HISTAMINERGIC MECHANISMS OF ANTINOCICEPTION

描述（改编自申请人摘要）：一类新的非阿片类药物 最近发现的止痛药在化学上与 组胺 原型（名为improgan）显示了以下特征 在直接注射到啮齿动物脑中后：a）高度有效， 吗啡样镇痛作用的热和机械试验，B）无损害 运动协调或自发活动，c）非阿片类机制， 独立于已知的组胺受体和60种其他靶标，d）缺乏 每日给药的耐受性，和e）独特的结构-活性关系 在化学同源物中，这表明可能存在一种新的 组胺受体 然而，对这些疾病的发生部位和机制知之甚少。 不正当的行为。 为了解决这些问题，将进行以下研究： 在大鼠中进行。 1)显微注射定位研究将确定CNS 介导不适当镇痛的区域。 已知包含内源性 将研究疼痛缓解系统（导水管周围灰质，吻侧灰质， 腹侧髓质[包括中缝大核]和脊髓）。 （二） 这些微量注射的效果将通过两项运动指标进行评估。 功能（旋转杆试验和自发活动），以评估特异性 不适当的镇痛 3)用递质激动剂进行的显微注射研究， 拮抗剂将确定脊髓上和脊髓递质机制 介导不正常的镇痛作用 4)两种实验将寻找 Improgan受体：a）Improgan诱导的35 S-GTP γ S的调节 将研究在脑膜中的结合，和B）匀浆和 放射自显影技术将研究放射性标记的衍生物 即兴的。 这些研究也可能有助于开发一种体外检测方法， 即兴表演 5)为了确定是否有类似promogan的止痛药 在人类炎性疼痛的临床前模型中有效， Improgan将在大鼠福尔马林伤害感受试验中进行研究。 的 提出的实验将表征基本的神经机制， 非阿片类镇痛，并可能导致发现一种新的组胺 受体，和/或开发新的药物治疗急性和 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.