Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain
Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain
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DOI：
10.1038/srep32799
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发表时间：
2016-09-08
影响因子：
4.6
通讯作者：
Machelska, Halina
中科院分区：
文献类型：
--
作者：
Labuz, Dominika;Celik, Melih O.;Machelska, Halina
神经病理性疼痛通常由周围神经损伤引起，这可能涉及免疫反应。局部白细胞衍生的阿片肽或外源性阿片激动剂在动物模型中抑制神经病诱导的机械超敏反应。由于神经性疼痛也可以通过热增强，在这项研究中，我们研究了阿片类药物在神经性疼痛诱发的热超敏反应的调制中的作用。我们在野生型和阿片肽敲除小鼠中使用了坐骨神经的慢性压迫性损伤，并分别使用Hargreaves和von Frey试验测试了阿片在热和机械超敏反应中的作用。我们发现，虽然神经周围的外源性阿片受体激动剂，包括肽能配体，是有效的，内源性阿片肽β-内啡肽，甲硫氨酸脑啡肽和强啡肽A没有减轻热过敏。具体而言，促肾上腺皮质激素释放因子，一种药剂触发阿片肽分泌的白细胞，应用perineurally没有减弱热过敏性野生型小鼠。外源性阿片类药物，也显示通过激活白细胞阿片受体释放阿片肽，同样镇痛野生型和阿片肽敲除小鼠，表明内源性阿片类药物不有助于外源性阿片镇痛热超敏反应。此外，外源性应用的阿片肽也是无效的。相反，阿片肽缓解机械超敏反应。因此，阿片类药物类型和感觉方式可能决定神经性疼痛治疗的结果。
Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides beta-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment.