TNF-α contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2

Tumor necrosis factor-alpha (TNF-α) is a key proinflammatory cytokine. It is generally believed that TNF-α exerts its effects primarily via TNF receptor subtype-1 (TNFR1). We investigated the distinct roles of TNFR1 and TNFR2 in spinal cord synaptic transmission and inflammatory pain. Compared to wild-type (WT) mice, TNFR1- and TNFR2-knockout (KO) mice exhibited normal heat sensitivity and unaltered excitatory synaptic transmission in the spinal cord, as revealed by spontaneous excitatory postsynaptic currents in lamina II neurons of spinal cord slices. However, heat hyperalgesia after intrathecal TNF-α and the second-phase spontaneous pain in the formalin test were reduced in both TNFR1- and TNFR2-KO mice. In particular, heat hyperalgesia after intraplantar injection of complete Freund's adjuvant (CFA) was decreased in the early phase in TNFR2-KO mice but reduced in both the early and later phase in TNFR1-KO mice. Consistently, CFA elicited a transient increase of TNFR2 mRNA levels in the spinal cord on day 1. Notably, TNF-α evoked a drastic increase in spontaneous excitatory postsynaptic current frequency in lamina II neurons, which was abolished in TNFR1-KO mice and reduced in TNFR2-KO mice. TNF-α also increased N-methyl-d-aspartate (NMDA) currents in lamina II neurons, and this increase was abolished in TNFR1-KO mice but retained in TNFR2-KO mice. Finally, intrathecal injection of the NMDA receptor antagonist MK-801 prevented heat hyperalgesia elicited by intrathecal TNF-α. Our findings support a central role of TNF-α in regulating synaptic plasticity (central sensitization) and inflammatory pain via both TNFR1 and TNFR2. Our data also uncover a unique role of TNFR2 in mediating early-phase inflammatory pain. TNF-α is shown to play a critical role in regulating spinal cord synaptic plasticity and central sensitization, and TNFR1 and TNFR2 play a distinct role in regulating different phases of inflammatory pain.