Chen Ing-Jung, Yang Chih-Ping, Lin Sheng-Hsiung, Lai Chang-Mei, Wong Chih-Shung
Department of Anesthesiology, Cathay General Hospital, Taipei 10630, Taiwan.
Department of Medical Research, Cathay General Hospital, Taipei 10630, Taiwan.
Antioxidants (Basel). 2020 Aug 22;9(9):780. doi: 10.3390/antiox9090780.
Opioids are commonly prescribed for clinical pain management; however, dose-escalation, tolerance, dependence, and addiction limit their usability for long-term chronic pain. The associated poor sleep pattern alters the circadian neurobiology, and further compromises the pain management. Here, we aim to determine the correlation between constant light exposure and morphine tolerance and explore the potential of melatonin as an adjuvant of morphine for neuropathic pain treatment.
Wistar rats were preconditioned under constant light (LL) or a regular light/dark (LD) cycle before neuropathic pain induction by chronic constriction injury. An intrathecal (i.t.) osmotic pump was used for continued drug delivery to induce morphine tolerance. Pain assessments, including the plantar test, static weight-bearing symmetry, and tail-flick latency, were used to determine the impact of the light disruption or exogenous melatonin on the morphine tolerance progression.
constant light exposure significantly aggravates morphine tolerance in neuropathic rats. Continued infusion of low-dose melatonin (3 μg/h) attenuated morphine tolerance in both neuropathic and naïve rats. This protective effect was independent of melatonin receptors, as shown by the neutral effect of melatonin receptors inhibitors. The transcriptional profiling demonstrated a significant enhancement of proinflammatory and pain-related receptor genes in morphine-tolerant rats. In contrast, this transcriptional pattern was abolished by melatonin coinfusion along with the upregulation of the gene. Moreover, melatonin increased the antioxidative enzymes SOD2, HO-1, and GPx1 in the spinal cord of morphine-tolerant rats.
Dysregulated circadian light exposure significantly compromises the efficacy of morphine's antinociceptive effect, while the cotreatment with melatonin attenuates morphine tolerance/hyperalgesia development. Our results suggest the potential of melatonin as an adjuvant of morphine in clinical pain management, particularly in patients who need long-term opioid treatment.
阿片类药物常用于临床疼痛管理；然而，剂量递增、耐受性、依赖性和成瘾性限制了它们在长期慢性疼痛中的可用性。相关的不良睡眠模式会改变昼夜神经生物学，并进一步损害疼痛管理。在此，我们旨在确定持续光照与吗啡耐受性之间的相关性，并探索褪黑素作为吗啡辅助药物治疗神经性疼痛的潜力。
在通过慢性缩窄损伤诱导神经性疼痛之前，将Wistar大鼠置于持续光照（LL）或常规光照/黑暗（LD）周期下进行预处理。使用鞘内（i.t.）渗透泵持续给药以诱导吗啡耐受性。通过足底测试、静态负重对称性和甩尾潜伏期等疼痛评估来确定光照干扰或外源性褪黑素对吗啡耐受性进展的影响。
持续光照显著加重神经性大鼠的吗啡耐受性。持续输注低剂量褪黑素（3μg/h）可减轻神经性和未处理大鼠的吗啡耐受性。褪黑素受体抑制剂的中性作用表明，这种保护作用与褪黑素受体无关。转录谱分析表明，吗啡耐受大鼠中促炎和疼痛相关受体基因显著增强。相比之下，褪黑素共同输注消除了这种转录模式，并上调了该基因。此外，褪黑素增加了吗啡耐受大鼠脊髓中的抗氧化酶SOD2、HO-1和GPx1。
昼夜节律光照失调显著损害吗啡的镇痛效果，而褪黑素联合治疗可减轻吗啡耐受性/痛觉过敏的发展。我们的结果表明，褪黑素作为吗啡辅助药物在临床疼痛管理中具有潜力，特别是在需要长期阿片类药物治疗的患者中。
