HISTAMINERGIC MECHANISMS OF ANTINOCICEPTION

描述：(申请人摘要) 阿片类止痛药吗啡(MOR)通过以下方式被证明可以缓解疼痛 机制包括神经元组胺(HA)的释放和 随后激活中脑导水管周围灰质(PAG)中的HA受体。哈 已知在中枢神经系统中起神经调节物质的作用 系统。拟议的研究将通过以下方式描述这些地点和机制 哪种HA可以缓解疼痛，并寻找新的止痛药 基于这些机制。实验将使用In的技术 在体微透析、脑内注射和伤害性测试 老鼠。将进行以下研究：1)MOR增加 PAG内神经元HA的释放。为了确定这一现象的机制 选择性阿片受体激动剂和拮抗剂的反应和作用 将研究HA在PAG中的体内释放情况。2)HA注射 进入PAG诱导疼痛缓解(即止痛剂)反应，并在较高 剂量，疼痛增强(即痛觉过敏)反应。要发现 HA诱导伤害性反应变化的药理学机制 阈值，选择性HD激动剂和HA拮抗剂的作用将是 PAG脑内给药后进行研究。独一无二的类HA 化合物SKF92374也将被研究，因为这种试剂似乎能诱导 止痛药，但不是先前未发现的痛觉过敏反应 机制。3)HA和MOR相互作用产生协同止痛剂 回应。为了描述这些相互作用的性质，量化 将进行不同剂量组合的抗伤害研究 HA和MOR。此外，拮抗剂选择性作用于 阿片受体和HA受体的亚型将在这些方面进行研究 在这些MOR-HA组合存在的情况下的反应。除了……之外 这些对PAG的研究和试点研究表明，HA也可能是一种 中缝大核(Rm，另一脑干)中的抗伤害性感受介质 已知的结构在止痛中很重要)。要解决这个问题 假设，上面为PAG提出的几个实验也将 在房间里进行。这些研究将阐明 MOR止痛，提高对组胺能的认识 抗伤害性机制，并可能导致非成瘾的发现， 治疗疼痛的新药。

DESCRIPTION: (Applicant's Abstract) The opiate analgesic drug morphine (MOR) has been shown to relieve pain by mechanisms that include the release of neuronal histamine (HA) and the subsequent activation of HA receptors in the periaqueductal grey (PAG). HA is known to function as a neuromodulator substance in the central nervous system. The proposed studies will characterize the sites and mechanisms by which HA relieves pain, and search for novel, pain-relieving medications based on these mechanisms. The experiments will use the techniques of in vivo microdialysis, intracerebral injections, and nociceptive testing in rats. The following studies will be performed: 1) MOR increases the release of neuronal HA in the PAG. To determine the mechanisms of this response, the effects of selective opiate receptor agonists and antagonists will be studied on the release of HA in the PAG in vivo. 2) HA injections into the PAG induce pain-relieving (i.e. analgesic) responses and, at higher doses, pain-enhancing (i.e. hyperalgesic) responses. To discover the pharmacological mechanisms underlying the HA-induced changes in nociceptive threshold, the effects of selective HD agonists and HA antagonists will be studied after intracerebral administration into the PAG. The unique HA-like compound SKF92374 will also be studied, since this agent appears to induce analgesic, but not hyperalgesic responses by a previously undiscovered mechanism. 3) HA and MOR interact to produce synergistic analgesic responses. To characterize the nature of these interactions, quantitative antinociceptive studies will be performed with combinations of various doses of HA and MOR. In addition, the effects of antagonists selective for sub-types of opiate receptors and HA receptors will be studied on these responses in the presence of these MOR-HA combinations. In addition to these studies of the PAG, pilot studies suggest that HA may also be an antinociceptive mediator in the raphe magnus (RM, another brain stem structure known to be important in pain relief). To address this hypothesis, several of the experiments proposed above for the PAG will also be performed in the RM. These studies will clarify the mechanisms by which MOR relieves pain, enhance the understanding of histaminergic antinociceptive mechanisms, and may lead to the discovery of non-addicting, novel medications for the treatment of pain.