Research into the mechanisms of hyperalgesia is ongoing with the goal of improving clinical management of chronic pain. One animal model of chronic musculoskeletal pain uses two injections of acidic saline into a lateral gastrocnemius muscle to induce a long-lasting bilateral decrease in paw withdrawal thresholds. This study tested whether the two injections need to occur in the same muscle. Male Sprague-Dawley rats were injected with acidic saline (pH 4.0) in either the lateral or medial head of gastrocnemius or the contralateral gastrocnemius (lateral head). All animals received a second injection in the ipsilateral gastrocnemius (lateral head). Mechanical withdrawal thresholds were reduced in all groups when tested 24 hours after the second injection. Animals in which the first muscle injection was substituted with a non-specific treatment (intraperitoneal injection of lipopolysaccharide) developed bilateral hyperalgesia after a single acidic saline injection. Thus, the mechanism of hyperalgesia in this model is not restricted to the injected tissues and may include central nervous system structures. Consistent with this, an inhibitor of glia cell activation (minocycline) blocked the development of bilateral hyperalgesia. These data indicate that the central nervous system may play a large role in mediating chronic musculoskeletal pain. / October 2007

Research into the mechanisms of hyperalgesia is ongoing with the goal of improving clinical management of chronic pain. One animal model of chronic musculoskeletal pain uses two injections of acidic saline into a lateral gastrocnemius muscle to induce a long-lasting bilateral decrease in paw withdrawal thresholds. This study tested whether the two injections need to occur in the same muscle. Male Sprague-Dawley rats were injected with acidic saline (pH 4.0) in either the lateral or medial head of gastrocnemius or the contralateral gastrocnemius (lateral head). All animals received a second injection in the ipsilateral gastrocnemius (lateral head). Mechanical withdrawal thresholds were reduced in all groups when tested 24 hours after the second injection. Animals in which the first muscle injection was substituted with a non-specific treatment (intraperitoneal injection of lipopolysaccharide) developed bilateral hyperalgesia after a single acidic saline injection. Thus, the mechanism of hyperalgesia in this model is not restricted to the injected tissues and may include central nervous system structures. Consistent with this, an inhibitor of glia cell activation (minocycline) blocked the development of bilateral hyperalgesia. These data indicate that the central nervous system may play a large role in mediating chronic musculoskeletal pain.

Research into the mechanisms of hyperalgesia is ongoing with the goal of improving clinical management of chronic pain. One animal model of chronic musculoskeletal pain uses two injections of acidic saline into a lateral gastrocnemius muscle to induce a long-lasting bilateral decrease in paw withdrawal thresholds. This study tested whether the two injections need to occur in the same muscle. Male Sprague-Dawley rats were injected with acidic saline (pH 4.0) in either the lateral or medial head of gastrocnemius or the contralateral gastrocnemius (lateral head). All animals received a second injection in the ipsilateral gastrocnemius (lateral head). Mechanical withdrawal thresholds were reduced in all groups when tested 24 hours after the second injection. Animals in which the first muscle injection was substituted with a non-specific treatment (intraperitoneal injection of lipopolysaccharide) developed bilateral hyperalgesia after a single acidic saline injection. Thus, the mechanism of hyperalgesia in this model is not restricted to the injected tissues and may include central nervous system structures. Consistent with this, an inhibitor of glia cell activation (minocycline) blocked the development of bilateral hyperalgesia. These data indicate that the central nervous system may play a large role in mediating chronic musculoskeletal pain.

Submitted by Sandra Pereira (srpereira@ufrrj.br) on 2016-08-24T15:39:27Z No. of bitstreams: 1 2011 - Raphael Andrade de Castro.pdf: 917522 bytes, checksum: f65a225b9fc808c90016c649f5cb2be1 (MD5) / Made available in DSpace on 2016-08-24T15:39:27Z (GMT). No. of bitstreams: 1 2011 - Raphael Andrade de Castro.pdf: 917522 bytes, checksum: f65a225b9fc808c90016c649f5cb2be1 (MD5) Previous issue date: 2011-02-18 / causing pain as a constant feature. The pyrazole compounds are the drugs of synthetic origin in their chemical structure consisting of a ring pirazol?nico, with which several studies show the effectiveness in controlling of pain, fever and inflammation. The need to develop new drugs with analgesic and anti-inflammatory, low cost and which have few adverse reactions, has stimulated the synthesis and study of pharmacological activities of pyrazole compounds. With this objective, we studied the antinociceptive and anti-inflammatory potential of compound 1.5-diphenyl-pyrazole-3-hidrazinopirazol(a) (DHP), administered orally in pharmacological models of the acetic acid writhing, tail-flick, formalin, ear edema induced by croton oil and carrageenan-induced peritonitis in mice, and mechanical allodynia (von Frey) and thermal hyperalgesia (Hargreaves) in rats. The administration of DHP (1, 3 and 10mg/kg) decreased in a dose-dependent (41.3, 62.7 and 76%) number of writhing (ID50 = 1.3mg/kg). In the tail-flick test, DHP (10mg/kg) was ineffective and the application of positive control fentanyl (200?g/kg, sc) increased the latency to thermal stimulation in up to 138%. Without changing the first phase of nociception (neurogenic pain) of the formalin test, DHP (10mg/kg) and the positive control indomethacin (10mg/kg, p.o.) inhibited the reactivity in the 2 phase (ndinflammatory pain) in 40.9 and 48.7% respectively. This same dose of DHP reduced by 54% the ear edema induced by croton oil, as well as the positive control, dexamethasone (2mg/kg, sc) at 55.3%. Also in a dose-dependent DHP (3, 10 and 30 mg / kg) inhibited by 11.8, 39 and 53.7%, respectively, leukocyte migration in peritonitis induced by carrageenan test (ID50 = 22.9mg/kg). In the assessment of mechanical allodynia incision group treated with DHP (GIDHP - 10mg/kg) showed a significant reversal of allodynia (RA) after one hour of administration, with maximum reading RA for 12 hours (28.2%) in the second stage of the experiment, remaining in the third stage with RA of 26.9, 43.4 and 60.4% in the 7th, 10th and 14th days of evaluations, when compared with the vehicle group incised (GIV). In thermal hyperalgesia GIDHP (10mg/kg) also significantly reversed the hyperalgesia (RH) after one hour of treatment, with RH maximum of three hours in reading (68.9%) in the second stage, obtaining in the third stage RA of 43.4, 32,1 and 64% in 7th, 10th and 14th days of evaluations, when compared to the GIV and obtaining similar values of the group not incised vehicle (GNIV) on 14 dayth. In the von Frey and Hargreaves GNIV showed similar readings in the three stages of the experiment. The DHP (10mg/kg) did not alter the motor activity of mice in rota-rod test. Whereas the compound DHP showed antinociceptive activity in writhing test, antiedematogenic in ear edema, inhibited the 2nd phase of nociception (inflammatory pain) in formalin test and leukocyte migration, promoting reversal of hypernociception in models of thermal hyperalgesia and allodynia mechanics, these results indicate that the effectiveness of DHP involves the participation of anti-inflammatory mechanisms and create favorable outlook for its future use with this therapeutic goal. / A inflama??o ? um processo fisiol?gico de resposta org?nica diante de les?o tissular ou infec??o, gerando a dor como caracter?stica constante. Os compostos piraz?licos s?o drogas de origem sint?tica com um anel pirazol?nico na sua estrutura qu?mica, com os quais diversos estudos demonstram a efic?cia no controle da dor, da febre e da inflama??o. A necessidade do desenvolvimento de novos f?rmacos com propriedades analg?sicas e anti-inflamat?rias, de baixo custo e que apresentem poucas rea??es adversas, tem estimulado a s?ntese e o estudo das atividades farmacol?gicas dos compostos piraz?licos. Com esse objetivo, foi estudado o potencial antinociceptivo e anti-inflamat?rio do composto piraz?lico 1,5-difenil-3-hidrazinopirazol(a) (DHP), administrado pela via oral, nos modelos farmacol?gicos das contor??es abdominais pelo ?cido ac?tico, tail-flick, formalina, edema de orelha induzido pelo ?leo de cr?ton e peritonite induzida pela carragenina em camundongos; e na alodinia mec?nica (von Frey) e hiperalgesia t?rmica (Hargreaves) em ratos. A administra??o do DHP (1, 3 e 10mg/kg) diminuiu de maneira dose-dependente (41,3, 62,7 e 76%) o numero de contor??es abdominais (ID50=1,3mg/kg). No teste de tail-flick, DHP (10mg/kg) n?o foi efetivo e a aplica??o do controle positivo fentanil (200?g/kg, s.c.) ampliou a lat?ncia ao est?mulo t?rmico em at? 138%. Sem alterarem a 1? fase de nocicep??o (dor neurog?nica) do teste da formalina, o DHP (10mg/kg) e o controle positivo indometacina (10mg/kg, p.o.) inibiram a reatividade na 2? fase (dor inflamat?ria) em 40,9 e 48,7% respectivamente. Essa mesma dose do DHP reduziu em 54% o edema de orelha induzido pelo ?leo de cr?ton, assim como o controle positivo dexametasona (2mg/kg, s.c.) em 55.3%. Tamb?m de forma dose-dependente o DHP (3, 10 e 30 mg/kg) inibiu em 11,8, 39 e 53,7% respectivamente, a migra??o de leuc?citos no teste da peritonite induzida pela carragenina (ID50=22,9mg/kg). Na avalia??o da alodinia mec?nica o grupo incisado tratado com o DHP (GIDHP - 10mg/kg) apresentou significativas revers?es da alodinia (RA) ap?s uma hora da administra??o, com RA m?xima na leitura de 12 horas (28,2%) na segunda etapa, mantendo-se na terceira etapa com RA de 26,9, 43,4 e 60,4% nos 7?, 10? e 14? dias de experimenta??o, comparados com o grupo incisado ve?culo (GIV). Na hiperalgesia t?rmica o GIDHP tamb?m produziu revers?o da hiperalgesia (RH) uma hora ap?s o tratamento, com RH m?ximo na leitura de 3 horas (68,9%) na segunda etapa, mantendo-se na terceira etapa com RH de 43,4, 32,1 e 64% nos 7?, 10? e 14? dias de experimenta??o, quando comparados ao GIV e obtendo valores semelhantes ao grupo n?o incisado ve?culo (GNIV) no 14? dia. No von Frey e no Hargreaves o GNIV apresentou leituras semelhantes nas tr?s etapas do experimento. O DHP (10mg/kg) n?o alterou a atividade motora de camundongos no teste do rota-rod. Considerando que o composto DHP apresentou atividade antinociceptiva no teste das contor??es, antiedematog?nica no edema de orelha, inibiu a 2? fase de nocicep??o (dor inflamat?ria) do teste da formalina e a migra??o leucocit?ria, promovendo ainda revers?o da hipernocicep??o nos modelos de hiperalgesia t?rmica e alodinia mec?nica; esses resultados indicam que a efetividade do DHP envolve a participa??o de mecanismos anti-inflamat?rios e criam perspectivas favor?veis para sua futura utiliza??o com esse objetivo terap?utico.

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