期刊
PLOS ONE
卷 9, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0090576
关键词
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资金
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Brazil (FAPESP) [07/03404-4, 07/00135-2]
- Instituto Nacional de Ciencia e Tecnologia em Toxinologia (INCTTOX PROGRAM) of Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [573790/2008-6]
- FAPESP [2008/57898-0]
- CAPES/CNPq [301508/2008-9, 305345/2011-7]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [07/00135-2] Funding Source: FAPESP
Inflammation enhances the peripheral analgesic efficacy of opioid drugs, but the mechanisms involved in this phenomenon have not been fully elucidated. Crotalphine (CRP), a peptide that was first isolated from South American rattlesnake C.d. terrificus venom, induces a potent and long-lasting anti-nociceptive effect that is mediated by the activation of peripheral opioid receptors. Because the high efficacy of CRP is only observed in the presence of inflammation, we aimed to elucidate the mechanisms involved in the CRP anti-nociceptive effect induced by inflammation. Using real-time RT-PCR, western blot analysis and ELISA assays, we demonstrate that the intraplantar injection of prostaglandin E2 (PGE(2)) increases the mRNA and protein levels of the mu-and kappa-opioid receptors in the dorsal root ganglia (DRG) and paw tissue of rats within 3 h of the injection. Using conformation state-sensitive antibodies that recognize activated opioid receptors, we show that PGE(2), alone does not increase the activation of these opioid receptors but that in the presence of PGE(2), the activation of specific opioid receptors by CRP and selective mu-and kappa-opioid receptor agonists (positive controls) increases. Furthermore, PGE2 down-regulated the expression and activation of the delta-opioid receptor. CRP increased the level of activated mitogen-activated protein kinases in cultured DRG neurons, and this increase was dependent on the activation of protein kinase C zeta. This CRP effect was much more prominent when the cells were pretreated with PGE(2). These results indicate that the expression and activation of peripheral opioid receptors by opioid-like drugs can be up- or down-regulated in the presence of an acute injury and that acute tissue injury enhances the efficacy of peripheral opioids.
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