Acute Topical Application of Tumor Necrosis Factor α Evokes Protein Kinase A-Dependent Responses in Rat Sensory Neurons

Abstract

Local perfusion of the dorsal root ganglion (DRG) with tumor necrosis factor α (TNF-α) in rats induces cutaneous hypersensitivity to mechanical stimuli. Thus we investigated the cellular mechanisms of TNF-α-induced mechanical hyperalgesia. The L4and L5 DRGs with the sciatic nerves attached were excised from rats for in vitro dorsal root microfilament recording. After baseline recording for 15 min, TNF-α (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-α application. TNF-α (1 ng/ml) induced neuronal discharges in 67% (14/21) of C fibers and 27% (4/15) of Aβ fibers when applied topically to the DRG. Acute TNF-α 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 μM) and Rp-cAMPS (100 μM) each completely blocked the TNF-α-evoked response in most C and Aβ fibers tested but did not affect fiber conductivity. Our results demonstrates that exogenous inflammatory cytokines such as TNF-α can elicit a PKA-dependent response in sensory neurons and thus strongly suggest that endogenous TNF-α may contribute to the development of certain pathological pain states.