Functional coupling between peripheral nociceptor terminals in vivo is enhanced during acute inflammation

ABSTRACT: Primary nociceptors are essentially characterized as afferent neurons carrying noxious sensory information from the periphery to the central nervous system. However, the information flow on primary nociceptors is bidirectional. Nociceptor peripheral terminals release a variety of mediators to the target organ near the injured area. These mediators promote sensitization of adjacent sensory neurons, vasodilation, and edema, affecting innate and adaptive immunity, leading to hyperalgesia and inflammation that often expands beyond the injured areas. While many studies associate these phenomena with the antidromic action-potential propagation along nociceptor terminals, direct evidence demonstrating that activation of a single nociceptor terminal can, through efferent signaling, recruit neighboring unstimulated terminals has been missing. In this study, using in vivo calcium imaging from the individual nociceptive terminals innervating the cornea of male mice, together with a computational approach, we demonstrated that brief activation of a single terminal in vivo by capsaicin was sufficient to evoke a response in a remote, unstimulated terminal, branching from the same nociceptor fiber. The activation of the remote unstimulated terminal was dependent on the activation of voltage-gated sodium and calcium channels. Moreover, we showed that in the model of acute hyperalgesia, following exposure to proinflammatory cytokines, the efferent signaling along nociceptive terminals increases, culminating in enhanced calcium signaling in the remote unstimulated terminals. This increase in intraterminal calcium could trigger an enhanced release of inflammatory mediators, affecting wider areas and terminals from adjacent unstimulated receptive fields, leading to the expansion of hyperalgesia and inflammation.