Activation of acid-sensing ion channel 3 by lysophosphatidylcholine 16:0 mediates psychological stress-induced fibromyalgia-like pain

Abstract

ObjectivesFibromyalgia is commonly considered a stress-related chronic pain disorder, and daily stressors are known triggers. However, the relation between stress and pain development remains poorly defined by clinical approaches. Also, the aetiology remains largely unknown.MethodsWe used a newly developed mouse model and lipidomic approaches to probe the causation and explore the biological plausibility for how perceived stress translates into chronic non-inflammatory pain. Clinical and lipidomic investigations of fibromyalgia were conducted for human validation.ResultsUsing non-painful sound stimuli as psychological stressors, we demonstrated that mice developed long-lasting non-inflammatory hyperalgesia after repeated and intermittent sound stress exposure. Elevated serum malondialdehyde level in stressed mice indicated excessive oxidative stress and lipid oxidative damage. Lipidomics revealed upregulation of lysophosphatidylcholine 16:0 (LPC16:0), a product of lipid oxidisation, in stressed mice. Intramuscular LPC16:0 injection triggered nociceptive responses and a hyperalgesic priming-like effect that caused long-lasting hypersensitivity. Pharmacological or genetic inhibition of acid-sensing ion channel 3 impeded the development of LPC16:0-induced chronic hyperalgesia. Darapladib and antioxidants could effectively alleviate the stress-induced hyperalgesia by inhibiting LPC16:0 synthesis. Clinical investigations showed that excessive oxidative stress and LPC16:0 expression also exist in patients with fibromyalgia. Moreover, LPC16:0 expression was correlated with pain symptoms in patients with high oxidative stress and disease severity.ConclusionsOur study provides experimental evidence for the causal effect of psychological stressors on chronic pain development. The findings identify a possible pathophysiological mechanism of stress-induced chronic non-inflammatory pain at molecular, behavioural and clinical levels that might indicate a new therapeutic approach for fibromyalgia.

Lysophosphatidyl-choline 16:0 mediates persistent joint pain through Acid-Sensing Ion Channel 3: preclinical and clinical evidences

“…Conversely, these cytokines appeared upregulated in CFA-injected joints, as expected. Hung and colleagues 18 also failed to observe any inflammatory signs following intramuscular administration of LPC16:0 in mouse muscle. Because bone alteration/remodeling has been suggested to contribute to chronic joint pain in rheumatic diseases such as OA 32–34 and RA 35 , the Cathepsin K activity as well as joint expression of TRAP and RANK-L has been investigated in our model.…”

“…It is thus very likely that the two consecutive intra-articular injections of LPC16:0 drive a nociceptive ASIC3-dependent input leading to a persistent pain state originating from joints. ASIC3 has been already associated to long-lasting pain states following acid injections in rodent joints 24 and muscles 25 and it has been more recently proposed to participate in pain behaviors induced by LPC16:0 muscle injections in mice 18 . The stimulation of ASIC3 channels in nerve endings of deep tissues, such as muscles or joints, is thus a key step for the development of persistent pain state.…”

“…ASIC3 have been involved in animal models of inflammatory and non-inflammatory pain 20,21 , especially in the development of chronic pain states originating from joints [22][23][24] and muscles 18,25,26 . Accordingly, ASIC3-dependent pain behaviors can be induced in rodent upon injection of LPC in the paw or the muscle 6,18 . Here we investigated the clinical relevance of LPC in chronic joint pain and we explored its mechanism of action that involved peripheral ASIC3 channels, using a new preclinical pain model in mice induced by intra-articular administrations of LPC 16:0.…”

Dorsal root ganglia: fibromyalgia pain factory?

“…After sound stress exposure, mice developed long-lasting hyperalgesia. Affected mice had lysophosphatidylcholine 16:0 overexpression, which triggered nociceptive signaling via activation of acid sensing ion channel 3 and upregulated expression of DRG phosphorylated extracellular signal-regulated kinase [14].…”

Electroacupuncture Reduces Cold Stress-Induced Pain through Microglial Inactivation and Transient Receptor Potential V1 in Mice

“…Recent evidence implied that the central nervous system (CNS) plays an important role in the ampli cation of pain signals and the neurotransmitters associated with it [2]. Well-established bromyalgia animal models can be produced by acidic saline injection into the gastrocnemius muscle [3], sound stress [4], and cold stress [5].…”