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

描述（由申请人提供）：数以百万计的人开mu阿片受体（MOR）激动剂，如羟考酮、芬太尼和吗啡，用于治疗恶性和非恶性中重度疼痛。虽然这些药物非常有效，但它们也会引起便秘、镇静、瘙痒、身体依赖等明显的副作用，并有滥用的可能（Ko et al., 2009）。因此，临床需要确定新的受体靶点来缓解疼痛。在20世纪90年代初，阿片受体家族的第四个成员被发现并命名为NOP，以前称为阿片样受体1 (ORL1) （Lambert, 2008）。结合NOP的激动剂能够在非人灵长类动物中产生深刻的镇痛作用，而不会滥用、呼吸抑制或瘙痒。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激动剂的有利特性是否包括其他重要的行为作用，本研究将研究NOP激动剂与目前标准治疗MOR激动剂的区别刺激、镇静和便秘作用。为了更好地了解这些药物如何在大脑中产生作用，NOP将使用正电子发射断层扫描（PET）在体内成像。NOP激动剂产生镇痛、判别刺激作用、镇静作用和胃肠道转运时间变化的剂量将与受体占用数据相关，以确定：1)不同受体占用水平是否会产生不同的行为效应；2)对于给定效应，哪个脑区显示出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影响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可以缓解疼痛，但其作用机制尚不清楚。众所周知，经典的阿片肽（如脑啡肽）是在对疼痛做出反应时释放的，有人提出，这是对疼痛刺激强度的反馈（Bencherif et al., 2002）。临床和临床前研究发现，在各种疼痛状态下，NOP的内源性配体痛觉肽水平升高（Ko et al., 2002; Rosen et al., 2000）。因此，使用PET，我们将测试伤害肽是否内源性释放在大脑区域，已知的调节疼痛的感觉和情感维度，以应对有害刺激。了解疼痛与内源性痛觉肽系统之间的关系将为开发NOP激动剂作为新型镇痛药物提供强有力的理论依据。

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.