Methylphenidate and Morphine Combination Therapy in a Rat Model of Chronic Pain.
Methylphenidate and Morphine Combination Therapy in a Rat Model of Chronic Pain.
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哌醋甲酯和吗啡联合治疗慢性疼痛大鼠模型
DOI：
10.1213/ane.0000000000004273
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发表时间：
2020-02
影响因子：
5.7
通讯作者：
Mao J
中科院分区：
文献类型：
--
作者：
You Z;Ding W;Doheny JT;Shen S;Yang J;Yang L;Chen L;Zhu S;Mao J
背景技术背景：在慢性疼痛管理中使用的阿片类药物的剂量增加通常会导致阿片类药物镇痛作用降低，阿片类药物滥用和成瘾。中枢多巴胺（DA）功能障碍导致疼痛的慢性化和阿片类镇痛作用的降低。哌醋甲酯（MPH/利他林）通过抑制DA再摄取增强中枢DA功能。在这项研究中，我们使用大鼠慢性疼痛模型来检查MPH与吗啡（莫尔）的组合是否会改善慢性疼痛条件下的莫尔镇痛效果。方法：采用大鼠胫跗关节注射完全弗氏佐剂（CFA）诱导慢性伤害性感受。在CFA大鼠中检查低剂量MPH（0.25 mg/kg）、低剂量莫尔（2.5 mg/kg）及其组合的镇痛作用。采用von Frey试验评价大鼠的伤害性行为。采用条件性位置偏爱（CPP）和旷场实验（OFTs）分别观察大鼠的奖赏行为和自发活动。研究结果：我们的调查结果如下：（1）在慢性疼痛的CFA大鼠中，在损伤后28天，2.5 mg/kg的莫尔的镇痛作用低于10 mg/kg的莫尔（von Frey阈值均值差异的95%置信区间[CI]（g）：−11.9 [−6.5至−17.3]）;（2）在注射后30-90分钟的1小时时间窗内，MPH的组合（0.25 mg/kg）与莫尔与MPH或莫尔单独给药相比，2.5 mg/kg剂量组可协同增强CFA大鼠的镇痛作用，并延长其镇痛时间（MPH与莫尔相互作用的P = 0.01，von Frey阈值平均值差异（克）的95%CI：组合与MPH为3.3 [1.37-6.12]，组合与莫尔为3.2 [1.35-5.74]）;（3）在低剂量（0.25 mg/kg）下，MPH并没有增加CFA大鼠的自发活动（莫尔+ MPH vs莫尔，P = 0.13），也没有显著增强莫尔奖赏行为（莫尔+ MPH vs莫尔，P = 0.63）。结论：我们的数据表明，使用低剂量MPH和莫尔的联合治疗可能在慢性疼痛管理中产生MOR保留效应。
BACKGROUND: The incremental dose of opioids used in chronic pain management often leads to a reduced opioid analgesic effect, opioid misuse, and addiction. Central dopamine (DA) dysfunction contributes to the chronicity of pain and a decreased opioid analgesic effect. Methylphenidate (MPH/Ritalin) enhances central DA function by inhibiting DA reuptake. In this study, we used a rat model of chronic pain to examine whether combination of MPH with morphine (MOR) would improve the MOR analgesic effect under a chronic pain condition. METHODS: Tibiotarsal joint Complete Freund’s Adjuvant (CFA) injection in rats was utilized to induce chronic nociception. The analgesic effect of low-dose MPH (0.25 mg/kg), low-dose MOR (2.5 mg/kg), and their combination was examined in CFA rats. Nociceptive behavior was assessed by von Frey test. Conditioned place preference (CPP) and open field tests (OFTs) were used to examine the rewarding behavior and locomotor activity in rats, respectively. RESULTS: Our findings are as follows: (1) in CFA rats with chronic pain, 2.5 mg/kg of MOR had less analgesic effect than 10 mg/kg of MOR at 28 days after injury (95% confidence intervals [CIs] for difference of means of von Frey threshold in gram: −11.9 [−6.5 to −17.3]); (2) in the 1-hour time window of 30–90 minutes after injection, the combination of MPH (0.25 mg/kg) with MOR (2.5 mg/kg) increased synergistically and prolonged the analgesic effect in CFA rats as compared with MPH or MOR alone (P = .01 for MPH by MOR interaction, and 95% CIs for difference of means of von Frey threshold in gram: 3.3 [1.37–6.12] for the combination versus MPH and 3.2 [1.35–5.74] for the combination versus MOR); (3) at the low dose (0.25 mg/kg), MPH did not increase locomotor activity (MOR + MPH versus MOR, P = .13) nor significantly enhanced MOR reward behavior (MOR + MPH versus MOR, P = .63) in CFA rats. CONCLUSIONS: Our data suggest that a combination therapy using low-dose MPH and MOR may produce a MOR-sparing effect in chronic pain management.