Evaluating the NOP receptor as a novel target for pain control: characterizing t

描述（由申请人提供）：数百万人被处方μ阿片受体（莫尔）激动剂，如羟考酮、芬太尼和吗啡，用于治疗恶性和非恶性中度至重度疼痛。尽管这些药物是高度有效的，但它们也引起显著的副作用，例如便秘、镇静、瘙痒、身体依赖，并且具有滥用的可能性（Ko等人，2009年）。因此，临床上需要鉴定用于疼痛缓解的新型受体靶标。 在20世纪90年代早期，阿片受体家族的第四个成员被鉴定并命名为痛敏肽/痛敏FQ（NOP），以前称为阿片样受体1（ORL 1）（Lambert，2008）。结合NOP的激动剂能够在非人灵长类动物中产生深度镇痛，而没有滥用、呼吸抑制或瘙痒的可能性。尽管支持这些药物开发的临床前数据很有希望，但限制传统阿片类药物治疗的几个重要药效学特征尚未得到评估。为了测试NOP激动剂的有利特征是否可能包括其他重要的行为效应，本研究将研究NOP激动剂与当前治疗标准莫尔激动剂相比的辨别刺激、镇静、便秘效应。 为了更好地了解这些药物如何在大脑中产生作用，将使用正电子发射断层扫描（PET）对NOP进行体内成像。将产生镇痛、区别性刺激效应、镇静和胃肠道通过时间变化的NOP激动剂的剂量与受体占有率数据相关联，以确定：1）不同水平的受体占有率是否产生不同的行为效应和2）对于给定效应，哪些脑区域显示最高水平的受体结合。这些研究将有助于更好地理解疼痛控制的神经解剖学，并提供有关产生阿片类药物行为效应的不同大脑结构的信息。 最后，尽管NOP激动剂在临床前模型中产生疼痛缓解，但其作用机制知之甚少。已知经典阿片肽（例如脑啡肽）响应于疼痛而释放，并且已经提出这用于对疼痛刺激的强度进行反馈（Bencherif等人，2002年）。临床和临床前研究已经发现，在各种疼痛状态中，伤害感受素（NOP的内源性配体）的水平升高（Ko等人，2002和罗森等人，2000年）。因此，使用PET，我们将测试伤害感受素是否在已知调节疼痛的感觉和情感维度以响应伤害性刺激的脑区域中内源性释放。了解疼痛和内源性痛感受素系统之间的关系将为开发NOP激动剂作为新型镇痛治疗药物提供强有力的理论基础。

DESCRIPTION (provided by applicant): Millions of people are prescribed mu opioid receptor (MOR) agonists such as oxycodone, fentanyl, and morphine for the treatment of malignant and non-malignant moderate to severe pain. Although these drugs are highly effective, they also cause significant side effects such as constipation, sedation, itch, physical dependence, and have the potential for abuse (Ko et al., 2009). Thus, there is a clinical need to identify novel receptor targets for pain relief. In the early 1990's a fourth member of the opioid receptor famil was identified and named the nociceptin/orphanin FQ (NOP), formerly known as the opioid-like receptor 1 (ORL1) (Lambert, 2008). Agonists that bind NOP are capable of producing profound analgesia in non-human primates without the potential for abuse, respiratory depression, or itch. Although the preclinical data supporting the development of these drugs is promising, several important pharmacodynamic characteristics that have limited traditional opioid therapy have not been evaluated. In order to test if the favorable profile of NOP agonist may include other important behavioral effects, this study will investigate the discriminative stimulus, sedating, an constipating effects of NOP agonists in comparison to the current standard of treatment, MOR agonists. To better understand how these drugs produce their effects in the brain, NOP will be imaged in vivo using Positron Emission Tomography (PET). The doses of NOP agonist that produce analgesia, discriminative stimulus effects, sedation, and changes in gastrointestinal transit time, will be correlated with receptor occupancy data to determine: 1) if different behavioral effects are produced with different levels of receptor occupancy and 2) which brain regions display the highest level of receptor binding for a given effect. These studies will lead t a better understanding of the neuroanatomy of pain control as well as provide information on the different brain structures that are involved in producing the behavioral effects of opioids. Finaly, although NOP agonists produce pain relief in preclinical models, their mechanism of action is poorly understood. It is known that classic opioid peptides (e.g. enkephalin) are released in response to pain, and it has been proposed that this serves to feedback on the intensity of painful stimuli (Bencherif et al., 2002). Clinical and preclinical studies have found elevated leves of nociceptin, the endogenous ligand for NOP, in various pain states (Ko et al., 2002 and Rosen et al., 2000). Therefore, using PET we will test if nociceptin is endogenously released in brain regions known to regulate the sensory and affective dimensions of pain in response to noxious stimuli. Understanding the relationship between pain and the endogenous nociceptin system would provide a strong rationale for developing NOP agonists as novel therapeutic agents for analgesia.