期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 53, 期 2, 页码 376-389出版社
WILEY
DOI: 10.1111/ejn.14985
关键词
hyperalgesia; rats; TNFR1; TNF-alpha; inflammation
资金
- Brazilian National Council for Scientific and Technological Development [132634/2015-5]
- Sao Paulo Research Foundation [2014/25153-7, 2017/23485-0]
TNF-alpha plays a key role in the development of inflammatory hyperalgesia by stimulating the release of pro-inflammatory cytokines and increasing nociceptors' susceptibility to the action of final inflammatory mediators. This mechanism may also explain the analgesic action of thalidomide.
The mechanism underlying the role of tumor necrosis factor alpha (TNF-alpha) in the development of inflammatory hyperalgesia has been extensively studied, mainly the role of TNF-alpha in the release of pro-inflammatory cytokines. The current concept relies in the fact that TNF-alpha stimulates the cascade release of other pro-inflammatory cytokines, such as IL-1 beta, IL-6, and IL-8 (CINC-1 in rats), triggering the release of the final inflammatory mediator prostaglandin E-2(PGE(2)) and sympathetic amines that directly sensitize the nociceptors. However, this may not be the sole mechanism involved as the blockade of TNF-alpha synthesis by thalidomide prevents hyperalgesia without interrupting the synthesis of IL-1 beta, IL-6, and CINC-1. Therefore, we hypothesized that activation of TNF-alpha receptor type 1 (TNFR1) by TNF-alpha increases nociceptors' susceptibility to the action of PGE(2)and dopamine. We have found out that intrathecal administration of oligodeoxynucleotide-antisense (ODN-AS) against TNFR1 or thalidomide prevented carrageenan-induced hyperalgesia. The co-administration of TNF-alpha with a subthreshold dose of PGE(2)or dopamine that does not induce hyperalgesia by itself in the hind paw of Wistar rats pretreated with dexamethasone (to prevent the endogenous release of cytokines) induced a robust hyperalgesia that was prevented by intrathecal treatment with ODN-AS against TNFR1. We consider that the activation of neuronal TNFR1 by TNF-alpha decisively increases the susceptibility of the peripheral afferent neuron to the action of final inflammatory mediators - PGE(2)and dopamine - that ultimately induce hyperalgesia. This mechanism may also underlie the analgesic action of thalidomide.
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