Brain Institute, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
SE LA Veterans Health Care System, New Orleans, LA, 70119, USA.
J Neuroinflammation. 2019 May 21;16(1):100. doi: 10.1186/s12974-019-1480-x.
Numerous studies have identified the proinflammatory, pronociceptive effects of morphine which ultimately exacerbate pain. Our novel endomorphin analog ZH853 does not produce proinflammatory effects on its own and gives potent, long-lasting analgesia. This study investigates whether ZH853's lack of interaction with the neuroimmune system reduces the risk of prolonged pain.
Adult male Sprague-Dawley rats were subjected to one of two treatment paradigms. Either (1) chronic pain followed by chronic treatment with morphine, ZH853 or vehicle, or (2) chronic drug administered prior to pain induction. Complete Freund's adjuvant (CFA) was injected or paw incision surgery was performed on the left hind plantar foot pad. Drugs were administered through Alzet osmotic minipumps at a rate of 1 μl/h for 5 days at appropriate doses based on prior experiments. Animals were tested for mechanical allodynia and thermal hyperalgesia using von Frey filaments and the Hargreaves apparatus, respectively. Additionally, several gait parameters were measured using the CatWalk XT. When all animals had recovered from pain, 1 mg/kg of naltrexone was administered to test for development of latent sensitization (LS). A second set of animals was used to investigate dorsal horn inflammation following CFA and drug treatment. ANOVAs were used to assess differences between drug treatment groups.
As expected, morphine increased and prolonged pain in all experiments compared to vehicle treatment. However, ZH853 treatment reduced the overall time spent in pain and the severity of pain scores compared to morphine. ZH853 not only reduced inflammation versus morphine treatment but also, in some instances, acted as an anti-inflammatory drug compared to vehicle treatment. Finally, ZH853 prevented the development of LS while vehicle- and morphine-treated animals showed robust relapse to pain.
ZH853 has a favorable side effect profile versus morphine and provides superior analgesia in a number of pain states. We now know that chronic use of this compound reduces time spent in a chronic pain state, the opposite of common opioids like morphine, and reduces the risk of LS, making ZH853 an excellent candidate for clinical development in humans for inflammatory and postoperative pain.
许多研究已经确定了吗啡的促炎、致痛作用，这些作用最终会加剧疼痛。我们新的内吗啡肽类似物 ZH853 本身不会产生促炎作用，并且具有强大而持久的镇痛作用。本研究旨在探讨 ZH853 与神经免疫系统缺乏相互作用是否会降低长期疼痛的风险。
成年雄性 Sprague-Dawley 大鼠接受两种治疗方案之一。一种是（1）慢性疼痛后给予吗啡、ZH853 或载体慢性治疗，另一种是（2）慢性药物预先给予疼痛诱导。完全弗氏佐剂（CFA）注射或左后足底垫行爪切口手术。根据先前的实验，以适当剂量通过 Alzet 渗透微型泵以 1μl/h 的速率给药 5 天。使用 von Frey 纤维和 Hargreaves 仪器分别测试动物的机械性痛觉过敏和热痛觉过敏。此外，使用 CatWalk XT 测量了几个步态参数。当所有动物从疼痛中恢复后，给予 1mg/kg 的纳曲酮以测试潜在致敏（LS）的发展。第二组动物用于研究 CFA 和药物治疗后的背角炎症。使用 ANOVA 评估药物治疗组之间的差异。
正如预期的那样，与载体治疗相比，吗啡在所有实验中均增加并延长了疼痛。然而，与吗啡治疗相比，ZH853 治疗减少了疼痛的总时间和疼痛评分的严重程度。与吗啡治疗相比，ZH853 不仅减少了炎症，而且在某些情况下，与载体治疗相比，它还具有抗炎作用。最后，ZH853 预防了 LS 的发展，而载体和吗啡治疗的动物则表现出强烈的疼痛复发。
与吗啡相比，ZH853 的副作用谱良好，并在多种疼痛状态下提供更好的镇痛效果。我们现在知道，这种化合物的慢性使用会减少处于慢性疼痛状态的时间，与吗啡等常见阿片类药物相反，并且降低 LS 的风险，使 ZH853 成为人类炎症和术后疼痛临床开发的优秀候选药物。
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