Encoding of inflammatory hyperalgesia in mice spinal cord

Abstract

Inflammation modifies the input-output properties of peripheral nociceptive neurons, thus leading to hyperalgesia, i.e., changes in the perception of noxious heat stimuli 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 the application of noxious heat stimuli to the mice hind paw in naive conditions 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 leads to activation of previously non-responded cells and de-suppression of the "suppressed" neurons. We demonstrate that reduction in synaptic inhibition mimics the response to the noxious stimuli in the hyperalgesic conditions. Using a computational model of SDH network, we predict that inflammation-induced "disinhibition"-like changes result in increased activity of excitatory projection neurons. Our model also predicts that the observed "disinhibitory" effect of hyperalgesic stimuli does not require changes in the inhibitory transmission and may result from the SDH networks' intrinsic cytoarchitecture.

Scratching increases epidermal neuronal branching and alters psychophysical testing responses in atopic dermatitis and brachioradial pruritus

“…However, we cannot exclude peripheral sensitization, such as sensitization of tactile C-fibers in pruritic skin in BRP (Hashimoto and Yosipovitch, 2019). Since we found the most extensive branching in the two pruritic areas with alloknesis, increased excitability (Barkai et al, 2020;Wong et al, 2022) and an expanded receptive field by increased branching could enhance the spinal pruriceptive input inducing alloknesis (Finnerup et al, 2021).…”

“…This again suggests an underlying hypersensitivity in the patients, which can already be observed in the healthy-appearing skin of the patients. Importantly, sensitization to electrical stimulation by extreme branching (Barkai et al, 2020;Wong et al, 2022) might primarily increase the pain sensation and thus explain the combination of higher pain ratings and lower innervation density in BRP as compared to HCs. In line with this, in patients with type 2 diabetes, immunofluorescence staining of GAP-43, a marker of neuronal regeneration, showed that they had more pain with increased branching of GAP-positive fibers (Galosi et al, 2018).…”

Adaptation of pain-related projection neurons in acute but not chronic pain

“…In pathological conditions, such as inflammation or nerve injury, primary afferents become hyperexcitable, thus modifying the rate and timing of their firing toward the nociceptive dorsal horn network 9,[16][17][18][19] . There, it produces overall increased activity of dorsal horn interneurons [20][21][22] , resulting in amplified activation of PNs [23][24][25] , thus enhancing the output of the first CNS nociceptive networks to higher centers and leading to increased nociception and pain [25][26][27][28] .…”