The input-output relation of primary nociceptive neurons is determined by the morphology of the peripheral nociceptive terminals

Abstract

The output from the peripheral terminals of primary nociceptive neurons, which detect and encode the information regarding noxious stimuli, is crucial in determining pain sensation. The nociceptive terminal endings are morphologically complex structures assembled from multiple branches of different geometry, which converge in a variety of forms to create the terminal tree. The output of a single terminal is defined by the properties of the transducer channels producing the generation potentials and voltage-gated channels, translating the generation potentials into action potential firing. However, in the majority of cases, noxious stimuli activate multiple terminals; thus, the output of the nociceptive neuron is defined by the integration and computation of the inputs of the individual terminals. Here we used a computational model of nociceptive terminal tree to study how the architecture of the terminal tree affects input-output relation of the primary nociceptive neurons. We show that the input-output properties of the nociceptive neurons depend on the length, the axial resistance, and location of individual terminals. Moreover, we show that activation of multiple terminals by capsaicin-like current allows summation of the responses from individual terminals, thus leading to increased nociceptive output. Stimulation of terminals in simulated models of inflammatory or nociceptive hyperexcitability led to a change in the temporal pattern of action potential firing, emphasizing the role of temporal code in conveying key information about changes in nociceptive output in pathological conditions, leading to pain hypersensitivity.Significance statementNoxious stimuli are detected by terminal endings of the primary nociceptive neurons, which are organized into morphologically complex terminal trees. The information from multiple terminals is integrated along the terminal tree, computing the neuronal output, which propagates towards the CNS, thus shaping the pain sensation. Here we revealed that the structure of the nociceptive terminal tree determines the output of the nociceptive neurons. We show that the integration of noxious information depends on the morphology of the terminal trees and how this integration and, consequently, the neuronal output change under pathological conditions. Our findings help to predict how nociceptive neurons encode noxious stimuli and how this encoding changes in pathological conditions, leading to pain.

Electrically Evoked Itch in Human Subjects

“…However, due to the lack of established markers for human pruriceptive nerve fibers-the mentioned studies used the pan-fiber marker protein gene product 9.5 (PGP9.5)-the significance of such epidermal innervation changes for electrical induction of pruritus in AD patients remains unclear and needs further investigation. Epidermal thickening, especially prevalent in eczematous AD skin, adds an additional layer of complexity as it might increase the distance between the most superficial nerve fibers and the transdermal stimulation electrodes as well as the length and axonal branching pattern of the nerve terminals, both of which might influence their excitability (65,66). b) Most ion channels with established roles in the transduction of natural nociceptive stimuli, including the polymodal transient receptor potential (TRP) superfamily members TRP vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1), are only weakly voltage dependent, limiting their contribution to electrically induced depolarization (67,68).…”