Efferent signaling along nociceptive peripheral terminals in vivo is enhanced during inflammation

Abstract

Primary nociceptors are essentially characterized as afferent neurons carrying noxious sensory information from the periphery to the CNS. However, the information flow on primary nociceptors is bidirectional. Nociceptor peripheral terminals release a variety of mediators to the target organ in the vicinity of the injured area. These mediators promote sensitization of adjacent sensory neurons, vasodilation, and edema and affect innate and adaptive immunity, leading to hyperalgesia and inflammation that often expands beyond the injured areas. Many theories associate these phenomena with the antidromic action potential propagation along nociceptor terminals; however, the antidromic efferent signaling at the single nociceptor terminals has never been demonstrated. Here, using in vivo calcium imaging from the individual nociceptive terminals innervating the mouse cornea together with a computational approach, we demonstrated that short-lasting activation of a single terminal in vivo was sufficient to activate the remote, non-activated terminal, which branches from the same nociceptor fiber. This increase was dependent on the activation of voltage-gated sodium and calcium channels. Moreover, we showed that the efferent signaling along nociceptive terminals increases under inflammatory conditions, culminating in enhanced calcium signaling in the remote non-activated terminals. This inflammation-induced increase in intra-terminal calcium could trigger the enhanced release of inflammatory mediators, spilling over wider areas and affecting terminals from adjacent unstimulated receptive fields, leading to the expansion of hyperalgesia and inflammation.