Opioids in chronic pain
Opioids in chronic pain
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DOI：
10.1016/s0014-2999(01)01308-5
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发表时间：
2001-10-19
影响因子：
5
通讯作者：
Przewlocka, B
中科院分区：
文献类型：
--
作者：
Przewlocki, R;Przewlocka, B
我们对各种内源性阿片肽的生物发生、它们的解剖分布以及与其相互作用的多种受体的特征的理解的进展，为理解阿片肽系统在慢性疼痛中的作用开辟了新的途径。阿片肽的主要类别：脑啡肽、强啡肽和β-内啡肽分别源自脑啡肽原、强啡肽原和阿片黑皮质素原。最近，在大脑中发现了一组新的肽，并将其命名为内吗啡肽、内吗啡肽-1和-2。与其他阿片肽相比，它们的独特之处在于非典型结构和对 mu -阿片受体的高选择性。过去几年加入内源性阿片肽家族的另一类药物是 pronociceptin 系统，包含源自这种激素原的肽，作用于 ORL1 受体。阿片受体家族的三个成员在 20 世纪 90 年代初被克隆，首先是小鼠 delta -阿片受体 (DOR1)，随后克隆了 mu -阿片受体 (MOR1) 和 kappa -阿片受体 (KOR1)。这三种受体属于七个跨膜 G 蛋白偶联受体家族，并且具有广泛的结构同源性。这些阿片受体和肽系统与抗伤害过程密切相关。他们被发现存在于涉及伤害感受和疼痛的区域。阿片类药物在炎症性疼痛动物模型中的作用已得到详细研究。外周炎症影响中枢部位并改变阿片类药物的作用。炎症增加了各种阿片受体激动剂的脊髓效力。一般来说，阿片类药物对患有外周炎症的动物的各种有害刺激的抗伤害作用比对照动物更强。炎症诱导的阿片类镇痛效力的增强主要是μ阿片受体的特征，因为与δ-和κ-阿片受体激动剂相比，吗啡引起μ-脊髓效力的更大增加。炎症期间μ-阿片受体激动剂效力的增强可能源于阿片受体中发生的变化，主要是μ-阿片受体的亲和力或数量的变化。炎症已被证明会改变脊髓背角中几个基因的表达。多项研究表明，当存在外周炎症或慢性关节炎时，脊髓 PDYN 系统会发生深刻的变化。在与脊髓损伤和周围神经损伤后的神经性疼痛相关的各种条件下，内源性强啡肽生物合成也会增加。有趣的是，吗啡对神经性疼痛缺乏有效的镇痛功效。大量临床证据表明，神经性疼痛并不对阿片类药物产生耐药性，只是在这种情况下观察到对全身阿片类药物的敏感性降低，为了获得足够的镇痛作用，有必要增加其剂量。吗啡镇痛效力的降低被认为是由于神经损伤降低了脊髓阿片类药物受体或阿片类信号转导的活性。我们最近对μ-阿片类受体内源性配体的研究，内吗啡肽使问题进一步复杂化，因为内吗啡肽似乎对神经性疼痛有效。识别所涉及的差异可能对于理解阿片类药物在神经性疼痛中作用的分子机制以及开发更好和更有效的治疗人类神经性疼痛的药物具有重要意义。 (C) 2001 Elsevier Science B.V. 保留所有权利。
The advance in our understanding of the biogenesis of various endogenous opioid peptides, their anatomical distribution, and the characteristics of the multiple receptors with which they interact open a new avenue for understanding the role of opioid peptide systems in chronic pain. The main groups of opioid peptides: enkephalins, dynorphins and beta -endorphin derive from proenkephalin, prodynorphin and proopiomelanocortin, respectively. Recently, a novel group of peptides has been discovered in the brain and named endomorphins, endomorphin-1 and -2. They are unique in comparison with other opioid peptides by atypical structure and high selectivity towards the mu -opioid receptor. Another group, which joined the endogenous opioid peptide family in the last few years is the pronociceptin system comprising the peptides derived from this prohormone, acting at ORL1 receptors. Three members of the opioid receptor family were cloned in the early 1990s, beginning with the mouse delta -opioid receptor (DOR1) and followed by cloning of mu -opioid receptor (MOR1) and kappa -opioid receptor (KOR1). These three receptors belong to the family of seven transmembrane G-protein coupled receptors, and share extensive structural homologies. These opioid receptor and peptide systems are significantly implicated in antinociceptive processes. They were found to be represented in the regions involved in nociception and pain. The effects of opioids in animal models of inflammatory pain have been studied in great detail. Inflammation in the periphery influences the central sites and changes the opioid action. Inflammation increased spinal potency of various opioid receptor agonists. In general, the antinociceptive potency of opioids is greater against various noxious stimuli in animals with peripheral inflammation than in control animals. Inflammation-induced enhancement of opioid antinociceptive potency is characteristic predominantly for mu opioid receptors, since morphine elicits a greater increase in spinal potency of mu- than of delta- and kappa -opioid receptor agonists. Enhancement of the potency of mu -opioid receptor agonists during inflammation could arise from the changes occurring in opioid receptors, predominantly in affinity or number of the mu -opioid receptors. Inflammation has been shown to alter the expression of several genes in the spinal cord dorsal hom. Several studies have demonstrated profound alterations in the spinal PDYN system when there is peripheral inflammation or chronic arthritis. Endogenous dynorphin biosynthesis also increases under various conditions associated with neuropathic pain following damage to the spinal cord and injury of peripheral nerves. Interestingly, morphine lacks potent analgesic efficacy in neuropathic pain. A vast body of clinical evidence suggests that neuropathic pain is not opioid-resistant but only that reduced sensitivity to systemic opioids is observed in this condition, and an increase in their dose is necessary in order to obtain adequate analgesia, Reduction of morphine antinociceptive potency was postulated to be due to the fact that nerve injury reduced the activity of spinal opioid receptors or opioid signal transduction.Our recent study with endogenous Ligands of the mu -opioid receptor, endomorphins, further complicates the issue, since endomorphins appear to be effective in neuropathic pain. Identification of the involved differences may be of importance to the understanding of the molecular mechanism of opioid action in neuropathic pain, as well as to the development of better and more effective drugs for the treatment of neuropathic pain in humans. (C) 2001 Elsevier Science B.V. All rights reserved.