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.

Maximum axonal following frequency separates classes of cutaneous unmyelinated nociceptors in the pig

“…2016; Barkai et al . 2020). Moreover, higher axonal discharge frequencies as recorded in the periphery do not necessarily reach the spinal cord, as they can still be filtered at the T‐junction at the level of the dorsal root ganglion (Du et al .…”

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 ).…”

Optical Assessment of Nociceptive TRP Channel Function at the Peripheral Nerve Terminal

“…Electrical recordings of the cell body or of membrane patches of primary sensory neurons of different modalities have also been used to further define the contribution of TRP and voltage-gated channels to the generator potential and specific responsiveness to their natural stimuli. However, considering that the terminal’s functional environment [ 133 , 134 , 135 , 136 , 137 ], geometry [ 25 , 26 , 138 ], and likely its passive membrane properties [ 19 , 139 ] differ from cell bodies situated in DRGs or TGs, the actual detection and transmission of noxious stimuli may be significantly different from predictions made based on data obtained from studying neuronal somata. Thus, some of the basic questions in nociception and pain cannot be answered by solely studying cell bodies.…”

“…Also, studying only DRG somata makes it impossible to determine the contribution of TRP and voltage-gated channels to the generator potential and the location of the transition between the generator potential to action potential. Moreover, a recent computational study predicted that nociceptive output resulting from activation of terminal TRPV1 channels depends on the terminal tree structure [ 19 ], emphasizing once again the importance of direct investigation of signal propagation along nociceptive terminals. Our knowledge of normal and abnormal transmission of pain signals is dependent on having a full understanding of the occurrences in the nerve terminals that lead to the sensation of pain.…”

“…Although this provided invaluable information on the roles TRP channels play in nociception, the possible alteration of expression, distribution, and modulation by endogenous factors of TRP channels under non-physiological conditions [ 17 , 18 ], and other factors such as distinct morphology between the nerve terminal and soma, might account for different coding of noxious stimuli by TRP channels in their physiological environment. Indeed, a recently published computational model revealed that the structure of peripheral nociceptive terminal tree determines the output of the nociceptive neurons at the central terminal [ 19 ]. Since in vitro models do not recapitulate the entire nerve terminal complexity, there is an obvious need to assess TRP channel functionality directly on the nerve terminal in more physiological conditions.…”