Sensory Transduction in Peripheral Nerve Axons Elicits Ectopic Action Potentials

Abstract

Sensory properties of unmyelinated axons in the isolated rat sciatic nerve have been revealed previously by measuring stimulated neuropeptide release in response to noxious stimuli. In addition, axonal sensitization by inflammatory mediators has been demonstrated and shown to depend on the heat-and proton-activated ion channel transient receptor potential vanilloid receptor-1. It was unclear whether this responsiveness is accompanied by ectopic generation of action potentials, which may play a crucial role in painful neuropathies. We explored this hypothesis using the isolated mouse skin-nerve preparation. This method enabled us to directly compare the sensory properties of axons in the peripheral nerve with their characterized cutaneous terminals in the receptive field using propagated action potentials as an index of axonal activation. Single-fiber recordings from 51 mechanosensitive mouse C-fibers revealed that a majority of the polymodal nociceptors responded with an encoding discharge rate to graded heating of the cutaneous receptive field (n ϭ 38) as well as of the saphenous nerve carrying the fiber under investigation (n ϭ 25; 66%). Axonal heat responses paralleled those of the receptive fields with regard to thresholds and discharge rates (41.5 Ϯ 4.3°C; 7.7 Ϯ 9.6 spikes in a 20 s 32-48°C ranged stimulation). In contrast, axonal mechanosensitivity was poor and noxious cold sensitivity more rarely encountered. In conclusion, peripheral nerve axons exhibit sensory transduction capacities similar to their nociceptive terminals in the skin with respect to noxious heat, although not to mechanical and cold sensitivity. This may become a source of ectopic discharge and pain if axonal heat threshold drops to body temperature, as may be the case during inflammation-like processes in peripheral nerves.

Phosphorylated Histone 3 at Serine 10 Identifies Activated Spinal Neurons and Contributes to the Development of Tissue Injury-Associated Pain

“…In contrast to burn injury and capsaicin application, exposure of the paw to 44 °C29 for 10 seconds repeatedly in every 20 seconds for 2 minutes (to avoid tissue damage) failed to induce p -S10H3 up-regulation (4.33 ± 1.2, n = 3; p = 0.351, GLM; Fig. 5F) whereas it significantly increased p -ERK1/2 expression (Fig.…”

Deconstructing the Neuropathic Pain Phenotype to Reveal Neural Mechanisms

“…Because TRPV1 activation threshold is modified by inflammatory mediators from immune cells, and injured nerves contain many macrophages and T-cells (Gaudet et al, 2011), it is quite possible, therefore, that axonal TRPV1, just like peripheral terminal TRPV1, may also become sensitized. Theoretically, a reduction in TRPV1 thermal threshold to levels close to body temperature along the axon could then lead to depolarization and generation of action potentials, producing spontaneous pain (Hoffmann et al, 2008). …”

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…Another, more global, technique focusing on the periphery is the measurement of basal and stimulated release of neuropeptides as an index of nociceptor activation in a large variety of ex vivo preparations (33). These peripheral nerve axons of primary nociceptive neurons that can serve, to a certain extent, as a model of their terminals, sharing remarkable sensory and neurosecretory capabilities with the nerve endings (288). According to the above considerations, the major aim of the present review is to highlight those molecular mechanisms and membrane targets of the discussed inflammatory mediators that have been revealed both in cellular models and in paradigms reflecting the activity of peripheral nociceptors and which are therefore likely to play a role in peripheral nociception in vivo.…”