Repeated Administration of Duloxetine Suppresses Neuropathic Pain by Accumulating Effects of Noradrenaline in the Spinal Cord
Repeated Administration of Duloxetine Suppresses Neuropathic Pain by Accumulating Effects of Noradrenaline in the Spinal Cord
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DOI：
10.1213/ane.0000000000002380
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发表时间：
2018-01-01
影响因子：
5.7
通讯作者：
Obata, Hideaki
中科院分区：
文献类型：
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作者：
Ito, Sachiko;Suto, Takashi;Obata, Hideaki
背景：抗抑郁药用于治疗神经性疼痛，尽管其作用的详细机制尚不清楚，降去甲肾上腺素能抑制系统可能起重要作用。我们验证了我们的假设，即反复给药度洛西汀通过恢复大鼠脊髓神经结扎（SNL）后6周的降去甲肾上腺素能抑制系统来抑制神经性疼痛。方法：连续3天，每天给SNL大鼠皮下注射度洛西汀(10 mg kg(-1) day(-1))，观察辣椒素皮下注射激活的行为超敏反应和有害刺激诱导镇痛（NSIA）。我们还对脊髓进行了微透析研究，对均质腰椎组织进行了去甲肾上腺素测量，并对蓝斑座进行了免疫组化。结果：每日3次注射度洛西汀可减轻SNL引起的机械痛感过敏（载药组SNL: 88 9.4 g比度洛西汀组SNL: 148 +/- 13 g， P < .001；估计度洛西汀治疗效果[95%可信区间{CI}]， 65 [50.6-79.4]; n = 6/组，第4天），恢复减少的NSIA（载药组：154 +/- 10 g比度洛西汀：213 +/- 33 g， P < .001; 71.3 [57.4-85.2]; n = 6/组，注射后30分钟）。双侧脊髓背侧去甲肾上腺素含量增加（药组SNL: 946.7 +/- 203.6 pg/g，比度洛西汀组SNL: 1593.5 +/- 181.4 pg/g, P < 0.001；同侧SNL: 646.79 pg/g[481.61-811.97]；药组SNL: 845.0 +/- 164.7 pg/g，比药组SNL: 1557.2 +/- 237.4 pg/g, P < 0.001；对侧SNL: 712.17 pg/g[449.31-975.02]）。鞘内注射2-肾上腺素受体拮抗剂idazoxan （IT）逆转了抗过敏作用（IT前：133 +/- 5.7 g， IT后30分钟：85.8 +/- 6.5 g, P < 0.001, -47[-39.1至-54.8],n = 6/组，NSIA；药-IT: 219 +/- 7.4 g, idazoxan-IT: 153 +/- 10 g, P < 0.001; -65.8 g[-25.2至-77.4]n = 6/组，前爪注射辣椒素后30分钟）。度洛西汀治疗没有改变辣椒素注射后脊髓中去甲肾上腺素的释放（P = 0.415），也没有改变蓝斑区磷酸化环腺苷单磷酸反应因子结合蛋白的细胞核阳性比例（前爪注射辣椒素120分钟后度洛西汀与对照P = 1.00，前爪注射辣椒素120分钟后度洛西汀与对照P = 1.00）。结论：这些结果提示，在神经损伤后6周，每日3次注射度洛西汀可抑制痛觉过敏并恢复受损的NSIA。度洛西汀的这两种作用被2-肾上腺素受体拮抗剂的IT所逆转。这些发现表明度洛西汀对神经性疼痛的抑制作用依赖于去甲肾上腺素能下降抑制系统的恢复，特别是在脊髓。
BACKGROUND: Antidepressants are used to treat neuropathic pain and although the detailed mechanisms of their effects are unclear, the descending noradrenergic inhibitory system might play an important role. We tested our hypothesis that repeated administration of duloxetine suppresses neuropathic pain by restoring the descending noradrenergic inhibitory system in rats 6 weeks after spinal nerve ligation (SNL).METHODS: We subcutaneously injected SNL rats with duloxetine (10 mg kg(-1) day(-1)) daily for 3 consecutive days and assessed behavioral hypersensitivity and noxious stimulus-induced analgesia (NSIA) activated by subcutaneous injection of capsaicin. We also performed microdialysis studies of the spinal cord, noradrenaline measurements of homogenized lumbar spinal tissue, and immunohistochemistry of the locus coeruleus.RESULTS: Three daily injections of duloxetine attenuated the mechanical hyperalgesia induced by SNL (SNL treated with vehicle: 88 9.4 g versus SNL treated with duloxetine: 148 +/- 13 g, P < .001; estimated treatment effect of duloxetine [95% confidence interval {CI}], 65 [50.6-79.4]; n = 6/group, on day 4) and recovered the decreased NSIA (vehicle: 154 +/- 10 g versus duloxetine: 213 +/- 33 g, P < .001; 71.3 [57.4-85.2]; n = 6/group, 30 minutes after injection). The noradrenaline content in the dorsal spinal cord increased bilaterally (SNL treated with vehicle: 946.7 +/- 203.6 pg/g versus SNL treated with duloxetine: 1593.5 +/- 181.4 pg/g, P < .001; 646.79 pg/g [481.61-811.97] on the ipsilateral side; SNL treated with vehicle: 845.0 +/- 164.7 pg/g versus SNL treated with vehicle: 1557.2 +/- 237.4 pg/g, P < .001; 712.17 pg/g [449.31-975.02] on the contralateral side). Intrathecal injection (IT) of the 2-adrenoceptor antagonist idazoxan reversed both the antihyperalgesic effect (before IT: 133 +/- 5.7 g versus 30 minutes after IT: 85.8 +/- 6.5 g, P < .001, -47 [-39.1 to -54.8], n = 6/group, and NSIA; vehicle-IT: 219 +/- 7.4 g versus idazoxan-IT: 153 +/- 10 g, P < .001; -65.8 g [-25.2 to -77.4] n = 6/group, 30 minutes after forepaw injection of capsaicin). Duloxetine treatment did not alter the noradrenaline release in the spinal cord after capsaicin injection (P = .415), or the fraction of nuclei positive for phosphorylated cyclic adenosine monophosphate response element binding protein in the locus coeruleus (P = 1.00 duloxetine versus vehicle 120 minutes after forepaw injection of vehicle and P = 1.00 duloxetine versus vehicle 120 minutes after forepaw injection of capsaicin).CONCLUSIONS: These findings suggest that 3 daily injections of duloxetine suppressed hyperalgesia and recovered impaired NSIA in rats 6 weeks after nerve injury. Both effects of duloxetine were reversed by IT of an 2-adrenoceptor antagonist. These findings suggest the inhibitory effects of duloxetine against neuropathic pain depend on recovery of the noradrenergic descending inhibitory system, especially in the spinal cord.