ASIC3-dependent spinal cord nociceptive signaling in cutaneous pain induced by lysophosphatidyl-choline

Abstract

Lysophosphatidyl-choline (LPC), a member of the phospholipid family, has recently emerged as an interesting new player in pain. It has been proposed to mediate pain through Acid-Sensing Ion Channel 3 (ASIC3), a pain-related channel mainly expressed in peripheral sensory neurons. LPC potentiates ASIC3 current evoked by mild acidifications, but can also activate the channel at physiological pH, and its local injection in rodents evokes ASIC3-dependent pain. We combine here in vivo recordings of spinal cord neuron activity with subcutaneous LPC injection to analyze the mechanism of action associated with the LPC-induced, ASIC3-dependent pain in peripheral and spinal cord neurons. We show that a single cutaneous injection of LPC exclusively affects the nociceptive pathway. It evokes an ASIC3-dependent short-term sensitization of nociceptive fibers that drives hyperexcitability of projecting neurons within the dorsal spinal cord without apparent central sensitization.

Lysophosphatidylcholine induces heat pain hypersensitivity in obese mice fed with a high-fat diet through activation of peripheral Acid-Sensing Ion Channel 3

“…ASIC1a, which is also expressed in DRGs (Deval & Lingueglia, 2015) was also tested. There was no effect of HFD-S on ASIC1a expressed in HEK-293 cells, and the evoked currents were not different from those measured with SD-S. ASIC1a is not activated by extracellular LPC (Jacquot et al, 2021; Marra et al, 2016; Pidoux et al, 2020), and these data are therefore consistent with a role of LPC present in HFD serum on ASIC3 activity in DRGs. We further investigated the contribution of lipids in HFD-S with HFD-dl serum applied on HEK-293 cells expressing ASIC3.…”

“…, in the absence of extracellular acidification (Deval et al, 2008; Jacquot et al, 2021; Marra et al, 2016). LPC alone evokes depolarizing current in DRGs at physiological pH 7.4, increases skin nociceptive C-fiber firing, and induces both acute and chronic pain behaviors in rodents, depending on whether it is injected into the skin or joints (Jacquot et al, 2021; Marra et al, 2016; Pidoux et al, 2020). To test this hypothesis, we depleted lipids from HFD-serum (HFD-dl), and we perfused HFD-dl on WT-DRG neurons.…”