Otis Colombe, Cristofanilli Katrine-Ann, Frezier Marilyn, Delsart Aliénor, Martel-Pelletier Johanne, Pelletier Jean-Pierre, Beaudry Francis, Lussier Bertrand, Boyer Alexandre, Troncy Eric
Research Group in Animal Pharmacology of Quebec (GREPAQ), Université de Montréal, Saint-Hyacinthe, QC, Canada.
Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Saint-Hyacinthe, QC, Canada.
Front Cell Dev Biol. 2024 Aug 8;12:1400650. doi: 10.3389/fcell.2024.1400650. eCollection 2024.
Micro-RNAs could provide great insights about the neuropathological mechanisms associated with osteoarthritis (OA) pain processing. Using the validated ontreal nduction of at rthritis esting (MI-RAT) model, this study aimed to characterize neuroepigenetic markers susceptible to correlate with innovative pain functional phenotype and targeted neuropeptide alterations.
Functional biomechanical, somatosensory sensitization (peripheral-via tactile paw withdrawal threshold; central-via response to mechanical temporal summation), and diffuse noxious inhibitory control (via conditioned pain modulation) alterations were assessed sequentially in OA ( = 12) and Naïve ( = 12) rats. Joint structural, targeted spinal neuropeptides and differential expression of spinal cord micro-RNAs analyses were conducted at the sacrifice (day (D) 56).
The MI-RAT model caused important structural damages (reaching 35.77% of cartilage surface) compared to the Naïve group ( < 0.001). This was concomitantly associated with nociceptive sensitization: ipsilateral weight shift to the contralateral hind limb (asymmetry index) from -55.61% ± 8.50% (D7) to -26.29% ± 8.50% (D35) ( < 0.0001); mechanical pain hypersensitivity was present as soon as D7 and persisting until D56 ( < 0.008); central sensitization was evident at D21 ( = 0.038); pain endogenous inhibitory control was distinguished with higher conditioned pain modulation rate ( < 0.05) at D7, D21, and D35 as a reflect of filtrated pain perception. Somatosensory profile alterations of OA rats were translated in a persistent elevation of pro-nociceptive neuropeptides substance P and bradykinin, along with an increased expression of spinal miR-181b ( = 0.029) at D56.
The MI-RAT OA model is associated, not only with structural lesions and static weight-bearing alterations, but also with a somatosensory profile that encompasses pain centralized sensitization, associated to active endogenous inhibitory/facilitatory controls, and corresponding neuropeptidomic and neuroepigenetic alterations. This preliminary neuroepigenetic research confirms the crucial role of pain endogenous inhibitory control in the development of OA chronic pain (not only hypersensitivity) and validates the MI-RAT model for its study.
微小RNA可为骨关节炎（OA）疼痛处理相关的神经病理机制提供深入见解。本研究使用经过验证的关节炎诱导测试（MI-RAT）模型，旨在鉴定易与创新性疼痛功能表型及靶向神经肽改变相关的神经表观遗传标志物。
对OA组（n = 12）和正常组（n = 12）大鼠依次评估功能生物力学、体感致敏（外周通过触觉缩爪阈值；中枢通过对机械性时间总和的反应）以及弥漫性伤害性抑制控制（通过条件性疼痛调制）的改变。在处死时（第56天）进行关节结构、靶向脊髓神经肽以及脊髓微小RNA差异表达分析。
与正常组相比，MI-RAT模型导致了严重的结构损伤（软骨表面损伤达35.77%）（P < 0.001）。这同时伴随着伤害性致敏：同侧体重向对侧后肢转移（不对称指数）从-55.61% ± 8.50%（第7天）降至-26.29% ± 8.50%（第35天）（P < 0.0001）；机械性疼痛超敏在第7天即出现并持续至第56天（P < 0.008）；中枢致敏在第21天明显（P = 0.038）；在第7天、第2... 显示全部
