Location and Plasticity of the Sodium Spike Initiation Zone in Nociceptive Terminals In Vivo

Nociceptive terminals possess the elements for detecting, transmitting, and modulating noxious signals, thus being pivotal for pain sensation. Despite this, a functional description of the transduction process by the terminals, in physiological conditions, has not been fully achieved. Here, we studied how nociceptive terminals in vivo convert noxious stimuli into propagating signals. By monitoring noxiousstimulus-induced Ca2+ dynamics from mouse corneal terminals, we found that initiation of Na+ channel (Nav)-dependent propagating signals takes place away from the terminal and that the starting point for Nav-mediated propagation depends on Nay functional availability. Acute treatment with the proinflammatory cytokines tumor necrosis factor a (TNF-alpha) and interleukin 1 beta (IL-1 beta) resulted in a shift of the location of Nay involvement toward the terminal, thus increasing nociceptive excitability. Moreover, a shift of Nay involvement toward the terminal occurs in corneal hyperalgesia resulting from acute photokeratitis. This dynamic change in the location of Nay-mediated propagation initiation could underlie pathological pain hypersensitivity.