PINEAL OPIOID RECEPTORS & ANALGESIC ACTION OF MELATONIN

描述：(逐字摘自申请人的摘要)目前的待遇 急性和/或慢性疼痛依赖非类固醇抗炎药和 麻醉性止痛药。然而，有各种持续的痛苦情况。 例如对现有止痛药反应不佳的神经退行性疾病 因此等待新的治疗途径。自那以后，医生们注意到 他们的病人抱怨疼痛更少，需要的更少的古老 晚上吃止痛药。在人类体内，循环中的褪黑素水平， 具有止痛和催眠作用的松果体物质，表现出明显的 昼夜节律，夜间血清水平很高，白天很低 泰晤士报。此外，褪黑激素在夜间表现出最大的止痛效果， 松果体摘除取消褪黑素和阿片受体的镇痛作用 拮抗剂打乱了伤害性感受的昼夜节律。自Delta阿片类药物以来 受体调节P物质的释放，这是这一过程的第一个特定目标 建议寻找和表征增量1和2阿片受体 [D-Ala2-，N-MePhe4，Gly-ol5]脑啡肽和 [D-Pen2，5]脑啡肽。由于Mu阿片类药物和阿片类药物之间存在交叉耐受 α-2肾上腺素能受体，但不是在Mu和Delta受体之间， 这项提案的第二个具体目标是描述 与G蛋白亚型不同偶联的Mu和Delta受体 松果体膜。由于添加麻醉剂会改变动力学参数 大脑中的D1和D2多巴胺能受体，这是研究的第三个特定目标 建议确定牛松果体中多巴胺转运体的性质 用[~3H]GBB-12935和放射自显影技术勾画腺体 用原位杂交技术表达多巴胺D_1和D_2受体基因 杂交组织化学。因为褪黑素可能表现为混合阿片类药物 受体激动剂-拮抗剂，这是值得怀疑的医生简单地 通过以下方式增强吗啡等麻醉剂的镇痛效果 共同服用褪黑素。因此，未来的研究必须高度综合 有效的褪黑素类似物，能够提供最大的止痛和 希望现在没有成瘾的责任，现在与目前 有可用的麻醉剂。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Present treatment for acute and/or chronic pain rely on non-steroidal anti-inflammatory agents and narcotic analgesics. However, there are various persistent painful conditions such as neurodegenerative diseases that respond poorly to existing analgesics and hence await novel therapeutic avenues. Physicians have noted since antiquity that their patients complained of less pain and required fewer analgesics at night times. In human, the circulating levels of melatonin, a pineal substance with analgesic and hypnotic properties, exhibit a pronounced circadian rhythm, with serum levels being high at night and very low during day times. Moreover, melatonin exhibits maximal analgesic effects at nights, pinealectomy abolishes the analgesia effects of melatonin, and opioid receptor antagonists disrupt the day-night rhythm of nociception. Since delta opioid receptors modulate the release of substance P, the first specific aim of this proposal is to search for and characterize delta one and two opioid receptor subtypes in bovine pinealocytes, using [D-Ala2-,N-MePhe4,Gly-ol5]enkephalin and [D-Pen2,5]enkephalin. Since cross-tolerance exists between mu opioid and alpha-2 adrenergic receptors, but not between mu and delta receptors, the second specific aim of this proposal is to characterize the specific nature of the mu and delta receptors, differentially coupled to G protein subtypes in pineal membranes. Since addition to narcotic alters the kinetic parameters of D1 and D2 dopaminergic receptors in the brain, the third specific aim of this proposal are to determine the nature of dopamine transporters in bovine pineal gland by using [3H]GBB-12935 and autoradiography and to delineate the expression of D1 and D2 dopamine receptor mRNA by employing in situ hybridization histochemistry. Since melatonin may behave as a mixed opioid receptor agonist-antagonism, it is doubtful that physician simply could potentiate the analgesic efficacy of narcotics such as morphine by co-administering melatonin. Therefore, future research must synthesize highly efficacious melatonin analogues capable of providing maximum analgesia and hopefully being devoid of addiction liability now associated with currently available narcotics.