HISTAMINERGIC MECHANISMS OF ANTINOCICEPTION

描述(改编自申请人摘要)：一类新的非阿片类药物 止痛药最近被发现在化学上与 组胺。原型(名为Improgan)显示了以下特征 在直接注射到啮齿类动物的大脑后：a)非常有效， 热和机械测试中的吗啡样抗伤害性感觉，b)没有损害 运动协调或运动活动，c)非阿片类机制，即 不依赖已知的组胺受体和60个其他靶点，d)缺乏 耐受每日给药，以及e)独特的结构-活性关系 在化学同系物中，表明可能存在一种新的 组胺受体。然而，人们对其发生的部位和机制知之甚少。 不适当的行为。为了处理这些问题，将进行以下研究 在大鼠身上进行。1)微注射标测研究将识别中枢神经系统 介导不适当止痛的区域。已知的包含内源性 将研究止痛系统(中脑导水管周围灰质、吻部 延髓腹侧[包括中缝大核]和脊髓)。2) 这些微量注射的效果将通过两项运动指标进行评估 功能(转杆试验和运动活动)以评估特异度 不适当的止痛。3)用递质激动剂和 拮抗剂将确定脊髓上和脊髓递质的机制。 调节非正常止痛的药物。4)将进行两种类型的实验 异构体受体：a)异构体诱导的~(35)S-GTP-γ的调节 将研究脑膜中的结合，以及b)匀浆和 放射自显影技术将研究放射性标记衍生物的结合 即兴表演。这些研究也可能有助于开发一种体外检测方法。 类似即兴表演的活动。5)确定不适当的止痛药是否 在人类炎症性疼痛的临床前模型中有效， 将在福尔马林伤害试验中研究不适当的大鼠。这个 计划中的实验将描述神经的基本机制。 非阿片类镇痛，并可能导致一种新的组胺的发现 受体，和/或用于开发治疗急性和慢性白血病的新药物疗法 慢性疼痛。

DESCRIPTION (adapted from applicant's abstract): A new class of non-opioid pain-relieving drugs has recently been discovered that is chemically related to histamine. The prototype (named improgan) shows the following characteristics after direct injection into the rodent brain: a) highly effective, morphine-like antinociception on thermal and mechanical tests, b) no impairment of motor coordination or locomotor activity, c) a non-opioid mechanism that is independent of known receptors for histamine and 60 other targets, d) lack of tolerance with daily dosing, and e) unique structure-activity relationships among chemical congeners, suggesting the possible existence of a novel histamine receptor. However, little is known about the sites and mechanisms of action of improgan. To approach these issues, the following studies will be performed in rats. 1) Microinjection mapping studies will identify the CNS areas mediating improgan analgesia. Sites known to comprise the endogenous pain-relieving system will be studied (the periaqueductal grey, the rostral ventral medulla [including the nucleus raphe magnus] and the spinal cord). 2) The effects of these microinjections will be assessed on two measures of motor function (rotorod test and locomotor activity) to assess the specificity of improgan analgesia. 3) Microinjection studies with transmitter agonists and antagonists will identify the supraspinal and spinal transmitter mechanisms that mediate improgan analgesia. 4) Two kinds of experiments will search for the improgan receptor: a) the improgan-induced modulation of 35S-GTPgammaS binding in brain membranes will be studied, and b) homogenate and autoradiography techniques will study the binding of a radiolabeled derivative of improgan. These studies may also help to develop an in vitro assay for improgan-like activity. 5) To determine if improgan-like analgesics are effective in preclinical models of human inflammatory pain, the activity of improgan will be studied in the formalin nociceptive test in rats. The proposed experiments will characterize the fundamental neuronal mechanisms of non-opioid analgesia, and may lead to the discovery of a new histamine receptor, and/or to the development of new pharmacotherapies for acute and chronic pain.