One of the first signs of
viral infection is body-wide
aches and
pain. Although this type of
pain usually subsides, at the extreme,
viral infections can induce painful neuropathies that can last for decades. Neither of these types of
pain sensitization is well understood. A key part of the response to
viral infection is production of
interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause
pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical
pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated
eIF4E phosphorylation in DRG neurons to promote
pain hypersensitivity. Endogenous release of type I IFNs with the
double-stranded RNA mimetic
poly(I:C) likewise produces
pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how
viral infections promote
pain and can lead to neuropathies.SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to
infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that
type I interferons, one of the first mediators produced by
viral infection, act directly on nociceptors to produce
pain sensitization.
Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and
neuropathic pain conditions. Our work reveals a mechanism through which
viral infections cause heightened
pain sensitivity.