Mechanism of Chuanxiong Rhizoma intervention on central sensitization of Panx1-Src-NMDAR-2B signaling pathway in neuropathic pain model rats / 中国中药杂志

Excitatory toxicity(ET) is an important factor of neuropathic pain(NPP) induced by central sensitization(CS), and the association of pannexin-1(Panx1)-Src-N-methyl-D-aspartate receptor subunit 2 B(NMDAR-2 B) is an important new pathway for ET to initiate CS. The present study confirmed whether the central analgesic effect of Chuanxiong Rhizoma extract(CRE) was achieved through the synchronous regulation of the brain and spinal pathways of Panx1-Src-NMDAR-2 B. In this study, dynamic and simulta-neo-us microdialysis of the brain and spinal cord in vivo combined with behavioristics, high performance liquid chromatography(HPLC)-fluorescence detection, microdialysis analysis(ISCUS~(flex)), ultrasensitive multifactorial electrochemiluminescence immunoassay, ELISA, and Western blot was employed to investigate the protein expression of NMDAR-2 B, Src, and Panx1, extracellular excitatory amino acids, cytokines, energy metabolites, and substance P in spinal dorsal horn(SDH) and anterior cingulate cortex(ACC) after CRE intervention with the rat model of spared sciatic nerve injury(SNI) as the experimental tool. Compared with the sham group, the SNI group exhibited diminished mechanical withdrawal threshold(MWT)(P<0.01), increased cold spray scores(P<0.01), glutamate(Glu), D-serine(D-Ser), and glycine(Gly) in extracellular fluids of ACC, and Glu, D-Ser, interleukin-1β(IL-1β), and lactic acid(Lac) in extracellular fluids of SDH(P<0.05), dwindled tumor necrosis factor(TNF-α)(P<0.05), and elevated protein levels of NMDAR-2 B, Src, and Panx1 in ACC(P<0.05). Compared with the SNI model rats, high-and medium-dose CRE(CRE-H/M) could potentiate the analgesic activity as revealed by the MWT test(P<0.05) and CRE-M enabled the decrease in cold spray scores(P<0.05). CRE-H/M could inhibit the levels of Glu, D-Ser and Gly in the extracellular fluids of ACC(P<0.05), and the levels of Glu in the extracellular fluids of SDH(P<0.05) in SNI rats. CRE-M significantly increased the levels of glucose(Gluc), Lac, interferon-gamma(IFN-γ), keratinocyte chemoattractant/human growth-regulated oncogenes(KC/GRO), and IL-4 in extracellular fluids of SDH in SNI rats(P<0.05). CRE-H/M/L could also inhibit the levels of NMDAR-2 B, Src and Panx1 in ACC and SDH in SNI rats(P<0.05). The central analgesic effect of CRE is presumedly related to the inhibited release of excitatory amino acid transmitters(Glu, D-Ser and Gly) in ACC and SDH of SNI rats, decreased protein expression of NMDAR-2 B, Src and Panx1 in the two regions, and the regulation of the Panx1-Src-NMDAR-2 B pathway in the spinal cord and brain. The above findings partially clarified the scientific basis of clinical analgesic effect of Chuanxiong Rhizoma.

Elemene Emulsion Injection Administration Reduces Neuropathic Pain by Inhibiting Astrocytic NDRG2 Expression within Spinal Dorsal Horn / 中国结合医学杂志

OBJECTIVE@#To investigate the mechanisms underlying elemene-induced analgesia in rats with spared nerve injury (SNI).@*METHODS@#Sixty-five rats were equally divided into 5 groups using a random number table: naive group, sham group, SNI group, SNI + elemene (40 mg·kg@*RESULTS@#The SNI rat model exhibited a significant decrease in paw withdrawal threshold and exploratory behaviour in the EPM (P<0.05). Consecutive administration of elemene alleviated SNI-induced mechanical allodynia and anxiety in rats (P<0.05). Immunohistochemical data showed that elemene decreased SNI-induced upregulation of NDRG2 within the SDH (P<0.05). Double immunofluorescent staining data further showed that elemene decreased SNI-induced upregulation of the number of GFAP immunoreactive (-ir), NDRG-ir, and GFAP/NDRG2 double-labelled cells within the SDH (P<0.05). Immunoblotting data showed that elemene decreased SNI-induced upregulation of GFAP and NDRG2 within the SDH (P<0.05).@*CONCLUSION@#Elemene possibly alleviated neuropathic pain by downregulating the expression of NDRG2 in spinal astrocytes in a rat model of SNI.

Beneficial effects of octreotide in alcohol-induced neuropathic pain. Role of H 2S, BDNF, TNF-α and Nrf2

ABSTRACT Purpose To explore the role and molecular mechanisms of neuroprotective effects of octreotide in alcohol-induced neuropathic pain. Methods Male Wistar rats were employed and were administered a chronic ethanol diet containing 5% v/v alcohol for 28 days. The development of neuropathic pain was assessed using von Frey hair (mechanical allodynia), pinprick (mechanical hyperalgesia) and cold acetone drop tests (cold allodynia). The antinociceptive effects of octreotide (20 and 40 µg·kg-1) were assessed by its administration for 28 days in ethanol-treated rats. ANA-12 (0.25 and 0.50 mg·kg-1), brain-derived neurotrophic factor (BDNF) receptor blocker, was coadministered with octreotide. The sciatic nerve was isolated to assess the biochemical changes including hydrogen sulfide (H2S), cystathionine β synthase (CBS), cystathionine γ lyase (CSE), tumor necrosis factor-α (TNF-α), BDNF and nuclear factor erythroid 2-related factor 2 (Nrf2). Results Octreotide significantly attenuated chronic ethanol-induced neuropathic pain and it also restored the levels of H2S, CBS, CSE, BDNF, Nrf2 and decreased TNF-α levels. ANA-12 abolished the effects of octreotide on pain, TNF-α, BDNF, Nrf2 without any significant effects on H2S, CBS, CSE. Conclusions Octreotide may attenuate the behavioral manifestations of alcoholic neuropathic pain, which may be due to an increase in H2S, CBS, CSE, BDNF, Nrf2 and a decrease in neuroinflammation.

Effects of vitamin D administration on nociception and spinal cord pro-oxidant and antioxidant markers in a rat model of neuropathic pain

Reactive oxygen species (ROS) are involved in neuropathic pain, a complicated condition after nerve tissue lesion. Vitamin D appears to improve symptoms of pain and exhibits antioxidant properties. We investigated the effects of oral administration of vitamin D3, the active form of vitamin D, on nociception, the sciatic functional index (SFI), and spinal cord pro-oxidant and antioxidant markers in rats with chronic constriction injury (CCI) of the sciatic nerve, a model of neuropathic pain. Vitamin D3 (500 IU/kg per day) attenuated the CCI-induced decrease in mechanical withdrawal threshold and thermal withdrawal latency (indicators of antinociception) and SFI. The vitamin prevented increased lipid hydroperoxide levels in injured sciatic nerve without change to total antioxidant capacity (TAC). Vitamin D3 prevented increased lipid hydroperoxide, superoxide anion generation (SAG), and hydrogen peroxide (H2O2) levels in the spinal cord, which were found in rats without treatment at 7 and 28 days post-CCI. A significant negative correlation was found between mechanical threshold and SAG and between mechanical threshold and H2O2 at day 7. Vitamin D3 also prevented decreased spinal cord total thiols content. There was an increase in TAC in the spinal cord of vitamin-treated CCI rats, compared to CCI rats without treatment only at 28 days. No significant changes were found in body weight and blood parameters of hepatic and renal function. These findings demonstrated, for first time, that vitamin D modulated pro-oxidant and antioxidant markers in the spinal cord. Since antinociception occurred in parallel with oxidative changes in the spinal cord, the oxidative changes may have contributed to vitamin D-induced antinociception.

Pharmacological treatment of central neuropathic pain: consensus of the Brazilian Academy of Neurology / Tratamento farmacológico da dor neuropática central: consenso da Academia Brasileira de Neurologia

ABSTRACT Background: Central neuropathic pain (CNP) is often refractory to available therapeutic strategies and there are few evidence-based treatment options. Many patients with neuropathic pain are not diagnosed or treated properly. Thus, consensus-based recommendations, adapted to the available drugs in the country, are necessary to guide clinical decisions. Objective: To develop recommendations for the treatment of CNP in Brazil. Methods: Systematic review, meta-analysis, and specialists opinions considering efficacy, adverse events profile, cost, and drug availability in public health. Results: Forty-four studies on CNP treatment were found, 20 were included in the qualitative analysis, and 15 in the quantitative analysis. Medications were classified as first-, second-, and third-line treatment based on systematic review, meta-analysis, and expert opinion. As first-line treatment, gabapentin, duloxetine, and tricyclic antidepressants were included. As second-line, venlafaxine, pregabalin for CND secondary to spinal cord injury, lamotrigine for CNP after stroke, and, in association with first-line drugs, weak opioids, in particular tramadol. For refractory patients, strong opioids (methadone and oxycodone), cannabidiol/delta-9-tetrahydrocannabinol, were classified as third-line of treatment, in combination with first or second-line drugs and, for central nervous system (CNS) in multiple sclerosis, dronabinol. Conclusions: Studies that address the treatment of CNS are scarce and heterogeneous, and a significant part of the recommendations is based on experts opinions. The CNP approach must be individualized, taking into account the availability of medication, the profile of adverse effects, including addiction risk, and patients' comorbidities.

RESUMO Introdução: A dor neuropática central (DNC) é frequentemente refratária às estratégias terapêuticas disponíveis e há poucas opções de tratamento baseado em evidência. Muitos pacientes com dor neuropática não são diagnosticados ou tratados adequadamente. Desse modo, recomendações baseadas em consenso, adaptadas à disponibilidade de medicamentos no país, são necessárias para guiar decisões clínicas. Objetivo: Desenvolver recomendações para o tratamento da DNC no Brasil. Métodos: Revisão sistemática, metanálise e discussão dos resultados entre especialistas e pesquisadores da área, considerando eficácia, perfil de eventos adversos, custo e disponibilidade do fármaco na saúde pública. Resultados: Foram encontrados 44 estudos sobre tratamento da DNC, dos quais 20 foram incluídos na análise qualitativa e 15, na quantitativa. Classificaram-se as medicações em primeira, segunda e terceira linhas de tratamento, baseando-se em revisão sistemática, meta-análise e opinião de especialistas. Como primeira linha, foram incluídos gabapentina, duloxetina e antidepressivos tricíclicos. Como segunda, venlafaxina, pregabalina para DNC secundária à lesão medular, lamotrigina para DNC pós-acidente vascular cerebral e, em associação aos fármacos de primeira linha, opioides fracos, em particular tramadol. Para os pacientes refratários, opioides fortes (metadona e oxicodona) e canabidiol/delta-9-tetrahidrocanabinol foram classificados como terceira linha de tratamento, em associação com drogas de primeira ou segunda linha, e, para DNC na esclerose múltipla, dronabinol. Conclusões: Os estudos que abordam o tratamento da DNC são escassos e heterogêneos, e parte significativa das recomendações é baseada em opiniões de especialistas. A abordagem da DNC deve ser individualizada, levando em conta a disponibilidade de medicação, o perfil de efeitos adversos, incluindo risco de dependência e as comorbidades do paciente.

Escin alleviates chemotherapy-induced peripheral neuropathic pain by inducing autophagy in the spinal cord of rats / 南方医科大学学报

OBJECTIVE@#To investigate the effect of escin in relieving chemotherapy-induced peripheral neuropathic pain in rats and explore and the underlying mechanism.@*METHODS@#Eighteen SD rats were randomly divided into 3 groups (@*RESULTS@#The rats in both the escin preconditioning group and escin postconditioning group showed obviously increased thresholds of mechanical allodynia and thermal hyperalgesia as compared with those in the control group (@*CONCLUSIONS@#Escin can alleviate chemotherapy-induced peripheral neuropathic pain in rats possibly by upregulating the expressions of autophagy-related proteins in the spinal cord.

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

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

Calcitonin as an analgesic agent: review of mechanisms of action and clinical applications / Calcitonina como agente analgésico: revisão dos mecanismos de ação e das aplicações clínicas

Abstract Background and objectives: Calcitonin is a polypeptide hormone regulating the metabolism of calcium in the body. For many years calcitonin has been used to maintain and improve bone mineral density and to reduce the fracture rate. Many studies showed that calcitonin had analgesic role in several painful circumstances. This pain-ameliorating effect is irrelevant to its osteoclastic inhibitory effect and mechanisms like altering Na+ channel and serotonin receptor expression or hypothesis including the endorphin-mediated mechanism were used to explain this effect. In this study we performed a thorough review on the role of calcitonin as an analgesic agent in different scenarios and investigated the fact that calcitonin can be a feasible medication to relieve pain. Method: Many studies focused on the analgesic effect of calcitonin in several painful circumstances, including acute pains related to vertebral fractures, metastasis, migraine and reflex sympathetic dystrophy as well as neuropathic pains related to spinal injuries or diabetes, and phantom pain. Also, calcitonin was showed to be a useful additive to local anesthesia in the case of controlling postoperative pain or trigeminal neuralgia more effectively. However we faced some contradictory data for conditions like lumbar canal stenosis, complex regional pain syndrome, phantom pain and malignancies. Conclusion: This study showed that calcitonin could be helpful analgesic agent in different painful situations. Calcitonin can be considered an eligible treatment for acute pains related to vertebral fractures and a feasible alternative for the treatment of the acute and chronic neuropathic pains where other medications might fail.

Resumo Justificativa e objetivos: A calcitonina é um hormônio polipeptídico que regula o metabolismo do cálcio no organismo. Por muitos anos a calcitonina tem sido usada para manter e melhorar a densidade mineral óssea e reduzir a incidência de fraturas. Muitos estudos mostraram que a calcitonina teve efeito analgésico em várias condições físicas de dor. Esse efeito de melhoria da dor é irrelevante diante de seu efeito inibidor osteoclástico e de mecanismos, tais como a alteração do canal de Na+ e da expressão do receptor de serotonina, inclusive a hipótese do mecanismo mediado pela endorfina, que foram usados para explicar esse efeito. Neste estudo, fizemos uma revisão completa sobre o papel da calcitonina como agente analgésico em diferentes cenários e investigamos o fato de que a calcitonina pode ser uma medicação viável para aliviar a dor. Método: Muitos estudos centraram no efeito analgésico da calcitonina em várias condições de dor, inclusive dores agudas relacionadas a fraturas vertebrais, metástases, enxaqueca e distrofia simpática reflexa, bem como dores neuropáticas relacionadas a lesões medulares ou ao diabetes e dor fantasma. Além disso, a calcitonina mostrou ser um aditivo útil à anestesia local para o controle mais efecaz da dor pós-operatória ou neuralgia do trigêmeo. Porém, nos deparamos com alguns dados contraditórios em condições como estenose do canal lombar, síndrome complexa da dor regional, dor fantasma e malignidades. Conclusão: Este estudo mostrou que a calcitonina pode ser um analgésico útil em diferentes condições de dor. A calcitonina pode ser considerada um tratamento elegível para as dores agudas relacionadas a fraturas vertebrais e uma opção viável para o tratamento das dores neuropáticas agudas e crônicas em que outros medicamentos podem falhar.

Migraña crónica sin aura, dolor referido a ATM: informe de caso / Cronic migrain without aura, referall pain in TMJ: Case report

Resumen Muchos pacientes presentan dolores de cabeza primarios que no son tomados en cuenta en la consulta diaria de odontología. Es común que los asocien a un dolor referido a la articulación témporomandibular, inclusive a un dolor dental de origen no odontogénico, donde se ve incluida esta estructura.

Abstract A lot of the patients present primary headaches and most of the time, they are not connected in the general practice of dentistry, it´s common that the patient relates the pain to the symptom of TMJ referral pain, or another dental pain non odontogenic, muscular or others.

Botulinum toxin type A in chronic neuropathic pain in refractory leprosy / Toxina Botulínica Tipo A em Dor Neuropática Crônica em Hanseníase

ABSTRACT Neuropathic pain is a chronic syndrome that is difficult to treat and often affects patients with leprosy. Recommended treatment includes the the use of analgesic drugs, codeine, tricyclic antidepressants, neuroleptics, anticonvulsants and thalidomide, but without consensus on uniform dose and fully satisfactory results. Objective: To analyze botulinum toxin type A (BoNT-A) effectiveness in treatment of chronic neuropathic pain in refractory leprous patients, as well as evaluate and compare the quality of life of patients before and after using the medication. Methods: We used a specific protocol including clinical, demographic, DN4 protocol, analogue scale (VAS), sensory evaluation and evaluation of the WHOQOL-BREF. Therapeutic intervention was performed with BOTOX® BTX-A 100U administered subcutaneously. Fifteen patients were evaluated on days 0, 10 and 60. Results: Patients on VAS showed pain between 5 and 10, in one case there was complete pain relief in 60 days, while others showed improvement in the first week with the return of symptoms with less intensity after this period. WHOQOL-BREF's domains Quality of Life and Physical to have a significant increase in QOL. Conclusion: BoNT-A proved to be a good therapeutic option in relieving pain with improved quality of life for these patients.

RESUMO A dor neuropática é uma síndrome crônica que é difícil de tratar e freqüentemente afeta pacientes com hanseníase. O tratamento recomendado inclui o uso de drogas analgésicas, codeína, antidepressivos tricíclicos, neurolépticos, anticonvulsivantes e talidomida, mas sem consenso sobre dose uniforme e resultados plenamente satisfatórios. Objetivo: Busca-se analisar a efetividade da toxina botulínica tipo A no tratamento da dor neuropática crônica hansênica refratária. Método: Estudo de intervenção do tipo ensaio clínico em portadores de dor neuropática crônica hansênica. Foram coletados dados epidemiológicos, protocolo DN4, escala analógica da dor (EVA), avaliação sensitiva, motora a avaliação do WHOQOL-Bref. Realizado intervenção terapêutica com toxina botulínica tipo A 100U. Os pacientes foram avaliados nos dias de 0, 10 e 60. A dor neuropática foi mais frequente no sexo masculino, na faixa etária de 40 à 49 anos. Resultados: Da forma Dimorfa, multibacilar com baciloscopia positiva e incapacidades presentes. Os escores EVA variam entre 5 e 10, todos os pacientes apresentaram alterações sensoriais. O WHOQOL-Bref apresentou melhora após o tratamento com TxBA. A TxBA foi bem tolerada o único efeito adverso notável foi dor leve. E com apenas uma única aplicação de TxBA promoveu efeitos analgésicos a longo prazo em pacientes com dor associada à alodinia, sugerindo que a analgesia observada pode ser causada por um efeito periférico da TxBA em terminações nociceptivas. Conclusão: O estudo sugere que a TxBA é uma boa opção para os casos de dor neuropática crônica hansênica, no entanto, novos estudos são necessários para confirmar estes resultados.

Effect of melatonin on the daytime sleepiness side-effect of gabapentin in adults patients with neuropathic pain / Efeito da melatonina sobre o efeito colateral de sonolência diurna da gabapentina em pacientes adultos com dor neuropática

Abstract Background and objectives: Gabapentin is an antiepileptic drug. Widely used for the management of neuropathic pain. Although it is known to be well tolerated, somnolence and dizziness are the most frequent adverse effects. In this study, we aimed to evaluate the effect of melatonin on daytime sleepiness side effect of gabapentin, sleep quality and pain intensity of patients with neuropathic pain. Methods: Patients suffering from "neuropathic pain" and planed to receive gabapentin therapy were randomly divided into two groups. Group 1 received melatonin 3 mg and gabapentin 900 mg orally, group 2 received matching placebo capsule and gabapentin 900 mg. The Epworth Sleepiness Scale, the Pittsburgh sleep quality index for assessment of sleep quality and Verbal Rating Scale were completed at the 0th, 10th and 30th days of treatment. Additive analgesic drug requirements were recorded. Results: Eighty patients were enrolled to the study; age, gender, ratio of additive analgesic consumption, baseline Epworth Sleepiness Scale, Pittsburg Sleep Quality index and Verbal Rating Scale scores were similar between the groups. Epworth Sleepiness Scale scores, Pittsburgh sleep quality index scores and Verbal Rating Scale scores in Group 1 were significantly lower than group 2 at the 10th day of treatment (p = 0.002, p = 0.003, p = 0.002 respectively). At the 30th day of treatment, Epworth Sleepiness Scale scores and Verbal Rating Scale scores were significantly lower in Group 1 (p = 0.002, p = 0.008 respectively). However, Pittsburgh sleep quality index scores did not significantly differ between the groups (p = 0.0566). Conclusions: Melatonin supplementation rapidly and significantly improved daytime sleepiness side-effect of gabapentin, however sleep quality of the patients with neuropathic pain was similar between groups.

Resumo Justificativa e objetivos: Gabapentina é um agente antiepiléptico, amplamente utilizado para o tratamento da dor neuropática. Embora conhecida por ser bem-tolerada, sonolência e tontura são os seus efeitos adversos mais frequentes. Neste estudo, nosso objetivo foi avaliar o efeito da melatonina sobre o efeito colateral de sonolência diurna da gabapentina, a qualidade do sono e a intensidade da dor em pacientes com dor neuropática. Métodos: Os pacientes que sofriam de "dor neuropática" e com prescrição para receber terapia com gabapentina foram divididos aleatoriamente em dois grupos. O Grupo 1 recebeu 3 mg de melatonina e 900 mg de gabapentina por via oral, o Grupo 2 recebeu uma cápsula de placebo correspondente e 900 mg de gabapentina. A escala de sonolência de Epworth (ESS), o índice de qualidade do sono de Pittsburgh para avaliação da qualidade do sono (PSQI) e a escala de avaliação verbal (VRS) foram aplicados nos dias 0, 10 e 30 de tratamento. A necessidade de medicamentos analgésicos adicionais foi registrada. Resultados: Oitenta pacientes foram incluídos no estudo; idade, sexo, quantidade de analgésico adicional consumida e os escores basais de ESS, PSQI e VRS foram semelhantes entre os grupos. Os escores ESS, PSQI e VRS do Grupo 1 foram significativamente menores que os do Grupo 2 no décimo dia de tratamento (p = 0,002, p = 0,003, p = 0,002, respectivamente). No trigésimo dia de tratamento, os escores ESS e VRS foram significativamente menores no Grupo 1 (p = 0,002, p = 0,008, respectivamente). No entanto, os escores PSQI não diferiram significativamente entre os grupos (p = 0,0566). Conclusões: A suplementação de melatonina melhorou de forma rápida e significativa o efeito colateral de sonolência diurna da gabapentina, mas a qualidade do sono dos pacientes com dor neuropática foi semelhante entre os grupos.

Chronic treatment with carvacrol improves passive avoidance memory in a rat model of Parkinson's disease / O tratamento com carvacrol melhora a memória de esquiva passiva em um modelo da doença de Parkinson em ratos

ABSTRACT The present study investigated the effects of carvacrol on motor and memory deficits as well as hyperalgesia in the 6-OHDA-lesioned rat model of Parkinson's disease. The animals were subjected to unilateral microinjection of 6-OHDA into the medial forebrain bundle and treated with carvacrol (25, 50 and 100 mg/kg, ip) for six weeks after surgery. The 6-OHDA-lesioned rats showed contralateral rotations towards the lesion side, which was accompanied by learning and memory deficits in a passive avoidance test and a decrease in tail withdrawal latency in a tail flick test at the end of week 6. The results also showed that treatment with carvacrol at a dose of 25 mg/kg ameliorated memory deficits, with no effect on rotations and hyperalgesia in lesioned rats. In conclusion, carvacrol improves memory impairments in rats with Parkinson's disease; therefore, it may serve as an adjunct therapy for the alleviation of memory deficits in Parkinson's disease patients.

RESUMO O presente estudo investigou os efeitos do carvacrol nos déficits motores e de memória, bem como na hiperalgesia, em um modelo da doença de Parkinson (DP) em ratos com lesões 6-OHDA. Os animais foram submetidos a microinjeção unilateral de 6-OHDA no feixe mediano do prosencéfalo e tratados com carvacrol (25, 50 e 100 mg / kg, ip) durante 6 semanas após a cirurgia. Os ratos com lesões 6-OHDA mostraram rotações contralaterais para o lado da lesão, que foram acompanhadas de déficits de aprendizagem e de memória em um teste de evitação passiva, e de uma diminuição da latência de retirada da cauda em um teste de cauda no final da semana 6. Os resultados também mostraram que o tratamento crônico com carvacrol a uma dose de 25 mg / kg aliviou os déficits de memória, sem efeito sobre rotações e hiperalgesia em ratos lesados. Em conclusão, o carvacrol melhora a deficiência de memória em ratos com DP e, portanto, pode servir como uma terapia complementar para aliviar os déficits de memória em pacientes com DP.

Exogenous neuregulin-1 attenuates STZ-induced diabetic peripheral neuropathic pain in rats

Abstract Purpose: To investigate whether modulating NRG1 could attenuate diabetic neuropathic pain and analyze the underlying mechanism. Methods: Male SD rats were randomly divided into control group, diabetic group, NRG1 intervention group. After STZ-induced 2 weeks, NRG1 intervention daily for consecutive 7 days. 4 weeks after NRG1 intervention, both the mechanical withdrawal threshold and the morphological changes of the dorsal root ganglion and sural nerve were observed. Meanwhile, the expression of NGF, IL-1β, TNF-α in spinal cord were determined. Results: Compared with the diabetic group, NRG1 treatment improved the mechanical withdrawal threshold in diabetic rats, pathological changes of dorsal root ganglion and sural nerve were alleviated by NRG1 treatment with electron microscopy imagine. Moreover, compared with the control group, the expression of NGF was significantly decreased and the production of IL-1β, TNF-α were markedly induced in diabetic group. Furthermore, NRG1 treatment could normalized the above effect as compared to diabetic group. Conclusion: NRG1 exerted positive effects on the behavioral and pathological changes of rats with STZ-induced diabetic neuropathic pain, the underlying mechanism might be related to the promotion of NGF excretion and the inhibition of inflammatory cytokines excretion.

Effects of N-acetylcysteine on spinal cord oxidative stress biomarkers in rats with neuropathic pain

N-acetylcysteine (NAC) inhibits nociceptive transmission. This effect has been associated partly with its antioxidant properties. However, the effect of NAC on the levels of lipid hydroperoxides (a pro-oxidant marker), content of ascorbic acid (a key antioxidant molecule of nervous tissue) and total antioxidant capacity (TAC) is unknown. Thus, our study assessed these parameters in the lumbosacral spinal cord of rats with chronic constriction injury (CCI) of the sciatic nerve, one of the most commonly employed animal models of neuropathic pain. Thirty-six male Wistar rats weighing 200-300 g were equally divided into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve). All rats received intraperitoneal injections of NAC (150 mg·kg−1·day−1) or saline for 1, 3, or 7 days. Rats were killed 1, 3, and 7 days after surgery. NAC treatment prevented the CCI-induced increase in lipid hydroperoxide levels only at day 1, although the amount was higher than that found in naive rats. NAC treatment also prevented the CCI-induced increase in ascorbic acid content, which occurred at days 1, 3, and 7. No significant change was found in TAC with NAC treatment. The changes observed here may be related to the antinociceptive effect of NAC because modulation of oxidative-stress parameters seemed to help normalize the spinal cord oxidative status altered by pain.

N-acetylcysteine downregulates phosphorylated p-38 expression but does not reverse the increased superoxide anion levels in the spinal cord of rats with neuropathic pain

We determined the effect of N-acetylcysteine (NAC) on the expression of the phosphorylated p38 (p-p38) protein and superoxide anion generation (SAG), two important players in the processing of neuropathic pain, in the lumbosacral spinal cord of rats with chronic constriction injury (CCI)-induced neuropathic pain. The sciatic functional index (SFI) was also measured to assess the functional recovery post-nerve lesion. Thirty-six male Wistar rats were divided equally into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve), which received 2, 4, or 8 intraperitoneal injections of NAC (150 mg·kg-1·day-1) or saline beginning 4 h after CCI. Rats were sacrificed 1, 3, and 7 days after CCI. The SFI was measured on these days and the lumbosacral spinal cord was used for analysis of p-p38 expression and SAG. CCI induced a decrease in SFI as well as an increase in p-p38 expression and SAG in the spinal cord. The SFI showed a partial recovery at day 7 in saline-treated CCI rats, but recovery was improved in NAC-treated CCI rats. NAC induced a downregulation in p-p38 expression at all time-points evaluated, but did not reverse the increased SAG induced by CCI. Since p-p38 is a mediator in neuropathic pain and/or nerve regeneration, modulation of this protein may play a role in NAC-induced effects in CCI rats.

Uso de abobotulintoxina a para dolor neuropático intratable: reporte de 9 casos / Experience with abobotulintoxin a for intractable neuropathic pain: a nine-nases report

INTRODUCCIÓN: el uso de toxina botulínica tipo A por vía subcutánea ha sido reportado en la literatura durante la última década. el mecanismo de acción para este uso no ha sido del todo aclarado, y los pacientes con más probabilidades de beneficiarse de las inyecciones de toxina botulínica tipo a, son aquéllos con dolor periférico caracterizado por existencia de alodinia, hiperalgesia y dolor paroxístico. el reporte en literatura ha sido con uso de onabotulintoxina a. MATERIAL Y MÉTODO: el presente estudio descriptivo-observacional tuvo por fin analizar los resultados en alivio del dolor de 9 pacientes con dolor neuropático, tratados con inyecciones de preparado abobotulintoxina a en la unidad de alivio del dolor de hospital público de región metropolitana de Chile, considerados refractarios a tratamiento farmacológico combinado para dolor neuropático a dosis máximas, que tenían componente de alodinia y dolor paroxístico como característica de dolor neuropático y que recibieron inyección de abobotulintoxina a subcutánea. RESULTADOS: 7 de 9 pacientes obtuvieron resultados esperados según lo reportado por la literatura, con alivio del dolor medido en escala numérica: 50% de alodinia, tras primera dosis; y del 80% de dolor paroxístico incidental, tras segunda dosis; tres meses después de la primera dosis, disminución en escala numérica de alodinia en un 80%. de ellos, 5 lograron disminuir requerimiento de opioides potentes. 2 pacientes de los 9 no tuvieron resultados satisfactorios: 1 no tuvo ningún resultado y 1 tuvo resultado favorable, pero con breve duración del efecto.CONCLUSIONES: la inyección subcutánea de abobotulintoxina A puede constituir una herramienta terapéutica eficaz en pacientes con dolor neuropático, tal como ha demostrado ser onabotulintoxina a.

BACKGROUND: the use of botulinum toxin type a subcutaneously has been reported in the literature in the last decade. the mechanism of action for this use has not been fully elucidated, given the effect reported in relief of allodynia, paroxysmal pain and hyperalgesia. the report in the literature is with the use of onabotulintoxin a. MATERIAL AND METHOD: to analyze results in pain relief in 9 patients with intractable neuropathic pain treated with abobotulintoxin a injections, in the pain relief unit of a public hospital in the metropolitan region of Chile, with an observational, retrospective and descriptive study. clinical record analysis of 9 individuals with neuropathic pain considered refractory to combined pharmacological treatment for neuropathic pain at maximal doses, who had allodynia component and paroxysmal pain as a characeristic of neuropathic pain, and who received injection of subcutaneous or intradermal abobotulintoxin A in the area of persistent allodynia. RESULTS 7 patients out of 9 had expected outcomes, allodynia relief of at least 50% after the first dose, and 80% relief of incidental paroxysmal pain and with relief of 80% allodynia after the second dose three months after the first. of these, 5 were able to decrease the requirement of potent opioids. 2 patients out of 9 had no satisfactory results: 1 had no results, and 1 had a favorable outcome but with a short duration of effect. CONCLUSIONS: subcutaneous injection of abobotulintoxin a may be an effective therapeutic tool in patients with neuropathic pain characterized by allodynia and paroxysmal pain.

Paravertebral block for management of acute postoperative pain and intercostobrachial neuralgia in major breast surgery / Bloqueio paravertebral no controle da dor aguda pós-operatória e dor neuropática do nervo intercostobraquial em cirurgia mamária de grande porte

Abstract Background: Several locoregional techniques have been described for the management of acute and chronic pain after breast surgery. The optimal technique should be easy to perform, reproducible, with little discomfort to the patient, little complications, allowing good control of acute pain and a decreased incidence of chronic pain, namely intercostobrachial neuralgia for being the most frequent entity. Objectives: The aim of this study was to evaluate the paravertebral block with preoperative single needle prick for major breast surgery and assess initially the control of postoperative nausea and vomiting (PONV) and acute pain in the first 24 h and secondly the incidence of neuropathic pain in the intercostobrachial nerve region six months after surgery. Methods: The study included 80 female patients, ASA I-II, aged 18-70 years, undergoing major breast surgery, under general anesthesia, stratified into 2 groups: general anesthesia (inhalation anesthesia with opioids, according to hemodynamic response) and paravertebral (paravertebral block with single needle prick in T4 with 0.5% ropivacaine + adrenaline 3 µg mL−1 with a volume of 0.3 mL kg−1 preoperatively and subsequent induction and maintenance with general inhalational anesthesia). In the early postoperative period, patient-controlled analgesia (PCA) was placed with morphine set for bolus on demand for 24 h. Intraoperative fentanyl, postoperative morphine consumption, technique-related complications, pain at rest and during movement were recorded at 0 h, 1 h, 6 h and 24 h, as well as episodes of PONV. All variables identified as factors contributing to pain chronicity age, type of surgery, anxiety according to the Hospital Anxiety and Depression Scale (HADS), preoperative pain, monitoring at home; body mass index (BMI) and adjuvant chemotherapy/radiation therapy were analyzed, checking the homogeneity of the samples. Six months after surgery, the incidence of neuropathic pain in the intercostobrachial nerve was assessed using the DN4 scale. Results: The Visual Analog Scale (VAS) values of paravertebral group at rest were lower throughout the 24 h of study 0 h 1.90 (±2.59) versus 0.88 (±1.5) 1 h 2.23 (±2.2) versus 1.53 (±1.8) 6 h 1.15 (±1.3) versus 0.35 (±0.8); 24 h 0.55 (±0.9) versus 0.25 (±0.8) with statistical significance at 0 h and 6 h. Regarding movement, paravertebral group had VAS values lower and statistically significant in all four time points: 0 h 2.95 (±3.1) versus 1.55 (±2.1); 1 h 3.90 (±2.7) versus 2.43 (±1.9) 6 h 2.75 (±2.2) versus 1.68 (±1.5); 24 h 2.43 (±2.4) versus 1.00 (±1.4). The paravertebral group consumed less postoperative fentanyl (2.38 ± 0.81 µg kg−1 versus 3.51 ± 0.81 µg kg−1) and morphine (3.5 mg ± 3.4 versus 7 mg ± 6.4) with statistically significant difference. Chronic pain evaluation of at 6 months of paravertebral group found fewer cases of neuropathic pain in the intercostobrachial nerve region (3 cases versus 7 cases), although not statistically significant. Conclusions: Single-injection paravertebral block allows proper control of acute pain with less intraoperative and postoperative consumption of opioids but apparently it cannot prevent pain chronicity. Further studies are needed to clarify the role of paravertebral block in pain chronicity in major breast surgery.

Resumo Justificativa: Estão descritas várias técnicas locorregionais para a abordagem da dor aguda e dor crônica após cirurgia de mama. O ideal seria uma técnica fácil de fazer, reprodutível, com pouco desconforto para as doentes, com poucas complicações e que permitirá um bom controle da dor aguda e uma diminuição da incidência de dor crônica, notadamente dor neuropática do intercostobraquial, por ser a entidade mais frequente. Objetivos: Estudar a aplicação de bloqueio paravertebral com picada única no pré-operatório de cirurgia mamária de grande porte. Avaliar numa primeira fase o controle de dor aguda e náuseas-vômitos no pós-operatório (NVPO) nas primeiras 24 horas e numa segunda fase a incidência de dor neuropática na região do nervo intercostobraquial seis meses após a cirurgia. Métodos: Foram incluídas 80 doentes do sexo feminino, ASA I-II, entre 18 e 70 anos, submetidas a cirurgia mamária de grande porte sob anestesia geral, estratificadas em dois grupos: anestesia geral (anestesia geral inalatória com opioides segundo resposta hemodinâmica) e paravertebral (bloqueio paravertebral com picada única em T4 com ropivacaína 0,5% + adrenalina 3 µg/mL com um volume de 0,3 mL/kg pré-operatoriamente e posterior indução e manutenção com anestesia geral inalatória). No pós-operatório imediato foi colocada PCA (Patient-controlled analgesia) de morfina programada com bolus a demanda durante 24 horas. Foram registados fentanil intraoperatório, consumo de morfina pós-operatória, complicações relacionadas com as técnicas, dor em repouso e ao movimento a 0, 1 h, 6 h e 24 h, assim como os episódios de NVPO. Foram analisadas todas as variáveis identificadas como fatores de cronificação da dor idade, tipo de cirurgia, ansiedade segundo escala de HADS (Hospital Anxiety and Depression scale), dor pré-operatória; acompanhamento no domicílio; índice de massa corporal (IMC), tratamentos adjuvantes de quimioterapia/radioterapia e foi verificada a homogeneidade das amostras. Aos seis meses da cirurgia foi avaliada, segundo escala DN4, a incidência de dor neuropática na área do nervo intercostobraquial. Resultados: O grupo paravertebral teve valores de VAS (Escala Visual Analógica) em repouso mais baixos ao longo das 24 horas de estudo 0 h 1,90 (± 2,59) versus 0,88 (± 1,5); 1 h 2,23 (± 2,2) versus 1,53 (± 1,8); 6 h 1,15 (± 1,3) versus 0,35 (± 0,8); 24 h 0,55 (± 0,9) versus 0,25 (± 0,8) com significado estatístico às 0 e às 6 horas. Em relação ao movimento o grupo paravertebral teve valores de VAS mais baixos e com significância estatística nos quatro momentos de avaliação: 0 h 2,95 (± 3,1) versus 1,55 (± 2,1); 1 h 3,90 (± 2,7) versus 2,43 (± 1,9) 6 h 2,75 (± 2,2) versus 1,68 (± 1,5); 24 h 2,43 (± 2,4) versus 1,00 (± 1,4). O grupo paravertebral consumiu menos fentanil (2,38 ± 0,81 µg/Kg versus 3,51 ± 0,81 µg/Kg) e menos morfina no pós-operatório (3,5 mg ± 3,4 versus 7 mg ± 6,4), com diferença estatisticamente significativa. Na avaliação de dor crônica aos seis meses no grupo paravertebral houve menos casos de dor neuropática na região do nervo intercostobraquial (três versus sete) embora sem significância estatística. Conclusões: O bloqueio paravertebral com picada única permite um adequado controle da dor aguda com menor consumo de opioides intraopreatórios e pós-operatórios, mas aparentemente não consegue evitar a cronificação da dor. Mais estudos são necessários para esclarecer o papel do bloqueio paravertebral na cronificação da dor em cirurgia mamária de grande porte.

Cannabinoids in neurology – Brazilian Academy of Neurology / Canabinoides e seu uso em neurologia – Academia Brasileira de Neurologia

O uso do canabidiol em algumas condições neurológicas foi liberado pelo Conselho Regional de Medicina de São Paulo e pela Agência Nacional de Vigilância Sanitária (ANVISA). Especialistas em nome da Academia Brasileira de Neurologia prepararam uma posição crítica sobre o uso do canabidiol e outros derivados da cannabis em doenças neurológicas.

The use of cannabidiol in some neurological conditions was allowed by Conselho Regional de Medicina de São Paulo and by Agência Nacional de Vigilância Sanitária (ANVISA). Specialists on behalf of Academia Brasileira de Neurologia prepared a critical statement about use of cannabidiol and other cannabis derivatives in neurological diseases.

Placebo and nocebo effects in the neurological practice / Efeitos placebo e nocebo na prática neurológica

Knowledge of placebo and nocebo effects is essential to identify their influence on the results in clinical practice and clinical trials, and thereby properly interpret their results. It is known that the gold standard of clinical trials research is the double-blind, placebo-controlled, randomized clinical study. The objective of this review is to distinguish specific from non-specific effects, so that the presence of positive effects in the group that received placebo (placebo effect) and the presence of adverse effects in the group receiving placebo (nocebo effect) lead to confounding in interpreting the results. Placebo and nocebo effects have been considered in neurological diseases such as depression, pain, headache, multiple sclerosis, epilepsy. As placebo and nocebo effects are also present in clinical practice, the purpose of this review is to draw attention to their influence on neurological practice, calling attention to the development of measures that can minimize them.

O conhecimento dos efeitos placebo e nocebo é essencial para identificar a sua influência sobre os resultados na prática clínica e ensaios clínicos, e, assim, interpretar corretamente seus resultados. Sabe-se que o padrão-ouro dos estudos clínicos de pesquisa é o ensaio clínico randomizado, placebo-controlado, duplo-cego. O objetivo da revisão é distinguir os efeitos específicos e não específicos, de modo que a presença de efeitos positivos no grupo que recebeu placebo (efeito placebo) e a presença de efeitos adversos no grupo que recebeu placebo (efeito nocebo) levam à confusão na interpretação dos resultados. Placebo e nocebo são descritos em doenças neurológicas como a depressão, dor, cefaleia, esclerose múltipla, epilepsia. Como os efeitos placebo e nocebo também se projetam na prática clínica, o objetivo desta revisão é o de destacar sua influência na prática neurológica, chamando a atenção para o desenvolvimento de medidas que possam minimizá-los.

Efficacy of Direct Injection of Etanercept into Knee Joints for Pain in Moderate and Severe Knee Osteoarthritis

PURPOSE: Osteoarthritic (OA) pain is largely considered to be inflammatory pain. However, during the last stage of knee OA, sensory nerve fibers in the knee are shown to be significantly damaged when the subchondral bone junction is destroyed, and this can induce neuropathic pain. Several authors have reported that tumor necrosis factor-alpha (TNFalpha) in a knee joint plays a crucial role in pain modulation. The purpose of the current study was to evaluate the efficacy of etanercept, a TNFalpha inhibitor, for pain in knee OA. MATERIALS AND METHODS: Thirty-nine patients with knee OA and a 2-4 Kellgren-Lawrence grading were evaluated in this prospective study. Patients were divided into two groups; hyaluronic acid (HA) and etanercept injection. All patients received a single injection into the knee. Pain scores were evaluated before and 4 weeks after injection using a visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and they were compared between the groups. RESULTS: Before injection, VAS and WOMAC scores were not significantly different between the groups (p>0.05). Significant pain relief was found in the etanercept group at 1 and 2 weeks by VAS, and at 4 weeks by WOMAC score, compared with the HA group (p<0.05). No adverse events were observed in either group. CONCLUSION: Direct injection of etanercept into OA knee joints was an effective treatment for pain in moderate and severe OA patients. Furthermore, this finding suggests that TNFalpha is one factor that induces OA pain.