Acute inhibition of signalling phenotype of spinal GABAergic neurons by tumour necrosis factor-α

Non-technical summary Spinal application of tumour necrosis factor-α (TNFα) is shown to suppress inhibitory synaptic transmission and enhance excitatory synaptic transmission in spinal dorsal horn, but the underlying mechanisms are not fully known. We show that acute application of TNFα inhibits the excitability of a subset of spinal GABAergic neurons through TNF receptor 1 probably by suppressing hyperpolarization-activated cation currents (I_h) through the activation of p38 mitogen-activated protein kinase within these neurons. These results suggest a novel cellular mechanism of how TNFα modulates spinal synaptic transmission which may be involved in the development of pain. Spinal application of TNFα induces both allodynia and hyperalgesia, and at least part of the pronociceptive effects of TNFα have been suggested as due to the impaired function of spinal inhibitory neurons (disinhibition). The present study explores the effects of TNFα on the signalling phenotype of spinal GABAergic neurons identified in transgenic mice expressing green fluorescent protein at the glutamic acid decarboxylase 67 (GAD67) promoter. Acute application of TNFα directly inhibits the excitability of a subset of GAD67⁺ spinal neurons. TNFα-induced inhibition was dependent on the activation of p38 mitogen-activated protein kinase (MAPK) within these GAD67⁺ neurons. TNFα receptor 1 (TNFR1) but not receptor 2 (TNFR2) was identified on spinal GAD67⁺ neurons, suggesting that TNFα signals through TNFR1. Voltage-clamp recordings of GAD67⁺ neurons indicated that the inhibitory effect of TNFα was through suppression of the hyperpolarization-activated cation current (I_h). This study defines a novel mechanism of spinal disinhibition mediated by a TNFα-TNFR1-p38 pathway within GABAergic inhibitory interneurons.