Lenert, M. E. | Search bioRxiv

bioRxiv2025

TLR4+ Dermal fibroblasts induce acute and transitional pain states

The prominence of non-neuronal cells driving pain states has gained attention in recent years. Fibroblasts, a major stromal cell, perform essential functions during inflammation, tissue remodeling, and wound healing; however, recent studies suggest that fibroblasts may play a role in pain. Toll-like receptor 4 (TLR4) is an essential component of the innate immune system and activation of the receptor promotes pain. This study utilized a novel mouse model with dermal fibroblast specific expression of TLR4 on a TLR4-null background, which allows us to understand the sufficiency of skin fibroblast activation in pain development. Here we demonstrate that dermal fibroblast activation induces both acute inflammatory pain and hyperalgesic priming in both male and female mice. In vivo, activated dermal fibroblasts change cellular morphology in mice and humans. In vitro we observed pro-inflammatory cytokine production and activation of calcium signaling pathways. These data demonstrate that dermal fibroblast activation can cause acute pain and drive mechanisms involved in the transition to chronic pain.

neuroscience↗

bioRxiv2021

Translating outcomes from the clinical setting to preclinical models: chronic pain and functionality in chronic musculoskeletal pain

Fibromyalgia (FM) is a chronic pain disorder characterized by chronic widespread musculoskeletal pain (CWP), tenderness, and fatigue, which interferes with daily functioning and quality of life. In clinical studies, this symptomology is assessed, while preclinical models of CWP are limited to nociceptive assays. The aim of the study was to investigate the human-to-model translatability of clinical behavioral assessments for pain and muscle function in a preclinical model of CWP. We assessed correlations between pain behaviors and muscle function in a preclinical model of CWP and in women with fibromyalgia to examine whether similar relationships between outcomes existed in both settings, for usability of clinical assays in model systems. For preclinical measures, the acidic saline model of FM which induces widespread muscle pain, was used in adult female mice. Two gastrocnemius injections of acidic or physiological pH saline were given following baseline measures, five days apart. An array of adapted pain measures and functional assays were assessed for three weeks. For clinical measures, pain and functional assays were assessed in adult women with FM. For both preclinical and clinical outcomes, movement-evoked pain (MEP) was associated with mechanical pain sensitivity. Mechanical sensitivity was correlated to shifts in weight-bearing preclinically and was predictive of functionality in patients. Preclinically, it is imperative to expand how the field assesses pain behaviors when studying multi- symptom disorders like FM. Targeted pain assessments to match those performed clinically is an important aspect of improving preclinical to clinical translatability of animal models. SummaryPreclinical assessments of chronic musculoskeletal pain recapitulate several outcome measures for clinical assessment of patients with FM, particularly prolonged resting pain, and MEP.

neuroscience↗