Adipocyte Adrb3 Receptor Mediates Mechanical Hypersensitivity in Chronic Overlapping Pain Conditions

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      Chronic overlapping pain conditions (COPCs), such as temporomandibular disorder and fibromyalgia, are recognized as a significant healthcare problem. While the underlying mechanisms are not fully understood, the origins of COPCs are linked to genetic and environmental factors resulting in enhanced catecholaminergic tone. Patients with COPCs have genetic variants that lead to reduced activity of catechol-O-methyltransferase (COMT), a ubiquitously expressed enzyme that metabolizes NE, and corresponding increases in basal and stress-induced levels of norepinephrine (NE) in circulation and. We established a novel clinically relevant mouse model of COPCs that integrates COMT genetic background, stress, and minor surgery. Using this novel model, here we show an essential role of the adipocyte adrenergic receptor beta 3 (Adrb3) in driving mechanical hypersensitivity that affects multiple body sites. Results from in vitro studies of differentiated mature primary adipocytes, demonstrates that stimulation of Adrb3 with NE induces the release of pro-inflammatory cytokine interleukin-6 (IL-6) evokes calcium influx in a dose-dependent manner. To demonstrate the specific role of adipocyte Adrb3 in our mouse model of COPCs, we selectively deleted Adrb3 in adipocytes by crossing Adrb3 flox mice with AdipoQ-Cre mice to generate Adrb3 conditional knockout in adipocyte (Adrb3 fl/fl;AdipoQ-Cre mice). We then crossed these mice with COMT-/- mice to get Adrb3 fl/fl;AdipoQ-Cre; COMT+/- mice. Our results demonstrate that compared to WT:COMT+/- mice, the AdipoQAdrb3+/-:COMT+/- mice exhibit reduced stress-induced increases in NE and reduced mechanical hypersensitivity. In summary, our findings suggest that adipocyte Adrb3 promotes mechanical hypersensitivity through NE-dependent increases in cytokines/adipokines. Further, this work provides the first direct evidence that adipocytes (fat cells) contribute to multi-site body pain. Unraveling the adipocyte Adrb3 mechanisms involved in COPCs may facilitate the discovery of peripherally-targeted therapeutics that effectively and safely alleviate pain in patients with COPCs. Grant support from NIH/NINDS R01 NS109541 to AN.
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