Modulation of spinal cord synaptic activity by tumor necrosis factor α in a model of peripheral neuropathy

Background: The cytokine tumor necrosis factor alpha (TNF alpha) is an established pain modulator in both the peripheral and central nervous systems. Modulation of nociceptive synaptic transmission in the spinal cord dorsal horn (DH) is thought to be involved in the development and maintenance of several pathological pain states. Increased levels of TNF alpha and its receptors (TNFR) in dorsal root ganglion (DRG) cells and in the spinal cord DH have been shown to play an essential role in neuropathic pain processing. In the present experiments the effect of TNF alpha incubation on modulation of primary afferent synaptic activity was investigated in a model of peripheral neuropathy. Methods: Spontaneous and miniature excitatory postsynaptic currents (sEPSC and mEPSCs) were recorded in superficial DH neurons in acute spinal cord slices prepared from animals 5 days after sciatic nerve transection and in controls. Results: In slices after axotomy the sEPSC frequency was 2.8 +/- 0.8 Hz, while neurons recorded from slices after TNF alpha incubation had significantly higher sEPSC frequency (7.9 +/- 2.2 Hz). The effect of TNF alpha treatment was smaller in the slices from the control animals, where sEPSC frequency was 1.2 +/- 0.2 Hz in slices without and 2.0 +/- 0.5 Hz with TNF alpha incubation. Tetrodotoxin (TTX) application in slices from axotomized animals and after TNF alpha incubation decreased the mEPSC frequency to only 37.4 +/- 6.9% of the sEPSC frequency. This decrease was significantly higher than in the slices without the TNF alpha treatment (64.4 +/- 6.4%). TTX application in the control slices reduced the sEPSC frequency to about 80% in both TNF alpha untreated and treated slices. Application of low concentration TRPV1 receptors endogenous agonist N-oleoyldopamine (OLDA, 0.2 mu M) in slices after axotomy induced a significant increase in mEPSC frequency (175.9 +/- 17.3%), similar to the group with TNF alpha pretreatment (158.1 +/- 19.5%). Conclusions: Our results indicate that TNF alpha may enhance spontaneous transmitter release from primary afferent fibres in the spinal cord DH by modulation of TTX-sensitive sodium channels following sciatic nerve transection. This nerve injury also leads to enhanced sensitivity of presynaptic TRPV1 receptors to endogenous agonist. Modulation of presynaptic receptor activity on primary sensory terminals by TNF alpha may play an important role in neuropathic pain development.