Exogenous tumor necrosis factor-α rapidly alters synaptic and sensory transmission in the adult rat spinal cord dorsal horn

The proinflammatory cytokine tumor necrosis factor-α (TNF-α) is involved in the generation of inflammatory and neuropathic pain. This study investigated if TNF-α has any effect on spinal synaptic and/ or sensory transmission by using whole-cell recordings of substantia gelatinosa (SG) neurons in transverse lumbar spinal cord slices of adult rats and by using behavioral tests. After intrathecal administration of TNF-α in adult rats, spontaneous hind paw withdrawal behavior and thermal hyperalgesia were rapidly induced (∼30 min), while mechanical allodynia slowly developed. Bath application of TNF-α (0.1-1 nM, 8 min) depressed peak amplitude of monosynaptic Aδ and C fiber-evoked excitatory postsynaptic currents (EPSCs) without changing in holding currents and input resistances, whereas this application generally potentiated polysynaptic Aδ fiber-evoked EPSCs. Moreover, the frequencies, but not the amplitudes, of spontaneous and miniature EPSCs and spontaneous inhibitory postsynaptic currents were significantly increased by bath-applied TNF-α in most of the SG neurons. The effects of TNF-α on Aδ/C fiber-evoked monosynaptic and polysynaptic or spontaneous EPSCs were significantly blocked by 5 μM TNF-α antagonist that inhibits TNF-α binding to its type 1 receptor (TNFR1). Because this study also found high protein expression of TNFR1 in the adult dorsal root ganglion and no change of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) induced whole-cell currents by TNF-α, we conclude that presynaptic TNFR1 at Aδ/ C primary afferent terminals contributes to the rapid alteration of synaptic transmission in the spinal SG, and the development of abnormal pain hypersensitivity by exogenous TNF-α.