Neuroendocrine mechanisms in oxaliplatin-induced hyperalgesic priming.
Neuroendocrine mechanisms in oxaliplatin-induced hyperalgesic priming.
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DOI：
10.1097/j.pain.0000000000002828
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发表时间：
2023-06-01
期刊：
影响因子：
7.4
通讯作者：
中科院分区：
文献类型：
--
作者：
奥沙利铂给药可诱导持久的痛觉过敏引发，这种效应至少部分通过伤害感受器Gα i 1和Gαo以及蛋白激酶C β介导。压力在肿瘤患者的症状负担中起着重要作用，并且可以加剧癌症化疗诱导的周围神经病变（CIPN），这是许多类别化疗的主要不良反应。我们探讨了压力在奥沙利铂引起的持续性疼痛中的作用。奥沙利铂诱导了雄性大鼠的痛觉过敏启动，这是一种向慢性疼痛转变的模型，表现为前列腺素E2产生的痛觉过敏延长，在肾上腺切除大鼠中显著减弱。诱导成年大鼠应激恢复的新生儿处理方案可预防奥沙利铂诱导的痛觉过敏引发。为了阐明下丘脑-垂体-肾上腺和交感肾上腺神经内分泌应激轴在奥沙利铂CIPN中的作用，我们鞘内给予针对介导儿茶酚胺和糖皮质激素及其第二信使效应的受体mRNA的反义寡脱氧核苷酸（ODNs），以减少其在伤害感受器中的表达。鞘内注射β2-肾上腺素能受体和糖皮质激素受体反义寡核苷酸可减弱奥沙利铂诱导的痛觉过敏，但奥沙利铂诱导的痛觉过敏仅能被β2-肾上腺素能受体反义寡核苷酸减弱。Gαi/o蛋白的非选择性抑制剂百日咳毒素的给药可减弱痛觉过敏引发。Gαi1和Gαo反义寡核苷酸也能减弱痛觉过敏启动。此外，反义蛋白激酶C β，参与I型痛觉过敏启动的第二信使，也减弱奥沙利铂诱导的痛觉过敏启动。参与维持I型（虫草素）和II型（SSU 6656和U 0126）痛觉过敏启动的第二信使抑制剂均减弱痛觉过敏启动。这些实验支持奥沙利铂CIPN雄性大鼠中神经内分泌应激轴在痛觉过敏引发中的作用。
Oxaliplatin administration induces long-lasting hyperalgesic priming, an effect mediated, at least in part, through nociceptor Gαi1 and Gαo, as well as protein kinase Cɛ. Stress plays a major role in the symptom burden of oncology patients and can exacerbate cancer chemotherapy-induced peripheral neuropathy (CIPN), a major adverse effect of many classes of chemotherapy. We explored the role of stress in the persistent phase of the pain induced by oxaliplatin. Oxaliplatin induced hyperalgesic priming, a model of the transition to chronic pain, as indicated by prolongation of hyperalgesia produced by prostaglandin E2, in male rats, which was markedly attenuated in adrenalectomized rats. A neonatal handling protocol that induces stress resilience in adult rats prevented oxaliplatin-induced hyperalgesic priming. To elucidate the role of the hypothalamic–pituitary–adrenal and sympathoadrenal neuroendocrine stress axes in oxaliplatin CIPN, we used intrathecally administered antisense oligodeoxynucleotides (ODNs) directed against mRNA for receptors mediating the effects of catecholamines and glucocorticoids, and their second messengers, to reduce their expression in nociceptors. Although oxaliplatin-induced hyperalgesic priming was attenuated by intrathecal administration of β2-adrenergic and glucocorticoid receptor antisense ODNs, oxaliplatin-induced hyperalgesia was only attenuated by β2-adrenergic receptor antisense. Administration of pertussis toxin, a nonselective inhibitor of Gαi/o proteins, attenuated hyperalgesic priming. Antisense ODNs for Gαi1 and Gαo also attenuated hyperalgesic priming. Furthermore, antisense for protein kinase C epsilon, a second messenger involved in type I hyperalgesic priming, also attenuated oxaliplatin-induced hyperalgesic priming. Inhibitors of second messengers involved in the maintenance of type I (cordycepin) and type II (SSU6656 and U0126) hyperalgesic priming both attenuated hyperalgesic priming. These experiments support a role for neuroendocrine stress axes in hyperalgesic priming, in male rats with oxaliplatin CIPN.
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影响因子：
2.7
作者：
Burgess J;Ferdousi M;Gosal D;Boon C;Matsumoto K;Marshall A;Mak T;Marshall A;Frank B;Malik RA;Alam U
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Gi 的激活会诱发应激后机械痛觉过敏或炎症。
影响因子：
3.3
作者：
Dina, O. A.;Khasar, S. G.;Gear, R. W.;Levine, J. D.
通讯作者：
Levine, J. D.