PINEAL OPIOID RECEPTORS & ANALGESIC ACTION OF MELATONIN

描述：（申请人摘要中的逐字记录） 急性和/或慢性疼痛依赖于非甾体抗炎剂 麻醉性止痛药。然而，有各种持续的疼痛状况， 例如对现有镇痛剂反应差的神经变性疾病 并因此等待新的治疗途径。医生们注意到， 古代，他们的病人抱怨较少的痛苦，并要求更少 晚上服用止痛药。在人类中，褪黑激素， 具有镇痛和催眠作用的松果体物质， 昼夜节律，血清水平在夜间高，白天非常低 次此外，褪黑激素在夜间表现出最大的镇痛作用， 松果体切除取消褪黑激素和阿片受体的镇痛作用 拮抗剂破坏伤害感受的昼夜节律。因为δ阿片类药物 受体调节P物质的释放，这是第一个具体的目标， 一项研究计划是寻找和鉴定δ 1和δ 2阿片受体， 亚型牛松果体细胞，使用[D-Ala 2-，N-MePhe 4，Gly-ol 5]脑啡肽和 [D-Pen 2，5]脑啡肽。由于μ阿片类药物和 α-2肾上腺素能受体，但不是μ和δ受体之间， 本建议的第二个具体目标是描述 μ受体和δ受体，与G蛋白亚型差异偶联， 松果体膜由于加入麻醉剂改变了 D1和D2多巴胺能受体在大脑中，第三个具体的目的， 建议是确定牛松果体多巴胺转运蛋白的性质 用[~ 3 H]GBB-12935和放射自显影法对腺体进行了观察， 多巴胺D1和D2受体mRNA的表达 杂交组织化学由于褪黑激素可能作为一种混合阿片类药物 受体激动剂-拮抗剂，这是值得怀疑的，医生只是可以 增强麻醉剂如吗啡的镇痛功效， 共同施用褪黑激素。因此，今后的研究必须高度综合 能够提供最大镇痛作用的有效褪黑激素类似物， 希望没有成瘾的责任，现在与目前 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.