治疗肥胖患者慢性非癌性疼痛的一条新途径

Obesity is a complex disease that affects multiple organ functions. While chronic pain is frequently present in obese subjects, the effective treatment remains limited for this population. A significant challenge is that most pain medications such as opioids, glucocorticoid anti-inflammatory agents, antidepressants, and gabapentinoids, while effective for pain relief, often lead to weight gain and worsening obesity in long-term use, and produce a vicious circle of chronic pain and obesity. In light of an increasing number of overweight/obese patients and significant side effects including weight gain from conventional pain medications, it has become increasingly urgent to explore new approaches that would provide both effective long-term pain relief and weight control. Melatonin is a hormone secreted mainly by the pineal gland. Endogenous melatonin plays a regulatory role in circadian rhythm. Recent preclinical and clinical studies have shown that melatonin has both antinociceptive and weight control effects. In our preliminary studies, we have shown that 1) Zucker diabetic fatty (fa/fa) rats (ZDF) have a lower baseline nociceptive threshold and a prolonged course of nociceptive behaviors following peripheral nerve injury, 2) the plasma melatonin level was lowed in rats with persistent nociception, 3) melatonin attenuated nociceptive behaviors, and 4) melatonin inhibited N-methyl-D-aspartate (NMDA)-induced current in spinal cord dorsal horn slices and regulated the spinal NMDA receptor expression. Therefore, the goal of this preclinical research project is to determine whether melatonin and its analogue would be effective for the prevention and reversal of neuropathic pain in obese rats. Using an established model of neuropathic pain in ZDF in our lab, we will carry out a series of experiments to accomplish two specific aims. In Specific Aim 1, we will examine the role of melatonin in the prevention and reversal of neuropathic pain as well as obesity in ZDF. In Specific Aim 2, we will examine whether the effect of melatonin on neuropathic pain is mediated through modulation of the spinal NMDA receptor expression in ZDF. We will also examine whether a lower plasma melatonin level correlates with the development and maintenance of neuropathic pain in ZDF. The data from this project will guide us to explore a detailed cellular mechanism regarding the interaction between obesity and pain in future studies. The outcome will also be used to support translational clinical studies to evaluate the effectiveness of melatonin and its analogue in the treatment of chronic pain in obese or overweight patients.

肥胖是一影响多器官功能的复杂疾病。肥胖患者常伴有慢性疼痛，但对此缺乏有效的处理手段。最大挑战是，常规镇疼药，如阿片类、糖皮质激素类、抗抑郁或抗焦虑药物，尽管有效缓解疼痛，长期使用将加重肥胖。鉴于肥胖患者逐年增多，探索即可长期缓解疼痛又可控制体重的新途径日益紧迫。内源性褪黑素主要调节昼夜节律。最新研究显示，褪黑素具镇痛和减肥的双重作用。本题预实验显示：1)Zucker糖尿肥胖大鼠基础疼阈低,疼痛恢复慢；2)疼痛鼠血浆褪黑素水平低；3)褪黑素减少疼痛行为；4)褪黑素抑制N-甲基-D-天冬氨酸(NMDA)电流，调节NMDA受体表达。本题将建立肥胖神经病理性疼模型，研究1)褪黑素类预防和治疗慢性疼痛和肥胖的功效,2)褪黑素的疼痛调节作用是否由NMDA受体介导。该项目的成果将指导我们1)评估褪黑素类临床治疗肥胖患者慢性疼痛的可行性，2)进一步探索疼痛与肥胖关系的机制。

嘎巴喷丁（Gabapentin）是临床上被用来治疗癫痫等神经精神类疾病的常用药，但也是目前临床上治疗神经病理性痛的首选药。嘎巴喷丁的突出副作用是其增肥效应。由于神经病理性痛患者需要连续、大剂量和长期服用嘎巴喷丁，患者往往会在使用几个月后出现严重的向心性肥胖，因此，这一副作用可能诱使疼痛患者并发代谢性疾病，严重增加患者的心理和生理负担，由此也限制了该药的使用。寻找即有镇痛作用，又可以控制体重的药物，单独服用或与嘎巴喷丁配伍，以减轻体重增加的副作用，是本项目的主要目的。褪黑素是主要由松果体在夜间睡眠和胃肠道在进食时分泌的一类神经激素，是已知的即具有镇痛作用，又对脂代谢具有调节作用的激素。研究表明，褪黑素对脂代谢的调节作用表现在抑制生脂和促进脂解两方面，即能够减少动物的食物摄入、抑制脂肪酸转运、抑制细胞总脂肪酸的摄入、减少脂质堆积，又能够增加对脂肪的交感激动，促进脂肪动员、增加脂解、减少脂质合成、减少腹部脂肪。项目研究了褪黑素与嘎巴喷丁配伍，对后者增肥效应的抑制作用和对其镇痛作用的协同作用。结果发现，在Zucker糖尿病肥胖大鼠，耳甲区迷走神经刺激，能够诱发褪黑素的节律性分泌，促进大鼠中枢神经系统和骨骼肌内胰岛素受体的表达，且这一分泌模式和受体表达促进效应，能够延缓Zucker大鼠的糖尿病发病进程；而在Zucker肥胖大鼠坐骨神经慢性挤压疼痛（CCI）模型，连续8周的治疗，同时服用嘎巴喷丁1/4有效剂量(2.5mg/kg)和褪黑素1/4有效剂量(15mg/kg)的模型组，尽管体重高于单独灌服嘎巴喷丁10mg/kg剂量组，但其体脂比显著降低，即对模型大鼠的体重正常增长没有影响，而对腹部脂肪的形成起到了有效抑制，且对嘎巴喷丁的镇痛作用没有影响。这一重要研究结果证明，与嘎巴喷丁联用时，褪黑素具有减轻嘎巴喷丁的增肥效应，并协同镇痛的作用。项目在大鼠的研究结果证明，开发褪黑素对慢性非癌性肥胖患者长期、大剂量使用嘎巴喷丁时的增肥抑制作用，使这一配伍临床化，有望造福广东神经痛患者和癫痫患者。