Inflammatory Pain In Peripheral Tissue Depends On The Activation Of The Tnf-Alpha Type 1 Receptor In The Primary Afferent Neuron

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.