Department of Neurology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA; Department of Neurology, University of Iowa, Iowa City, IA, USA.
Department of Neurology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA.
Neuroscience. 2019 Sep 1;415:121-134. doi: 10.1016/j.neuroscience.2019.06.043. Epub 2019 Jul 8.
How obesity exacerbates migraine and other pain disorders remains unknown. Trigeminal nociceptive processing, crucial in migraine pathophysiology, is abnormal in mice with diet induced obesity. However, it is not known if this is also true in genetic models of obesity. We hypothesized that obese mice, regardless of the model, have trigeminal hyperalgesia. To test this, we first evaluated trigeminal thermal nociception in leptin deficient (ob/ob) and control mice using an operant thermal assay. Unexpectedly, we found significant hypoalgesia in ob/ob mice. Because thermal hypoalgesia also occurs in mice lacking the transient receptor potential vanilloid 1 channel (TRPV1), we tested capsaicin-evoked trigeminal nociception. Ob/ob and control mice had similar capsaicin-evoked nocifensive behaviors, but ob/ob mice were significantly less active after a facial injection of capsaicin than were diet-induced obese mice or lean controls. Conditioned place aversion in response to trigeminal stimulation with capsaicin was similar in both genotypes, indicating normal negative affect and pain avoidance. Supporting this, we found no difference in TRPV1 expression in the trigeminal ganglia of ob/ob and control mice. Finally, we assessed the possible contribution of hyperphagia, a hallmark of leptin deficiency, to the behavior observed in the operant assay. Ob/ob and lean control mice had similar reduction of intake when quinine or capsaicin was added to the sweetened milk, excluding a significant contribution of hyperphagia. In summary, ob/ob mice, unlike mice with diet-induced obesity, have trigeminal thermal hypoalgesia but normal responses to capsaicin, suggesting specificity in the mechanisms by which leptin acts in pain processing.
肥胖如何加剧偏头痛和其他疼痛障碍尚不清楚。三叉神经伤害性处理在偏头痛病理生理学中至关重要，在饮食诱导肥胖的小鼠中异常。然而，肥胖的遗传模型是否也是如此还不得而知。我们假设，无论肥胖模型如何，肥胖小鼠都有三叉神经痛觉过敏。为了验证这一点，我们首先使用操作性热测定法评估了瘦素缺乏（ob/ob）和对照小鼠的三叉神经热痛觉。出乎意料的是，我们发现 ob/ob 小鼠明显的痛觉减退。由于热痛觉减退也发生在缺乏瞬时受体电位香草酸 1 通道（TRPV1）的小鼠中，我们测试了辣椒素诱发的三叉神经疼痛。ob/ob 和对照小鼠的辣椒素诱发的伤害性行为相似，但 ob/ob 小鼠在面部注射辣椒素后比饮食诱导肥胖的小鼠或瘦对照小鼠的活动明显减少。对辣椒素刺激三叉神经的条件性位置厌恶在两种基因型中相似，表明正常的负面情绪和疼痛回避。支持这一点，我们发现 ob/ob 和对照小鼠的三叉神经节中 TRPV1 表达没有差异。最后，我们评估了肥胖的标志——多食症对操作性测定中观察到的行为的可能贡献。当奎宁或辣椒素添加到加糖牛奶中时，ob/ob 和瘦对照小鼠的摄入量有相似的减少，排除了多食症的显著贡献。总之，ob/ob 小鼠与饮食诱导肥胖的小鼠不同，它们有三叉神经热痛觉减退，但对辣椒素的反应正常，这表明瘦素在疼痛处理中的作用机制具有特异性。
