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

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]

Afiliação do(s) autor(es)

^[1] Inst Butantan, Lab Especial Dor & Sinalizacao, Sao Paulo - Brazil

• 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
• Modalidade de apoio: 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
• Modalidade de apoio: Auxílio à Pesquisa - Temático