Inflammatory pain in peripheral tissue depends on the activation of the TNF-α type 1 receptor in the primary afferent neuron.

The mechanism underlying the role of tumor necrosis factor alpha (TNF-α) in the development of inflammatory hyperalgesia has been extensively studied, mainly the role of TNF-α in the release of pro-inflammatory cytokines. The current concept relies in the fact that TNF-α stimulates the cascade release of other pro-inflammatory cytokines, such as IL-1β, IL-6 and IL-8 (CINC-1 in rats), triggering the release of the final inflammatory mediator prostaglandin E2 (PGE2 ) and sympathetic amines that directly sensitize the nociceptors. However, this may not be the sole mechanism involved since the blockade of TNF-α synthesis by thalidomide prevents hyperalgesia without interrupting the synthesis of IL-1β, IL-6 and CINC-1. Therefore, we hypothesized that activation of TNF-α receptor type 1 (TNFR1) by TNF-α increases nociceptors' susceptibility to the action of PGE2 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-α with a subthreshold dose of PGE2 or dopamine that does not induce hyperalgesia by itself in the hind paw of Wistar rats pre-treated 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- α decisively increases the susceptibility of the peripheral afferent neuron to the action of final inflammatory mediators - PGE2 and dopamine - that ultimately induce hyperalgesia. This mechanism may also underlie the analgesic action of thalidomide.