Binshtok, A. M. | Search bioRxiv

bioRxiv2021

Encoding of inflammatory hyperalgesia in mice spinal cord

Inflammation modifies the input-output properties of peripheral nociceptive neurons, thus leading to hyperalgesia, a condition in which the perception of noxious heat stimuli is altered such that the same stimulus produces enhanced pain. The increased nociceptive output enters the superficial dorsal spinal cord (SDH), which comprises the first CNS network integrating the noxious information. Here we used in vivo calcium imaging and a computational approach to investigate how the SDH network in mice encodes the injury-mediated abnormal input from peripheral nociceptive neurons. We show that the application of noxious heat stimuli to the hind paw in naive mice before induction of injury affects the activity of 70% of recorded neurons by either increasing or suppressing it. Application of the same noxious heat stimuli to hyperalgesic skin following injury leads to activation of previously non-responded cells and de-suppression of the "suppressed" neurons. We further demonstrate that reduction in synaptic inhibition mimics the response to the noxious stimuli in hyperalgesic conditions. Using a computational model of the SDH network, we predict that the "disinhibitory" effect of hyperalgesic stimuli results from the inflammation-mediated increased afferent input to the SDH network and a decrease in SDH inhibition. Both of these processes synergistically contribute to the injury-mediated increase in SDH output towards higher brain centers.

neuroscience↗

bioRxiv2020

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

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.

neuroscience↗