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.

Correlation between blood oxygen level dependent fMRI signal and GABA content in anterior cingulate cortex after acupuncture of Hegu (LI4) / 针刺研究

OBJECTIVE: To explore the correlation between blood oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) signal and neurotransmitter γ-aminobutyric acid (GABA) concentration in the prefrontal cortex area after acupuncture or Von Frey filament stimulation (epidermal stimulation) at the right Hegu (LI4). METHODS: A total of 76 healthy volunteers (23 men and 53 women, 24.5±1.4 years in age) were recruited in the pre-sent study. Each volunteer received two sessions of fMRI magnetic resonance scanning (MRS) examinations, with an interval of one week between two sessions. The MRI scan sequences included pre-task MRS, resting state BOLD and task MRS, BOLD. A region of Interest (ROI) of 35 mm×30 mm×25 mm was located at the bilateral medial prefrontal cortex areas. In the two sessions of examinations, the right LI4 point was stimulated by manual acupuncture or Von Frey filament-pressing. The tasks were designed as the block design. Each block contained 3 intermittent acupoint stimulations, lasting 30 s in each stimulation and with two minutes' pause between two stimulations. The MRS data were processed by using Linear Combination (LC) Model software (for assessing GABA content), and the BOLD data of fMRI was analyzed by using SPM12 software (comparison within each group), REST1.8 (comparison between two groups), separately. RESULTS: Extensive deactivations were induced by both stimulations, mainly involving the midline regions as the medial prefrontal lobe, and limbic lobe. The deactivation effect of manual acupuncture stimulation was more extensive and intensive than that of Von Frey filament stimulation, especially in the medial prefrontal lobe. Data from 66 volunteers (after exclusion of 10 participants due to bigger standard deviation of GABA/Glx) showed no marked correlation between the GABA concentration and BOLD activation in the anterior cingulate cortex area in both groups(manual acupuncture stimulation group: r=－0.07, －0.08, 0.04; P=0.57, 0.88, 0.74; Von Frey filament epidermal stimulation group: r=－0.10, －0.09, －0.01; P=0.43, 0.46, 0.96). CONCLUSION: Acupuncture of LI4 elicits a stronger and broader negative activation effect in the limbic-paralimbic-neocortical network including the medial prefrontal cortex in comparison with Von Frey filament stimulation, but no apparent correlation was found between the GABA concentration and BOLD activation in the anterior cingulate cortex after manual acupuncture and Von Frey stimulation.

Role of mast cells in experimental autoimmune prostatitis in rats / 中华男科学杂志

Objective@#To investigate the role of mast cells in chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS).@*METHODS@#Forty-five male SD rats were equally randomized into a control, an experimental autoimmune prostatitis (EAP) model, and an intervention group. The EAP model was made in the latter two groups by subcutaneous injection of mixed suspension of complete Freund's adjuvant and prostate tissue, while the controls were treated subcutaneously with 0.9% sodium chloride. Tactile allodynia was quantified in the pelvic region of the control and EAP animals using Von-Frey filaments at 5, 10, 20, 30 and 40 days. After successful establishment of the EAP model, the rats of the intervention group were injected intraperitonieally with cromolyn sodium for 10 days, and meanwhile tactile allodynia was detected in the rats of the intervention and EAP model groups every other day. Then the prostates of the rats were harvested for HE and toluidine blue staining and measurement of the expression of mast cell tryptase by immunohistochemistry and Western blot.@*RESULTS@#Von-Frey assessment showed a more severe pelvic pain in the EAP model than in the control rats, but milder in the intervention group than in the EAP models. HE staining revealed infiltration of lymphocytes and neutrophils in the prostate and congestion surrounding the gland in the EAP model rats, but none in the controls. However, both the infiltration and congestion were significantly alleviated in the intervention group. Toluidine blue staining shown that. Compared with the control group, the total count of mast cells and the number degranulated mast cells were markedly increased in the EAP models (P <0.01) but decreased in the intervention group (P <0.05). Both immunohistochemistry and Western blot manifested that the expression of tryptase in the mast cells was remarkably upregulated in the EAP (both P <0.01) but down-regulated in the intervention group (P <0.05 and P <0.01).@*CONCLUSIONS@#Both the total count of mast cells and the number of degranulated mast cells are significantly increased in the prostate of EAP rats. Mast cells are one of the most important mediators of type Ⅲ prostatitis-induced chronic pelvic pain, which can be used as a target for the intervention and treatment of type Ⅲ prostatitis.

Notalgia Paresthetica of the Back Successfully Controlled by Pregabalin / 대한피부과학회지

Notalgia paresthetica (NP) is a chronic localized itch, affecting mainly the inter-scapular area particularly between the T2-T6 dermatomes. Occasionally it has a more widespread distribution and involves the shoulders, back, and upper chest. There are no specific cutaneous signs, apart from those attributed to scratching and rubbing. Various etiologies have been reported, but the cause of NP is not established. The current hypothesis regarding its etiology postulates that a neuropathic itch develops due to nerve entrapment of the posterior rami of spinal nerve arising at T2-T6. Another recent documented case showed an increase in the number of intradermal nerves by neural immunochistochemistry staining of S-100 protein, protein gene product 9.5 (PGP 9.5). Herein, we experienced an uncommon case of NP of the back and tried to clarify pathogenesis by using quantitative sensory testing, such as neurometer and Von-Frey filaments. Also, we performed neural immunochemistry to confirm an increase in nerve fibers at the site of the lesion.

Maerua angolensis Extract Reduces Allodynia and Hyperalgesia in a Mouse Model of Vincristine-Induced Peripheral Neuropathy.

Allodynia and hyperalgesia comprise the main and frequent symptoms suffered by patients with neuropathic pain, which responds poorly to therapy. An earlier study reported that stem bark extracts of Maerua angolensis exhibited dose-dependent anti-nociceptive effect against the neurogenic and inflammatory phases of the formalin test. The current study evaluated the effect of petroleum ether/ethyl acetate stem bark extract of Maerua angolensis on vincristine-induced neuropathy. Neuropathic pain was induced by intraperitoneal injection of vincristine (0.1 mg/kg/day) using a 5-day-on, 2-day-off schedule over 12 days. On day 15, baseline responses were measured in the Randall-Selitto mechanical hyperalgesia test and paw withdrawal tests (using Von Frey filaments and cold water at 4.5 °C) and mice that developed allodynia/hyperalgesia were randomly assigned into 7 groups. Normal saline (i.p.), pregabalin (10, 30, and 100 mg/kg, p.o.) and extract (3, 10, and 20 mg/kg, p.o.) were administered to the individual groups. Allodynia/hyperalgesia was measured hourly for 5 hours post treatment. The extract produced significant (P<0.05) and dose-dependent inhibition of vincristine-induced mechanical hyperalgesia, tactile and cold allodynia responses. In all, the study shows that oral administration of Maerua angolensis stem bark extract inhibits vincristine-induced neuropathy in mice suggesting that it may exert analgesic effect in cancer patients with vincristine-induced neuropathic pain.

Hyperalgesic effect of subarachnoid administration of phentolamine in mice / Hyperalgesic effect of subarachnoid administration of phentolamine in mice / Efecto hiperalgésico de la fentolamina por vía subaracnoidea en ratones

BACKGROUND AND OBJECTIVES: Painful phenomenon is one of the most important and complex experiences. Phentolamine is a non-selective alpha-adrenergic antagonist. The objective of this study was to compare the effect of increasing doses of phentolamine into subarachnoid space in rats in the modulation of painful phenomenon. METHODS: 84 male Wistar rats were divided into formalin and plantar incision groups, subdivided into six subgroups (n = 7). Control group received only saline (10 µL); active subgroups received phentolamine 10 µmg (GF10), 20 mg (GF20), 30 mg (GF30), 40 mg (GF40), and 50 g (GF50). In formalin group, pain was induced by injection of 50 µL of 2% formalin in dorsal region of right posterior paw. In plantar incision group, pain was induced by plantar incision and evaluated using von Frey filaments. Induction and maintenance of anesthesia were performed with 3% halothane for catheter placement into subarachnoid space and plantar incision. Statistical analysis was performed using the JMP program from SAS with 5% significance level. RESULTS: Phentolamine at doses of 20 and 30 g increased the algesic response in the intermediate phase of the formalin test. In plantar incision test, it had hyperalgic effect on first, third, fifth, and seventh days at a dose of 10 g and on first, third, and fifth days at a dose of 20 g and on fifth day at a dose of 30 g. CONCLUSION: Subarachnoid administration of phentolamine showed hyperalgesic effect, possibly due to the involvement of different subclasses of alpha-adrenergic receptors in modulating pain pathways. .

JUSTIFICATIVA E OBJETIVOS: O fenômeno doloroso é uma das mais importantes e complexas experiências. A fentolamina é antagonista alfa-adrenérgico não seletivo. O objetivo foi comparar os efeitos de doses crescentes da fentolamina, por via subaracnóidea, em ratos na modulação do fenômeno doloroso. MÉTODO: Foram usados 84 ratos Wistar machos, divididos nos grupos formalina e incisão plantar, subdivididos em seis subgrupos (n = 7). No subgrupo controle (GC) apenas salina (10 µL), nos subgrupos ativos, 10 µg de fentolamina (GF10), 20 µg (GF20), 30 µg (GF30), 40 µg (GF40) e 50 µg (GF50). No grupo formalina, a dor foi induzida com injeção de 50 µL de formalina a 2%, na região dorsal da pata posterior direita. No grupo incisão plantar, a dor foi induzida por incisão plantar e avaliação pelos filamentos de Von Frey. Indução e manutenção anestésica com halotano a 3% para introdução de cateter no espaço subaracnóideo e feitura da incisão plantar. Análise estatística dos resultados pelo programa JMP do SAS com nível de significância 5%. RESULTADOS: A fentolamina nas doses de 20 e 30 µg produziu aumento da resposta álgica na fase intermediária do teste da formalina. No teste da incisão plantar, promoveu efeito hiperálgico no primeiro, terceiro, quinto e sétimo dias na dose de 10 µg, no primeiro, terceiro e quinto dias na dose de 20 µg e no quinto dia na dose de 30 µg. CONCLUSÃO: A fentolamina por via subaracnóidea promoveu efeito hiperálgico, possivelmente pela participação de diferentes subclasses de receptores alfa-adrenérgicos nas vias modulatórias da dor. .

JUSTIFICACIÓN Y OBJETIVOS: El fenómeno doloroso es una de las más importantes y complejas experiencias. La fentolamina es un antagonista alfaadrenérgico no selectivo. El objetivo fue comparar los efectos de dosis crecientes de fentolamina por vía subaracnoidea en la modulación del fenómeno doloroso en ratones. MÉTODO: Fueron usados 84 ratones Wistar machos, divididos en los grupos formalina e incisión plantar, subdivididos en 6 subgrupos (n = 7). En el subgrupo control (GC) solamente se administró solución salina (10 µL); en los subgrupos activos, 10 µg de fentolamina (GF10), 20 µg (GF20), 30 µg (GF30), 40 µg (GF40) y 50 µg (GF50). En el grupo formalina, el dolor fue inducido con una inyección de 50 µL de formalina al 2% en la región dorsal de la pata posterior derecha. En el grupo incisión plantar, el dolor se indujo por incisión plantar y evaluación por los filamentos de Von Frey. La inducción y el mantenimiento anestésico se llevó a cabo con halotano al 3% para la introducción de catéter en el espacio subaracnoideo y la realización de la incisión plantar. El análisis estadístico de los resultados se hizo mediante el programa JMP(r) del SAS con un nivel de significación del 5%. RESULTADOS: La fentolamina en las dosis de 20 y 30 µg produjo un aumento de la respuesta de dolor en la fase intermedia del test de la formalina. En el test de la incisión plantar, generó un efecto hiperalgésico en el primero, tercero, quinto y séptimo días con dosis de 10 µg; en el primero, tercero y quinto días con dosis de 20 µg; y en el quinto día con dosis de 30 µg. CONCLUSIÓN: La fentolamina por vía subaracnoidea generó un efecto hiperalgésico posiblemente por la participación de diferentes subclases de receptores alfaadrenérgicos en las vías moduladoras del dolor. .

Chronic spinal infusion of loperamide alleviates postsurgical pain in rats.

Plantar incision in rat generates spontaneous pain behaviour. The opioid drug, morphine used to treat postsurgical pain produces tolerance after long-term administration. Loperamide, a potent mu-opioid agonist, has documented analgesic action in various pain conditions. However, loperamide analgesia and associated tolerance following continuous spinal administration in postsurgical pain has not been reported. Chronic spinal infusion of drugs was achieved using intrathecal catheters connected to osmotic minipump. Coinciding with the onset of spinal infusion of loperamide or morphine, rats were subjected to plantar incision. Pain-related behaviour was assessed by Hargreaves apparatus (thermal hyperalgesia) and von Frey filaments (mechanical allodynia). Morphine and loperamide (0.5, 1 and 2 µL/h) induced analgesia was observed until 7th day post-plantar incision in Sprague-Dawley rats. Morphine and loperamide produced dose-dependent analgesia. Loperamide, in the highest dose, produced analgesia till 7th day. However, the highest dose of morphine produced inhibition of thermal hyperalgesia till 5th day and mechanical allodynia only till 3rd day post-plantar incision. Morphine and loperamide produced analgesia in postsurgical pain, which may be mediated through different mechanisms. Longer duration of analgesia with loperamide could probably be due sustained blockade of calcium channels.

Tramadol effects on clinical variables and the mechanical nociceptive threshold in horses / Efeitos do tramadol sobre variáveis clínicas e limiar nociceptivo mecânico em equinos

This study assessed the clinical effects and the mechanical antinociceptive potential of intravenous (IV) tramadol in horses.A blinded and randomized study was designed with 7 horses treated with 1 (Tr1), 2 (Tr2) or 3 (Tr3) mg kg-1 of tramadol IV. The heart rate, respiratory rate (fR), arterial pressure, degree of sedation, gastrointestinal motility (GI), behavior changes and the mechanical nociceptive threshold (MNT) were evaluated. The MNT was determined with von Frey device method.Tr3 had a significant increase in their fR and more pronounced behavioral changes than other treatments.The Tr1 showed a significant increase in arterial pressure. The GI reduced significantly, mainly in Tr2. The tramadol did not change the MNT of the horses.The clinical alterations observed with the different treatments were considered mild and transitory, being most evident in Tr2. However the tramadol did not have any analgesic effect with any of the doses evaluated.

Avaliaram-se os efeitos clínicos e o potencial antinociceptivo mecânico de diferentes doses de tramadol administradas por via intravenosa (IV) em equinos. Sete animais foram tratados com 1 (Tr1), 2 (Tr2) ou 3 (Tr3) mg kg-1de tramadol IV em um estudo cruzado do tipo cego e randomizado. Foram avaliados frequência cardíaca, frequência respiratória, temperatura retal, pressão arterial, nível de sedação, motilidade gastrointestinal, alterações comportamentais e limiar antinociceptivo mecânico (Von Frey). As principais alterações evidenciadas pela administração do tramadol concentram-se no aumento na frequência respiratória em Tr3, aumento significativo da pressão arterial em Tr1 e redução da motilidade gastrointestinal, mais pronunciada em Tr2. O tramadol não promoveu alteração significativa no limiar nociceptivo mecânico. As alterações clínicas observadas nos diferentes tratamentos foram consideradas leves e transitórias. Diante dos resultados, pode-se concluir que o tramadol não apresentou efeito antinociceptivo passível de ser avaliado pelo método empregado no presente estudo, em nenhum dos tratamentos.

Changes of physiological pain threshold in gonadectomized rats / 第二军医大学学报

Objective: To investigate the modulatory effect of gonadal hormone on peripheral pain. Methods: Orchiectomized and ovariectomized rats models were established. Radio heater and Von-Frey hair were used to determine the peripheral mechanical and thermal pain threshold in gonadectomized rats and their corresponding sham-controls. Results: The body weight was increased and the uterus weight was decreased after ovariectomy in female rats(P<0.01). There was no significant change in the body weight of mate rats after orchiectomization. The 100% hind paw withdrawal threshold to Von-Frey hair stimulation was decreased significantly after ovariectomization in female rats, with no significant change in the thermal pain threshold. There was no significant changes in the 100% hind paw withdrawal threshold after Von-Frey hair stimulation or thermal pain threshold after orchidectomy in male rats. Conclusion: These results suggest that changes in androgen level of male rats have no influence on the peripheral basal pain threshold, and female gonadal hormone may inhibit the peripheral pain signaling and has no effect on thermal pain threshold.

Avaliação do uso de Tiletamina e Zolapezam por via epidural em cães / Assessment of the epidural use of tiletamine and zolazepam in dogs / Evaluación del uso de tiletamina y zolazepam por vía epidural en perros

Dez cães receberam administração epidural da associação de cloridrato de tiletamina e zolazepam, entre as vértebras L7 e S1, avaliando-se a analgesia pela observação dos padrões respiratório e comportamental, e pela aplicação dos filamentos de von Frey nos coxins plantares e ao redor do esfíncter anal externo. Não foram observadas as manifestações sistêmicas características da administração parenteral de anestésicos dissociativos, e todos os animais manifestaram completa analgesia, sendo que o emprego dos filamentos de von Frey permitiu testes de sensibilidade cutânea sem causar lesões teciduais. A técnica empregada promoveu ataxia e paresia, que perduraram por 41,25 (± 2,18) minutos, acompanhadas por relaxamento do esfíncter anal externo dos cães. Outros estudos sobre os efeitos da administração epidural da associação de cloridrato de tiletamina e zolazepam deverão ser efetuados, no que diz respeito a quantificar e qualificar a analgesia nesse período, bem como avaliar a possibilidade de realização de intervenções cirúrgicas cruentas, com essa técnica.

Ten dogs received an epidural administration of tiletamine HCl and zolazepam, between vertebrae L7 and S1. The analgesia was evaluated by observation breathing and behavioral patterns, and by the use of von Frey filaments applied to the external anal sphincter and footpads. Systemic manifestations from parenteral administration of dissociative anesthetics were not observed, and all the animals showed complete analgesia. The technique promoted ataxia and paresis which persisted for 41.25 (±2.18) minutes, followed by external anal sphincter myorelaxation. The von Frey filaments allowed cutaneous sensibility tests without causing any tissue lesion. Other investigations searching the tiletamine HCL and zolazepam effects should be performed in order to quantify and qualify the analgesia in that period, as well as to evaluate the possibility of accomplishment of painful surgical procedures with this technique.

Diez perros recibieron administración epidural de la asociación de clorhidrato de tiletamina y zolazepam, entre las vértebras L7 y S1, evaluándose la analgesia por observación de los estándares respiratorio y de comportamiento, y por la aplicación de los filamentos de von Frey en los asientos plantares y alrededor del esfínter anal externo. No fueron observadas las manifestaciones sistémicas características de la administración parenteral de anestésicos disociativos, y todos los animales manifestaron completa analgesia, siendo que el empleo de filamentos de von Frey permitió testes de sensibilidad cutánea sin causar lesiones en tejidos. La técnica empleada promovió ataxia y paresia, que perduraron por 41,25 (±2,18) minutos, acompañadas por relajamiento del esfínter anal externo de los perros. Otros estudios sobre los efectos de la administración epidural de la asociación de clorhidrato de tiletamina y zolazepam deberán ser efectuados, por lo que respecta a cuantificar y calificar la analgesia en ese período, bien como evaluar la posibilidad de realización de procedimientos quirúrgicos cruentos, con esa técnica.

Changes of physiological pain threshold in gonadectomized rats / 第二军医大学学报

Objective:To investigate the modulatory effect of gonadal hormone on peripheral pain.Methods:Orchiectomized and ovariectomized rats models were established.Radio heater and Von-Frey hair were used to determine the peripheral mechani- cal and thermal pain threshold in gonadectomized rats and their corresponding sham-controls.Results:The body weight was in- creased and the uterus weight was decreased after ovariectomy in female rats(P