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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Mitogen-Activated Protein Kinase Signaling Mediates Morphine Induced-Delayed Hyperalgesia

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Autor(es):
de Freitas, Barbara Guimaraes [1] ; Pereira, Leandro Marcio [1] ; Santa-Cecilia, Flavia Vianna [1] ; Hosch, Natalia Gabriele [1] ; Picolo, Gisele [1] ; Cury, Yara [1] ; Zambelli, Vanessa O. [1]
Número total de Autores: 7
Afiliação do(s) autor(es):
[1] Inst Butantan, Lab Especial Dor & Sinalizacao, Sao Paulo - Brazil
Número total de Afiliações: 1
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN NEUROSCIENCE; v. 13, SEP 20 2019.
Citações Web of Science: 0
Resumo

The use of morphine, the standard opioid drug, is limited by its undesirable effects, such as tolerance, physical dependence, and hyperalgesia (increased pain sensitivity). Clinical and preclinical studies have reported development of hyperalgesia after prolonged opioid administration or after a single dose of intrathecal (i.t.) morphine in uninjured rats. However, whether a single standard systemic morphine dose is sufficient to decrease the nociceptive threshold in rats is unknown. Here, we showed that a single morphine subcutaneous injection induces analgesia followed by a long-lasting delayed hyperalgesia in uninjured and PGE2 sensitized rats. The i.t injection of extracellular signal-regulated kinase (ERK) inhibitor blocked morphine-induced analgesia, without interfering with the morphine-induced hyperalgesia. However, i.t. injection of SB20358, a p38 inhibitor and SP660125, a JNK inhibitor, decreased the morphine-induced hyperalgesia. Consistently with the behavioral data, Western Blot analysis showed that ERK is more phosphorylated 1 h after morphine, i.e., when the analgesia is detected. Moreover, phospho-p38 and phospho-JNK levels are upregulated 96 h after morphine injection, time that coincides with the hyperalgesic effect. Intrathecal (i.t.) oligodeoxynucleotide (ODN) antisense to cAMP-responsive element binding protein (CREB) attenuated morphine-induced hyperalgesia. Real-time polymerase chain reaction (RT-PCR) analysis showed that CREB downstream genes expressions were significantly up-regulated 96 h after morphine injection in spinal cord. Together, our data suggest that central ERK is involved in the analgesic and hyperalgesic effects of morphine while JNK, p38, and CREB are involved in the morphine-induced delayed hyperalgesia. (AU)

Processo FAPESP: 13/07467-1 - CeTICS - Centro de Toxinas, Imuno-Resposta e Sinalização Celular
Beneficiário:Hugo Aguirre Armelin
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 08/57898-0 - Instituto Nacional de Ciência e Tecnologia em Toxinas
Beneficiário:Osvaldo Augusto Brazil Esteves Sant'Anna
Linha de fomento: Auxílio à Pesquisa - Temático