

Caffeine consumption during pregnancy has been shown in the scientific literature to be associated with teratogenicity such as low birth weight, fetal malformations, and miscarriage. However, the morphological alterations of the offspring of dams exposed during pregnancy have not been consistently described, and the mechanisms why they occur remain elusive. Thus, we aimed to characterize the offspring malformations induced by moderate and high doses of caffeine during pregnancy. Dams were divided into three groups: control, moderate (0.3 g/L), and high dose (1.0 g/L) of caffeine, which was provided in the drinking water beginning on gestational day 1 and continuing throughout the entire gestation. At moderate doses, only one of the dams had stillborn pups, although no macroscopic malformations were observed. High doses of caffeine induced significantly more malformations (P&lt;0.001) and early death (before P4). The malformations observed were related to fetal development and cardiovascular alterations, namely bruises, macrocephaly with short limbs, abnormal development (or absence) of head structures and limbs, labial malformations, hydrops fetalis, and poor placental formation. We discussed the proposed mechanisms by which caffeine might induce these phenotypes, which may involve down-regulation of adenosine A1 receptors, and increased mothers’ catecholamines. Our findings further confirm the evidence of the teratogenic effects of high doses of caffeine administered during pregnancy. These findings support the recommendation to avoid caffeine exposure during pregnancy. Keywords: Caffeine; offspring; teratogenicity; pregnancy; hydrops; cardiovascular alteration

Dor neuropática em pacientes com HIV/AIDS em uso de terapia antirretroviral

A infecção pelo vírus da imunodeficiência humana (HIV) representa um dos maiores problemas de saúde da atualidade em virtude de seu caráter pandêmico e gravidade. O uso da terapia antirretroviral está associado ao desenvolvimento de diferentes tipos de dor, sendo a dor neuropática uma delas. A dor neuropática ocorre pela lesão do sistema nociceptivo, que envolve mudanças moleculares, fisiológicas e anatômicas. Considerando que a infecção por HIV gera custos elevados para o sistema de saúde, e que suas comorbidades elevam ainda mais esses custos, a compreensão dos mecanismos da dor nessa população possibilita uma melhor assistência e uma redução da carga para o sistema. A dor neuropática pode apresentar diferentes possíveis mecanismos fisiopatológicos envolvidos, tornando-se um desafio para o tratamento de pacientes com HIV. A compreensão sobre a neurofisiologia da dor neuropática e o HIV pode promover melhores abordagens aos pacientes e a redução de comorbidades associadas, com impacto na qualidade de vida. Palavras-chave: Dor neuropática; HIV; terapia antirretroviral

Caffeine teratogenicity in rats : morphological characterization and hypothesized mechanisms

Caffeine consumption during pregnancy has been shown in the scientific literature to be associated with teratogenicity such as low birth weight, fetal malformations, and miscarriage. However, the morphological alterations of the offspring of dams exposed during pregnancy have not been consistently described, and the mechanisms why they occur remain elusive. Thus, we aimed to characterize the offspring malformations induced by moderate and high doses of caffeine during pregnancy. Dams were divided into three groups: control, moderate (0.3 g/L), and high dose (1.0 g/L) of caffeine, which was provided in the drinking water beginning on gestational day 1 and continuing throughout the entire gestation. At moderate doses, only one of the dams had stillborn pups, although no macroscopic malformations were observed. High doses of caffeine induced significantly more malformations (P<0.001) and early death (before P4). The malformations observed were related to fetal development and cardiovascular alterations, namely bruises, macrocephaly with short limbs, abnormal development (or absence) of head structures and limbs, labial malformations, hydrops fetalis, and poor placental formation. We discussed the proposed mechanisms by which caffeine might induce these phenotypes, which may involve down-regulation of adenosine A1 receptors, and increased mothers’ catecholamines. Our findings further confirm the evidence of the teratogenic effects of high doses of caffeine administered during pregnancy. These findings support the recommendation to avoid caffeine exposure during pregnancy

Neuropathic pain in HIV/AIDS patients using antiretroviral therapy

A infecção pelo vírus da imunodeficiência humana (HIV) representa um dos maiores problemas de saúde da atualidade em virtude de seu caráter pandêmico e gravidade. O uso da terapia antirretroviral está associado ao desenvolvimento de diferentes tipos de dor, sendo a dor neuropática uma delas. A dor neuropática ocorre pela lesão do sistema nociceptivo, que envolve mudanças moleculares, fisiológicas e anatômicas. Considerando que a infecção por HIV gera custos elevados para o sistema de saúde, e que suas comorbidades elevam ainda mais esses custos, a compreensão dos mecanismos da dor nessa população possibilita uma melhor assistência e uma redução da carga para o sistema. A dor neuropática pode apresentar diferentes possíveis mecanismos fisiopatológicos envolvidos, tornando-se um desafio para o tratamento de pacientes com HIV. A compreensão sobre a neurofisiologia da dor neuropática e o HIV pode promover melhores abordagens aos pacientes e a redução de comorbidades associadas, com impacto na qualidade de vida.Human immunodeficiency virus (HIV) infection is a major health problem nowadays due to its pandemic character and severity. The use of antiretroviral therapy is associated with the development of different types of pain, and neuropathic pain is one of them. Neuropathic pain is caused by an injury to the nociceptive system, which involves molecular, physiological and anatomical changes. Considering that HIV infection generates high costs for the health system, and that its comorbidities raise such costs even more, understanding the mechanisms of pain in this population can result in better care practices and reduction of burden to the system. Neuropathic pain may present different pathophysiological mechanisms becoming a challenge for HIV treatment. The understanding of the neurophysiology of neuropathic pain and the HIV can promote better patient approaches and the reduction of associated comorbidities with an impact on quality of life

Caffeine teratogenicity in rats: morphological characterization and hypothesized mechanisms

Caffeine consumption during pregnancy has been shown in the scientific literature to be associated with teratogenicity such as low birth weight, fetal malformations, and miscarriage. However, the morphological alterations of the offspring of dams exposed during pregnancy have not been consistently described, and the mechanisms why they occur remain elusive. Thus, we aimed to characterize the offspring malformations induced by moderate and high doses of caffeine during pregnancy. Dams were divided into three groups: control, moderate (0.3 g/L), and high dose (1.0 g/L) of caffeine, which was provided in the drinking water beginning on gestational day 1 and continuing throughout the entire gestation. At moderate doses, only one of the dams had stillborn pups, although no macroscopic malformations were observed. High doses of caffeine induced significantly more malformations (P<0.001) and early death (before P4). The malformations observed were related to fetal development and cardiovascular alterations, namely bruises, macrocephaly with short limbs, abnormal development (or absence) of head structures and limbs, labial malformations, hydrops fetalis, and poor placental formation. We discussed the proposed mechanisms by which caffeine might induce these phenotypes, which may involve down-regulation of adenosine A1 receptors, and increased mothers’ catecholamines. Our findings further confirm the evidence of the teratogenic effects of high doses of caffeine administered during pregnancy. These findings support the recommendation to avoid caffeine exposure during pregnancy.   Keywords: Caffeine; offspring; teratogenicity; pregnancy; hydrops; cardiovascular alteration

Comparison of pain burden and psychological factors in Brazilian women living with HIV and chronic neuropathic or nociceptive pain : an exploratory study

Psychological factors including pain catastrophizing and resilience associate with adjustment and quality of life in people living with chronic pain. Nevertheless, their presentation among females living with HIV and chronic pain has been poorly studied. Given that chronic pain in those living with HIV might occur due to different mechanisms (nociceptive or neuropathic), we hypothesize that the associated psychological states could also differ between these groups. We aimed to compare pain frequency and interference, psychological factors and sleep quality between females living with chronic nociceptive or neuropathic pain. Also, we explored correlations between psychological factors, pain severity and interference in females living with HIV and chronic pain. We performed a cross sectional study assessing females living with HIV and chronic pain, and compared it with a female HIV-positive, painfree control sample in Brazil. To discriminate the most likely underlying mechanism for the chronic pain, we applied the Leeds Assessment for Neuropathic Signs and Symptoms (LANSS). Forty-nine females living with HIV and chronic pain were assessed, and divided in control (n = 12), nociceptive (n = 10) and neuropathic pain (n = 27) groups. Using validated scales, their pain catastrophizing, resilience, depression, anxiety and sleep disorders were assessed between May 2014 and August 2015. Compared to controls, females living with HIV and neuropathic chronic pain had higher pain frequency (p<0.001), interference on activities (p = 0.002), interference with emotions (p<0.001), catastrophizing (p<0.001), depression (p = 0.015), and lower resilience (p = 0.011). Catastrophizing was also significantly correlated to the burden of chronic pain. The type of chronic pain in females living with HIV should raise concerns regarding significant burden in psychological states in this population (particularly neuropathic pain). Using scales such as the LANSS to identify the type of choric pain, could be of use to address relevant issues for the patients, and to propose tailored therapies

Electroacupuncture analgesia is associated with increased serum brain-derived neurotrophic factor in chronic tension-type headache : a randomized, sham controlled, crossover trial

Background: Chronic tension-type headache (CTTH) is characterized by almost daily headaches and central sensitization, for which electroacupuncture (EA) might be effective. The central nervous system (CNS) plasticity can be tracked in serum using the brain-derived neurotrophic factor (BDNF), a neuroplasticity mediator. Thus, we tested the hypothesis that EA analgesia in CTTH is related to neuroplasticity indexed by serum BDNF. Methods: We enrolled females aged 18–60 years with CTTH in a randomized, blinded, placebo-controlled crossover trial, comparing ten EA sessions applied for 30 minutes (2–10 Hz, intensity by tolerance) in cervical areas twice per week vs. a sham intervention. Treatment periods were separated by two washout weeks. Pain on the 10-cm visual analog scale (VAS) and serum BDNF were assessed as primary outcomes. Results: Thirty-four subjects underwent randomization, and twenty-nine completed the protocol. EA was superior to sham to alleviate pain (VAS scores 2.38 ± 1.77 and 3.02 ± 2.49, respectively, P = 0.005). The VAS scores differed according to the intervention sequence, demonstrating a carryover effect (P < 0.05). Using multiple regression, serum BDNF was adjusted for the Hamilton depression rating scale (HDRS) and the VAS scores (r-squared = 0.07, standard β coefficients = −0.2 and −0.14, respectively, P < 0.001). At the end of the first intervention period, the adjusted BDNF was higher in the EA phase (29.31 ± 3.24, 27.53 ± 2.94 ng/mL, Cohen’s d = 0.55). Conclusion: EA analgesia is related to neuroplasticity indexed by the adjusted BDNF. EA modulation of pain and BDNF occurs according to the CNS situation at the moment of its administration, as it was related to depression and the timing of its administration

Association of anxiety with intracortical inhibition and descending pain modulation in chronic myofascial pain syndrome

Background: This study aimed to answer three questions related to chronic myofascial pain syndrome (MPS): 1) Is the motor cortex excitability, as assessed by transcranial magnetic stimulation parameters (TMS), related to state-trait anxiety? 2) Does anxiety modulate corticospinal excitability changes after evoked pain by Quantitative Sensory Testing (QST)? 3) Does the state-trait anxiety predict the response to pain evoked by QST if simultaneously receiving a heterotopic stimulus [Conditional Pain Modulation (CPM)]? We included females with chronic MPS (n = 47) and healthy controls (n = 11), aged 19 to 65 years. Motor cortex excitability was assessed by TMS, and anxiety was assessed based on the State-Trait Anxiety Inventory. The disability related to pain (DRP) was assessed by the Profile of Chronic Pain scale for the Brazilian population (B:PCP:S), and the psychophysical pain measurements were measured by the QST and CPM. Results: In patients, trait-anxiety was positively correlated to intracortical facilitation (ICF) at baseline and after QST evoked pain (β = 0.05 and β = 0.04, respectively) and negatively correlated to the cortical silent period (CSP) (β = -1.17 and β = -1.23, respectively) (P <0.05 for all comparisons). After QST evoked pain, the DRP was positively correlated to ICF (β = 0.02) (P < 0.05). Pain scores during CPM were positively correlated with trait-anxiety when it was concurrently with high DRP (β = 0.39; P = 0.02). Controls’ cortical excitability remained unchanged after QST. Conclusions: These findings suggest that, in chronic MPS, the imbalance between excitatory and inhibitory descending systems of the corticospinal tract is associated with higher trait-anxiety concurrent with higher DRP