Huang Nian-Cih, Wong Chih-Shung
Department of Anesthesiology, Tri-Service General Hospital, Taipei 114, Taiwan.
Graduate Institute of Medical Sciences, National Defense Medical University, Taipei 114, Taiwan.
Int J Mol Sci. 2025 Jul 30;26(15):7372. doi: 10.3390/ijms26157372.
Disruption of circadian rhythms by abnormal light exposure and reduced melatonin secretion has been linked to heightened pain sensitivity and opioid tolerance. This study evaluated how environmental light manipulation and exogenous melatonin supplementation influence pain perception and morphine tolerance in a rat model of neuropathic pain induced by partial sciatic nerve transection (PSNT). Rats were exposed to constant darkness, constant light, or a 12 h/12 h light-dark cycle for one week before PSNT surgery. Behavioral assays and continuous intrathecal (i.t.) infusion of morphine, melatonin, or their combination were conducted over a 7-day period beginning immediately after PSNT. On Day 7, after discontinued drugs infusion, an acute intrathecal morphine challenge (15 µg, i.t.) was administered to assess tolerance expression. Constant light suppressed melatonin levels, exacerbated pain behaviors, and accelerated morphine tolerance. In contrast, circadian-aligned lighting preserved melatonin rhythms and mitigated these effects. Melatonin co-infusion attenuated morphine tolerance and enhanced morphine analgesia. Reduced pro-inflammatory cytokine expression and increase anti-inflammatory cytokine IL-10 level and suppressed astrocyte activation were also observed by melatonin co-infusion during morphine tolerance induction. These findings highlight the potential of melatonin and circadian regulation in improving opioid efficacy and reduced morphine tolerance in managing neuropathic pain.
异常光照和褪黑素分泌减少导致的昼夜节律紊乱与疼痛敏感性增强和阿片类药物耐受性增加有关。本研究评估了环境光照调控和外源性补充褪黑素对坐骨神经部分横断（PSNT）诱导的神经性疼痛大鼠模型中疼痛感知和吗啡耐受性的影响。在PSNT手术前一周，将大鼠置于持续黑暗、持续光照或12小时/12小时明暗循环环境中。在PSNT手术后立即开始，在7天的时间内进行行为学检测，并持续鞘内（i.t.）输注吗啡、褪黑素或它们的组合。在第7天，停止药物输注后，进行急性鞘内吗啡激发试验（15μg，i.t.）以评估耐受性表现。持续光照抑制了褪黑素水平，加剧了疼痛行为，并加速了吗啡耐受性。相比之下，符合昼夜节律的光照保留了褪黑素节律并减轻了这些影响。联合输注褪黑素减弱了吗啡耐受性并增强了吗啡镇痛作用。在吗啡耐受性诱导期间，联合输注褪黑素还观察到促炎细胞因子表达减少、抗炎细胞因子IL-10水平升高以及星形胶质细胞活化受到抑制。这些发现突出了褪黑素和昼夜节律调节在改善阿片类药物疗效以及降低吗啡耐受性以治疗神经性疼痛方面的潜力。
