Mixed NOP/mu Compounds and the Involvement of their Receptors in Analgesia

混合 NOP/mu 化合物及其受体在镇痛中的作用

基本信息

批准号：
8738129
负责人：
LAWRENCE R TOLL
金额：
$ 4.12万
依托单位：
TORREY PINES INST FOR MOLECULAR STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738129
关键词：
Absence of pain sensation Acute Acute Pain Adverse effects Affinity Agonist Analgesics Attenuated Binding Binding Sites Brain Brain region Buprenorphine C Fiber Capsaicin Characteristics Chronic Classification Clinical Clinical Trials Constipation Data Development Diabetic Neuropathies Drug Kinetics Drug abuse Family Fiber Grant Guanosine Triphosphate Hair Heating Hypersensitivity In Vitro Individual Injection of therapeutic agent Lead Left Ligands Ligation Location Measures Mechanics Mediating Messenger RNA Modeling Names Nerve Fibers Operative Surgical Procedures Opiates Opioid Opioid Peptide Opioid Receptor Pain Pathway interactions Peptide Receptor Peptides Pharmaceutical Preparations Physiological Processes Process Property Proteins Publications Rattus Receptor Activation Research Personnel Rewards Rodent Model Spinal Cord Spinal Ganglia Spinal cord posterior horn Spinal nerve structure Stimulus System Tail Temperature Testing Therapeutic Thermal Hyperalgesias Time Ventilatory Depression addiction allodynia analog base chronic pain design diabetic effective therapy improved in vivo mechanical allodynia mu opioid receptors nociceptin nociceptive response novel preference receptor research study response small molecule

项目摘要

DESCRIPTION (provided by applicant): Nociceptin/Orphanin FQ, the peptide in the opioid peptide family, and the endogenous ligand for the NOP receptor is widely distributed in the brain and involved in a large number of physiological processes. The high expression level in brain regions involved in nociceptive responses, the dorsal horn of the spinal cord, and dorsal root ganglion has strongly suggested this as a target for pain therapeutics. Nevertheless, neither agonists nor antagonists appear to have significant antinociceptive properties in rodent models of acute pain. Rather than using selective NOP receptor agonists or antagonists, one option would be to use a mixed NOP/mu receptor agonist, based upon the ability of NOP agonists to attenuate reward and tolerance development mediated by mu-receptor activation. Such compounds, such as SR14150, have been demonstrated to have antinociceptive activity without inducing a conditioned place preference. In addition, recent experiments have indicated that NOP agonists have anti-allodynic activity in chronic pain models and suggested a far greater potential for selective NOP agonists as a therapeutic for chronic rather than acute pain. The experiments described in Specific Aim 1 will test the hypothesis that NOP receptors and/or N/OFQ are upregulated in selected brain regions, spinal cord, and DRG of rats subjected to spinal nerve ligation (SNL) or diabetic neuropathy, inducing chronic pain. This will be examined by measuring mRNA level by quantitative rtPCR, and protein by Western analysis, by measuring [35S]GTP S binding in brain regions and spinal cord in SNL, diabetic, and control rats, and by determining the potency of NOP agonists for anti-allodynic activity after i.c.v. and i.t. administration in SNL, diabetic and control rats. Specific Aim 2 will determine whether the actions of NOP agonists are due to selective inhibition of C-fiber or A primary afferents. Using high or low heating rates C- or A -fibers can be independently activated. In addition, SNL and diabetic neuropathy induce differential sensitivity of these afferents. The ability of NOP agonists to block mechanical allodynia, cold allodynia, and thermal hyperalgesia will be determined to better understand both the ability of these compounds to attenuate the hypersensitivity of C- and A -fibers and also to better understand the potential clinical usefulness of NOP agonists for different chronic pain states. Finally, novel buprenorphine analogs will be synthesized for Specific Aim 3. These compounds will be designed to have higher NOP affinity and activity than buprenorphine to decrease the addiction liability and thus improve upon side effect profile of buprenorphine as an analgesic, and potentially as a drug abuse medication. These compounds, as well as other mixed NOP/mu compounds will be characterized in vitro for binding affinity and intrinsic activity, and in vivo for antinociceptive activity and abuse potential. These experiments will provide a greatly improved understanding of the mechanism by which NOP-active compounds mediate an antinociceptive or anti-allodynic response, and progress selective NOP agonists, and mixed NOP/mu agonists toward clinical use as analgesics with reduced addiction liability.

描述（申请人提供）：痛敏肽/孤啡肽FQ是阿片肽家族中的肽，是NOP受体的内源性配体，广泛分布于大脑中并参与大量的生理过程。参与伤害性反应的大脑区域、脊髓背角和背根神经节的高表达水平强烈表明它可以作为疼痛治疗的目标。然而，在急性疼痛的啮齿动物模型中，激动剂和拮抗剂似乎都不具有显着的镇痛特性。一种选择是使用混合的 NOP/mu 受体激动剂，而不是使用选择性 NOP 受体激动剂或拮抗剂，因为 NOP 激动剂能够减弱 mu 受体激活介导的奖赏和耐受性发展。此类化合物，例如 SR14150，已被证明具有抗伤害活性，且不会诱导条件性位置偏好。此外，最近的实验表明，NOP 激动剂在慢性疼痛模型中具有抗异常疼痛活性，并表明选择性 NOP 激动剂作为慢性而非急性疼痛的治疗剂具有更大的潜力。具体目标 1 中描述的实验将检验以下假设：在遭受脊神经结扎 (SNL) 或糖尿病神经病变的大鼠的选定大脑区域、脊髓和 DRG 中，NOP 受体和/或 N/OFQ 上调，从而诱发慢性疼痛。这将通过定量 rtPCR 测量 mRNA 水平，通过 Western 分析测量蛋白质，通过测量 SNL、糖尿病和对照大鼠的脑区和脊髓中的 [35S]GTP S 结合，并通过确定 NOP 激动剂的效力来进行检查。静脉注射后的抗异常疼痛活性和它。在 SNL、糖尿病和对照大鼠中给药。具体目标 2 将确定 NOP 激动剂的作用是否是由于 C 纤维或 A 初级传入神经的选择性抑制。使用高或低加热速率，C 纤维或 A 纤维可以独立激活。此外，SNL 和糖尿病神经病变会导致这些传入神经的敏感性不同。将测定 NOP 激动剂阻断机械异常性疼痛、冷异常性疼痛和热痛觉过敏的能力，以更好地了解这些化合物减轻 C 纤维和 A 纤维过敏的能力，并更好地了解 NOP 的潜在临床用途针对不同慢性疼痛状态的激动剂。最后，将针对具体目标 3 合成新型丁丙诺啡类似物。这些化合物将被设计为比丁丙诺啡具有更高的 NOP 亲和力和活性，以降低成瘾倾向，从而改善丁丙诺啡作为镇痛剂和潜在药物的副作用滥用药物。这些化合物以及其他混合的 NOP/mu 化合物将在体外表征结合亲和力和内在活性，并在体内表征抗伤害活性和滥用潜力。这些实验将大大提高对NOP活性化合物介导镇痛或抗异常疼痛反应的机制的理解，并推动选择性NOP激动剂和混合NOP/mu激动剂在临床上用作镇痛药，降低成瘾倾向。