A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic
A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic
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DOI：
10.1073/pnas.130181897
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发表时间：
2000-06-20
影响因子：
11.1
通讯作者：
Kream, RM
中科院分区：
文献类型：
--
作者：
Foran, SE;Carr, DB;Kream, RM
为了阐明急性和慢性疼痛的机制，重要的是要了解脊髓兴奋系统如何影响阿片类镇痛。速激肽P物质（SP）代表原型脊髓兴奋性肽神经递质/神经调质，与内源性阿片系统协同作用以调节对伤害性刺激的镇痛反应。我们已经合成了一种嵌合肽，其特征在于含有重叠的NH 2-和COOH-末端功能域的内源性阿片内吗啡肽-2（EM-2）和速激肽SP，分别。将嵌合分子YPFFGLM-NH 2（命名为ESP 7）重复施用到大鼠脊髓中产生阿片样物质依赖性镇痛，而在5天内没有效力损失。相比之下，重复施用ESP 7与同时的SP受体（SPR）阻断导致镇痛效力的进行性丧失，这与耐受性的发展一致。此外，耐受动物在事后单独施用ESP 7后完全恢复阿片类药物敏感性，表明SPR的共激活对于维持阿片类药物反应性是必不可少的。使用重组受体的放射性配体结合和信号传导测定证实了ESP 7可以在体外共激活μ阿片受体（莫尔）和SPR。我们假设，在脊髓中的莫尔-和SPR-表达系统的同时激活模仿了在伤害性处理中通常遇到的相互兴奋和抑制的持续状态。由于ESP 7与莫尔和SPR两者相互作用的能力，其代表了具有未来治疗潜力的独特原型、抗耐受形成镇痛剂。
To elucidate mechanisms of acute and chronic pain, it is important to understand how spinal excitatory systems influence opioid analgesia. The tachykinin substance P (SP) represents the prototypic spinal excitatory peptide neurotransmitter/neuromodulator, acting in concert with endogenous opioid systems to regulate analgesic responses to nociceptive stimuli. We have synthesized and pharmacologically characterized a chimeric peptide containing overlapping NH2- and COOH-terminal functional domains of the endogenous opioid endomorphin-2 (EM-2) and the tachykinin SP, respectively. Repeated administration of the chimeric molecule YPFFGLM-NH2, designated ESP7, into the rat spinal cord produces opioid-dependent analgesia without loss of potency over 5 days. In contrast, repeated administration of ESP7 with concurrent SP receptor (SPR) blockade results in a progressive loss of analgesic potency, consistent with the development of tolerance. Furthermore, tolerant animals completely regain opioid sensitivity after post hoc administration of ESP7 alone, suggesting that coactivation of SPRs is essential to maintaining opioid responsiveness. Radioligand binding and signaling assays, using recombinant receptors, confirm that ESP7 can coactivate mu-opioid receptors (MOR) and SPRs in vitro. We hypothesize that coincidental activation of the MOR- and SPR-expressing systems in the spinal cord mimics an ongoing state of reciprocal excitation and inhibition, which is normally encountered in nociceptive processing. Due to the ability of ESP7 to interact with both MOR and SPRs, it represents a unique prototypic, anti-tolerance-forming analgesic with future therapeutic potential.