Central Terminal Sensitization of TRPV1 by Descending Serotonergic Facilitation Modulates Chronic Pain

Abstract

SUMMARY The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediated by membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal horn to chronic pain has not been investigated directly. Combining primary sensory neuron-specific GCaMP3 imaging with a trigeminal neuropathic pain model, we detected robust neuronal hyperactivity in injured and uninjured nerves in the skin, soma in trigeminal ganglion, and central terminals in the spinal trigeminal nucleus. Extensive TRPV1 hyperactivity was observed in central terminals innervating all dorsal horn laminae. The central terminal TRPV1 sensitization was maintained by descending serotonergic (5-HT) input from the brainstem. Central blockade of TRPV1 or 5-HT/5-HT3A receptors attenuated central terminal sensitization, excitatory primary afferent inputs, and mechanical hyperalgesia in the territories of injured and uninjured nerves. Our results reveal new central mechanisms facilitating central terminal sensitization underlying chronic pain.

Identifying local and descending inputs for primary sensory neurons

“…Our tracing results suggest that some of the descending 5-HT terminals are positioned near the primary afferents and could therefore directly modulate sensory transmission ( Figure 7C). In agreement with this, a recent elegant study demonstrated that 5-HT directly sensitize central nociceptive terminals (66).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…In keeping with this concept, the "wind-up" phenomenon that develops after repeated C fiber stimulation (believed to be a marker of central sensitization) is abolished in rats desensitized to RTX (Xu et al, 1997). In a trigeminal neuropathic pain model, extensive TRPV1 hyperactivity was detected in central terminals innervating the dorsal horn (Kim et al, 2014b). This hyperactivity was maintained by descending serotonergic input from the brainstem.…”

TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain

“…TRPV1 is a nociception factor, which has pro-inflammatory effects in peripheral neuropathic pain (Kanai et al, 2005). The evidence of elevated TRPV1 demonstrates that hyperalgesia induced by injury depends on the sensitization of TRPV1 (Kim et al, 2014). Injury induces a release of inflammatory mediators, which lowers the threshold for the detection of painful levels of heat, a process known as heat hyperalgesia (Zhang et al, 2008).…”