Acute topical application of tumor necrosis factor alpha evokes protein kinase A-dependent responses in rat sensory neurons.

Local perfusion of the dorsal root ganglion (DRG) with tumor necrosis factor alpha (TNF-alpha) in rats induces cutaneous hypersensitivity to mechanical stimuli. Thus we investigated the cellular mechanisms of TNF-alpha-induced mechanical hyperalgesia. The L(4) and L(5) DRGs with the sciatic nerves attached were excised from rats for in vitro dorsal root microfilament recording. After baseline recording for 15 min, TNF-alpha (0.001, 0.01, 0.1, or 1 ng/ml) was applied to the DRG for 15 min, followed by washout for at least 30 min. Alternatively, H-89 or Rp-cAMPS, two specific cAMP-dependent protein kinase (PKA) inhibitors, was added to the perfusion solution for 15 min prior to TNF-alpha application. TNF-alpha (1 ng/ml) induced neuronal discharges in 67% (14/21) of C fibers and 27% (4/15) of Abeta fibers when applied topically to the DRG. Acute TNF-alpha application not only evoked discharges in silent fibers, but also enhanced ongoing activity of spontaneously active fibers and increased neuronal sensitivity to electrical stimulation of the peripheral nerves. H-89 (10 microM) and Rp-cAMPS (100 microM) each completely blocked the TNF-alpha-evoked response in most C and Abeta fibers tested but did not affect fiber conductivity. Our results demonstrates that exogenous inflammatory cytokines such as TNF-alpha can elicit a PKA-dependent response in sensory neurons and thus strongly suggest that endogenous TNF-alpha may contribute to the development of certain pathological pain states.