INSERM U894-CPN, Université Pierre et Marie Curie, Paris, France.
Eur J Pain. 2013 Jul;17(6):867-80. doi: 10.1002/j.1532-2149.2012.00259.x. Epub 2012 Dec 11.
Convergent data showed that neuropathic pain has specific characteristics at cephalic versus extra-cephalic level, where single-targeted drugs differentially alleviate pain. Because the novel analgesic drug, tapentadol, is acting at two targets, μ-opioid receptors (as agonist) and noradrenaline reuptake (as inhibitor), we tested its effects on neuropathic pain at both cephalic and extra-cephalic levels.
Sprague-Dawley rats underwent unilateral constriction injury (CCI) to the infraorbital nerve (ION; cephalic territory) or the sciatic nerve (SN; extra-cephalic territory), and alleviation of nerve lesion-induced mechanical allodynia/hyperalgesia was assessed after acute or repeated (for 4 days) treatment with tapentadol compared with morphine and/or reboxetine (noradrenaline reuptake inhibitor) 2 weeks after surgery. Possible changes in the expression of the neuroinflammatory markers activating transcription factor 3 (ATF3), interleukin-6 (IL-6) and brain-derived neurotrophic factor (BDNF) by repeated tapentadol treatment were quantified by real-time reverse transcription polymerase chain reaction in ganglia and central tissues.
Acute administration of tapentadol (1-10 mg/kg, i.p.) significantly reduced allodynia in both CCI-SN and CCI-ION rats. Although morphine (3 mg/kg, s.c.) or reboxetine (10 mg/kg, i.p.) alone was only marginally active, the combination of both drugs produced supra-additive effects like those observed with tapentadol. In contrast to repeated morphine whose effects vanished, the anti-allodynic effects of tapentadol remained unchanged after a 4-day treatment. However, the latter treatment with tapentadol did not affect nerve lesion-evoked overexpression of ATF3, IL-6 and BDNF transcripts.
The dual synergistic pharmacological properties of tapentadol, which result in clear-cut anti-neuropathic pain effects at both cephalic and extra-cephalic levels, probably involve mechanisms downstream of nerve injury-induced neuroinflammatory reaction.
汇聚的数据表明，神经性疼痛在头部和头部以外的部位具有特定的特征，而单一靶向药物则不同程度地缓解疼痛。由于新型镇痛药酒石酸布托啡诺（tapentadol）作用于两个靶点，μ-阿片受体（作为激动剂）和去甲肾上腺素再摄取（作为抑制剂），我们测试了它在头部和头部以外的神经性疼痛的作用。
Sprague-Dawley 大鼠单侧眶下神经（ION；头部区域）或坐骨神经（SN；头部以外区域）结扎损伤，手术后 2 周，与吗啡和/或瑞波西汀（去甲肾上腺素再摄取抑制剂）比较，急性或重复（4 天）治疗后，评估酒石酸布托啡诺对神经损伤引起的机械性痛觉过敏/痛觉的缓解作用。通过实时逆转录聚合酶链反应，在神经节和中枢组织中定量检测重复酒石酸布托啡诺治疗对激活转录因子 3（ATF3）、白细胞介素 6（IL-6）和脑源性神经营养因子（BDNF）等神经炎症标志物表达的可能变化。
急性给予酒石酸布托啡诺（1-10mg/kg，ip）可显著减轻 CCI-SN 和 CCI-ION 大鼠的痛觉过敏。虽然吗啡（3mg/kg，sc）或瑞波西汀（10mg/kg，ip）单独使用效果仅略有改善，但这两种药物的联合使用产生了与酒石酸布托啡诺相似的超相加作用。与反复给予吗啡后作用消失相反，酒石酸布托啡诺的抗痛觉过敏作用在 4 天治疗后保持不变。然而，酒石酸布托啡诺的这种治疗方法并不影响神经损伤引起的 ATF3、IL-6 和 BDNF 转录物的过度表达。
酒石酸布托啡诺的双重协同药理学特性，在头部和头部以外的部位均产生明显的抗神经性疼痛作用，可能涉及神经损伤诱导的神经炎症反应下游的机制。
