Protective Mechanism of Electroacupuncture on Peripheral Neurotoxicity Induced by Oxaliplatin in Rats / 中国结合医学杂志

OBJECTIVE@#To study the effect of electroacupuncture (EA) on oxaliplatin-induced peripheral neuropathy (OIPN) in rats.@*METHODS@#Male Sprague-Dawley rats were equally divided into 3 groups using a random number table: the control group, the OIPN group, and the EA (OIPN + EA) group, with 10 rats in each. The time courses of mechanical, cold sensitivity, and microcirculation blood flow intensity were determined. The morphology of the dorsal root ganglion (DRG) was observed by electron microscopic examination. The protein levels of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the transient receptor potential (TRP) protein family in DRGs were assayed by Western blot.@*RESULTS@#EA treatment significantly reduced mechanical allodynia and cold allodynia in OIPN rats (P<0.01). Notably, oxaliplatin treatment resulted in impaired microcirculatory blood flow and pathomorphological defects in DRGs (P<0.01). EA treatment increased the microcirculation blood flow and attenuated the pathological changes induced by oxaliplatin (P<0.01). In addition, the expression levels of Nrf2 and HO-1 were down-regulated, and the TRP protein family was over-expressed in the DRGs of OIPN rats (P<0.01). EA increased the expression levels of Nrf2 and HO-1 and decreased the level of TRP protein family in DRG (P<0.05 or P<0.01).@*CONCLUSION@#EA may be a potential alternative therapy for OIPN, and its mechanism may be mainly mediated by restoring the Nrf2/HO-1 signaling pathway.

The Mechanistic Basis for Photobiomodulation Therapy of Neuropathic Pain by Near Infrared Laser Light

Background and Objective Various irradiances have been reported to be beneficial for the treatment of neuropathic pain with near infrared light. However, the mechanistic basis for the beneficial outcomes may vary based on the level of irradiance or fluence rate used. Using in vivo and in vitro experimentalmodels, this study determined the mechanistic basis of photobiomodulation therapy (PBMT) for the treatment of neuropathic pain using a high irradiance. Study Design/Materials and Methods ln vitro experiments: Cultured, rat DRG were randomly assigned to control or laser treatment (L T) groups with different irradiation times (2, 5, 30, 60 or 120s). The laser parameters were: output power » 960 mW, irradiance » 300mW/cm2, 808 nm wavelength and spot size » 3cm diameter/ area » 7.07cm2, with different fluences according to irradiation times. Mitochondrial metabolic activity was measured with the MTS assay. The DRG neurons were immunostained using a primary antibody to ß-Tubulin III. ln vivo experiments: spared nerve injury surgery (SNI), an animal model of persistent peripheral neuropathic pain, was used. The injured rats were randomly divided into three groups (n » 5). 1) Control: SNI without LT, 2) Short term: SNI with LT on day 7 and euthanized on day 7, 3) Long term: SNI with LT on day 7 and euthanized on day 22. An 808 nm wavelength laser was used for all treatment groups. Treatment was performed once on Day 7 post-surgery. The transcutaneous treatment parameters were: output power: 10 W, fluence rate: 270 mW/cm2, treatment time: 120s. The laser probe was moved along the course of the sciatic/sural nerve during the treatment. Within 1 hour of irradiation, behavior tests were performed to assess its immediate effect on sensory allodynia and hyperalgesia caused by SNI. Results ln vitro experiments: Mitochondrial metabolism was significantly lower compared with controls for all LT groups. Varicosities and undulations formed in neurites of DRG neurons with a cell body diameter 30µm or less. ln neurites of DRG neurons with a cell body diameter of greater than 30µm, varicosities formed only in the 120s group. ln vivo experiments: For heat hyperalgesia, there was a statistically significant reduction in sensitivity to the heat stimulus compared with the measurements done on day 7 prior to LT. A decrease in the sensitivity to the heat stimulus was found in the LT groups compared with the control group on day 15 and 21. For cold allodynia and mechanical hyperalgesia, a significant decrease in sensitivity to cold and pin prick was found within 1 hour after L T. Sensitivity to these stimuli returned to the control levels after 5 days post-L T. No significant difference was found in mechanical allodynia between control and L T groups for all time points examined. Conclusion These in vitro and in vivo studies indicate that treatment with an irradiance/fluence rate at 270 m W/cm2 or higher at the level of the nerve can rapidly block pain transmission. A combination therapy is proposed to treat neuropathic pain with initial high irradiance/fluence rates for fast pain relief, followed by low irradiance/ fluence rates for prolonged pain relief by altering chronic inflammation.

Exercise training attenuates acute hyperalgesia in streptozotocin-induced diabetic female rats

OBJECTIVES: We investigated the effects of chronic (eight weeks) low-to moderate-intensity swimming training on thermal pain sensitivity in streptozotocin-induced diabetic female rats. METHODS: Female Wistar rats (n = 51) were divided into the following groups: trained streptozotocin-induced diabetic rats [hyperglycemic trained (HT)], sedentary streptozotocin-induced diabetic rats [hyperglycemic sedentary (HS)], normoglycemic trained rats (NT) and normoglycemic sedentary rats (NS). Diabetes was induced by a single injection of streptozotocin (50 mg/kg, i.p.). One day after the last exercise protocol (60 min/day, five days/week for eight weeks) in the trained groups or after water stress exposure (ten min/twice a week) in the sedentary groups, the rats were subjected to a hot plate test. RESULTS: After eight weeks of swimming training, streptozotocin-induced diabetic rats presented a significantly lower body mass (trained: 219.5±29 g, sedentary: 217.8±23 g) compared with the normoglycemic groups (trained: 271±24 g, sedentary: 275.7±32 g). Interestingly, we did not find differences in blood glucose levels (mg/dl) between the trained and sedentary groups of the hyperglycemic or normoglycemic rats (HT: 360.2±6.6, HS: 391.7±6.7, NT: 83.8±14.0, NS: 77.5±10.1). In the hot plate test, the rats from the HT group presented a significantly lower latency than the other rats (HT: 11.7±7.38 s, HS: 7.02±7.38 s, NT: 21.21±7.64 s, NS: 22.82±7.82 s). CONCLUSION: Low-to-moderate swimming training for a long duration reduces thermal hyperalgesia during a hot plate test in streptozotocin-induced diabetic female rats.

Tratamento farmacológico da hiperalgesia experimentalmente induzida pelo núcleo pulposo / Pharmacologic treatment of hyperalgesia experimentally induced by nucleus pulposus

OBJETIVO: Avaliar o efeito de drogas anti-inflamatórias (dexametasona, indometacina, atenolol, indometacina e atenolol) e analgésica (morfina) sobre a hiperalgesia experimentalmente induzida pelo núcleo pulposo em contato com o gânglio da raiz dorsal de L5. MÉTODOS: Trinta ratos Wistar machos com peso de 220 a 250g foram utilizados no estudo. A indução da hiperalgesia foi realizada por meio do contato de fragmento de núcleo pulposo retirado da região sacrococcígea e colocado sobre o gânglio da raiz dorsal de L5. Os 30 animais foram divididos em grupos experimentais de acordo com a droga utilizada. As drogas foram administradas durante duas semanas a partir da realização do procedimento cirúrgico para a indução da hiperalgesia. A hiperalgesia mecânica e térmica foram avaliadas por meio do teste da pressão constante da pata, von Frey eletrônico e Hargraves por um período de sete semanas. RESULTADOS: A maior redução da hiperalgesia foi observada no grupo de animais tratados pela morfina, seguido pela dexametasona, indometacina e atenolol. A redução da hiperalgesia foi observada após a interrupção da administração das drogas, com exceção do grupo de animais tratados com morfina, nos quais ocorreu aumento da hiperalgesia após a interrupção do tratamento. CONCLUSÕES: A hiperalgesia induzida pelo contato do núcleo pulposo com o gânglio da raiz dorsal pode ser reduzida com a administração de anti-inflamatórios e analgésicos, tendo sido observado a maior redução da hiperalgesia com a administração da morfina e dexametasona.

OBJECTIVE: To evaluate the effect of antiinflammatory (dexamethasone, indomethacin, atenolol, indomethacin and atenolol) and analgesic drugs (morphine) on hyperalgesia experimentally induced by nucleus pulposus (NP) contact with the L5- dorsal root ganglion (DRG). METHODS: Thirty male Wistar rats with weights ranging from 220 to 250 g were used in the study. The hyperalgesia was induced by contact of a fragment of NP removed from the sacrococcygeal region and placed on the dorsal root ganglion of L5. The 30 animals were divided into experimental groups according to the drug administered. The drugs were administered during the two weeks after the surgical procedure to induce hyperalgesia. Mechanical and thermal hyperalgesia was evaluated by the paw pressure test, von Frey electronic test, and the Hargraves test, for a period of seven weeks. RESULTS: The greatest reduction of hyperalgesia was observed in animals treated by morphine and dexamethasone, followed by dexamethasone, indomethacin, and atenolol. The reduction of hyperalgesia was observed after drug administration ceased, except for animals treated with morphine, in which there was an increased hyperalgesia after cessation of treatment. CONCLUSION: Hyperalgesia induced by NP contact with L5-DRG can be reduced by administration of antiinflammatory and analgesic drugs, but there was a greater reduction observed with the administration of dexamethasone and indometacin.

Nicotinamide adenine dinucleotide phosphate-diaphorase and c-fos expression in spinal cord neurons following noxious stimulation

To investigate nicotinamide adenine dinucleotide phosphate-diaphorase [NADPH-d] and fos expression in spinal cord dorsal horn neurons following noxious peripheral stimulation. Expression of the immediate-early gene c-fos and nitric oxide containing neurons one hour after unilateral formalin injection to the dorsal hind paw was investigated in rat lumbar spinal cord, using fos immunohistochemistry and NADPH-d histochemical techniques. The experiments were performed in 2004 and 2006 at Ege University Center for Brain Research in Izmir, Turkey. In 10 adult male Sprague-Dawley rats, an increase in fos-immunoreactive neurons was observed ipsilateral, and NADPH-d positive neurons equally ipsi- and contralateral to the formalin injection site. Approximately 20% of fos-immunoreactive neurons were NADPH-d positive ipsilateral to the formalin injection, whereas no double labeling was observed in the contralateral side. Also, a close relation of NADPH-d positive processes with fos-immunoreactive nuclei were also observed. The results of this study support the hypothesis that nitric oxide synthase blocking agents may serve as a possible alternative in treatment of hyperalgesia following inflammation and peripheral nerve injury

Hiperalgesia visceral e dor abdominal crônica: abordagem diagnóstica e terapêutica / Visceral hyperalgesia and chronic abdominal pain: diagnostic and therapeutic approach

JUSTIFICATIVA E OBJETIVOS: A dor abdominal crônica é uma das razões mais freqüentes para consulta médica. Não existe, entretanto, um protocolo bem estabelecido para a abordagem diagnóstica e, na maioria das vezes, essa investigação se torna uma prática médica onerosa e invasiva. A finalidade desta revisão é tentar esclarecer a fisiopatologia da dor visceral e estabelecer metas diagnósticas e terapêuticas, para portadores desta morbidade, baseada em critérios específicos. CONTEUDO: A dor abdominal crônica inespecífica ou funcional representa uma interação complexa entre distúrbio de motilidade, hipersensibilidade visceral e respostas neuroendócrina e psicossocial inadequadas. Mecanismos periféricos e centrais de nocicepção parecem estar envolvidos na hiperalgesia visceral. A abordagem diagnóstica requer uma avaliação minuciosa da história e exame clínico, levando em consideração os critérios de Roma II. Baseado nos mecanismos fisiopatológicos conhecidos, ou supostos, novas drogas vêm sendo pesquisadas, e algumas utilizadas mais recentemente, como os agonistas dos receptores 5-HT4 e bloqueadores dos canais de sódio, para o controle da dor abdominal. CONCLUSÕES: Os mecanismos fisiopatológicos da dor abdominal crônica, ainda não estão esclarecidos. A abordagem terapêutica e diagnóstica requer o conhecimento de tais mecanismos, bem como dos critérios de Roma II. Por outro lado, uma boa relação médico-paciente e a atuação de equipe intermultidisciplinar parecem fundamentais para melhorar a resposta ao tratamento instituído e a qualidade de vida do paciente.

BACKGROUND AND OBJECTIVES: Chronic abdominal pain is one of the most frequent reasons for medical consultation. There is, however, no well-established protocol for its diagnostic approach and, most of the times, investigation becomes an expensive and invasive medical practice. This review aimed at explaining visceral pain pathophysiology and establishing diagnostic and therapeutic goals for these patients, based on specific criteria. CONTENTS: Chronic nonspecific or functional abdominal pain is a complex interaction among impaired motility, visceral hypersensitivity and inadequate neuroendocrine and psychosocial responses. Peripheral and central nociception mechanisms seem to be involved in visceral hyperalgesia. Diagnosis requires detailed history and clinical evaluation, taking into consideration Rome II criteria. Based on known or assumed pathophysiological mechanisms, new drugs have been researched, and some have been more recently used to control abdominal pain, such as 5-HT4 receptor agonists and sodium channel blockers. CONCLUSIONS: Chronic pathophysiological abdominal pain mechanisms are still not well understood. Therapy and diagnosis require the understanding of such mechanisms, as well as of Rome II criteria. On the other hand, good patient-physician relationship and multidisciplinary team’s performance seem to be critical in improving treatment response and patients’ quality of life.

JUSTIFICATIVA Y OBJETIVOS: El dolor abdominal crónico es una de las razones más frecuentes para una consulta médica. No existe, entretanto, un protocolo bien establecido para el abordaje diagnóstico y, en la mayoría de las veces, esa investigación se hace una práctica médica onerosa e invasiva. La finalidad de esta revisión es tentar esclarecer la fisiopatología del dolor visceral y establecer metas diagnósticas y terapéuticas, para portadores de esta morbididad, fundamentada en criterios específicos. CONTENIDO: El dolor abdominal crónico inespecífico o funcional representa una interacción compleja entre disturbio de motilidad, hipersensibilidad visceral y respuestas neuroendócrina y psicosocial inadecuadas. Mecanismos periféricos y centrales de nocicepción parecen estar envueltos en la hiperalgesia visceral. El abordaje diagnóstico requiere una evaluación minuciosa de la historia y examen clínico, llevando en consideración los criterios de Roma II. Fundamentado en los mecanismos fisiopatológicos conocidos, o supuestos, nuevas drogas vienen siendo pesquisadas, y algunas utilizadas más recientemente, como los agonistas de los receptores 5-HT4 y bloqueadores de los canales de sodio, para el control del dolor abdominal. CONCLUSIONES: Los mecanismos fisiopatológicos del dolor abdominal crónico, aún no están esclarecidos. El abordaje terapéutico y diagnóstico requiere el conocimiento de tales mecanismos, así como de los criterios de Roma II. Por otro lado, una buena relación médico-paciente y la actuación de grupo intermultidiciplinar parecem fundamentais para mejorar la respuesta al tratamiento instituido y la calidad de vida del paciente.

Anti-hyperalgesic effect of electroacupuncture in a model of post-incisional pain in rats

Electroacupuncture has been proposed to be a low cost and practical method that allows effective pain management with minimal collateral effects. In this study we have examined the effect of electroacupuncture against the hyperalgesia developed in a model of post-incisional pain in rats. A 1-cm longitudinal incision was made through the skin and fascia of the plantar region of the animal hind paw. Mechanical hyperalgesia in the incision was evaluated 135 min after the surgery with von Frey filaments. The tension threshold was reduced from 75 g (upper limit of the test) to 1.36 + or - 0.36 g (mean + or - SEM) in control rats. It is shown that a 15-min period of electroacupuncture applied 120 min after surgery to the Zusanli (ST36) and Sanyinjiao (SP6) points, but not to non-acupoints, produces a significant and long-lasting reduction of the mechanical hyperalgesia induced by the surgical incision of the plantar surface of the ipsilateral hind paw. The tension threshold was reduced from 75 to 27.6 + or - 4.2 g in animals soon after the end of electroacupuncture. The mechanical threshold in this group was about 64 percent less than in control. Electroacupuncture was ineffective in rats treated 10 min earlier with naloxone (1 mg/kg, ip), thus confirming the involvement of opioid mechanisms in the antinociceptive effects of such procedure. The results indicate that post-incisional pain is a useful model for studying the anti-hyperalgesic properties of electroacupuncture in laboratory animals