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：
8330783
负责人：
LAWRENCE R TOLL
金额：
$ 35.75万
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：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8330783
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（由申请人提供）：Nocieptin/Orphanin FQ，阿片类肽家族中的肽以及NOP受体的内源配体的大脑中分布广泛分布，并参与了大量生理过程。涉及伤害感受反应的大脑区域的高表达水平，脊髓的背角和背根神经节强烈建议这是疼痛疗法的靶标。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没有明显的抗伤害感受特性。与其使用选择性的NOP受体激动剂或拮抗剂，一种选择是使用混合的NOP/MU受体激动剂，基于NOP激动剂减弱由MU受体激活介导的奖励和耐受性发展的能力。这样的化合物（例如SR14150）已被证明具有抗伤害性活性，而无需诱导条件的位置偏好。此外，最近的实验表明，NOP激动剂在慢性疼痛模型中具有抗差异活性，并提出了选择性NOP激动剂作为慢性疼痛而不是急性疼痛的治疗性的更大潜力。特定目标1中描述的实验将检验以下假设：NOP受体和/或N/OFQ在选定的大脑区域，脊髓和DRG中上调，受到脊柱神经结扎（SNL）或糖尿病神经病的大鼠的DRG，诱发了慢性疼痛。通过定量RTPCR测量mRNA水平，以及通过西方分析测量mRNA水平，通过测量脑区域中的[35S] GTP S结合[35S] GTP S的结合，在SNL，糖尿病和控制大鼠中测量[35S] GTP S的结合，并通过确定I.C.V.抗单体活性的NOP激动剂的效力。和I.T.在SNL，糖尿病和控制大鼠中给药。具体目标2将确定NOP激动剂的作用是由于选择性抑制C纤维还是主要传入。使用高或低的加热速率C-或A-纤维可以独立激活。另外，SNL和糖尿病神经病会引起这些传入的差异灵敏度。 NOP激动剂阻断机械性异常性疾病，冷异性痛和热痛觉过敏的能力将被确定，以更好地了解这些化合物减轻C-和A纤维的超敏反应的能力，并更好地了解不同慢性疼痛状态的NOP激动剂的潜在临床实用性。最后，将新型的丁丙诺啡类似物用于特定的目标3。这些化合物的设计旨在比丁丙诺啡具有更高的NOP亲和力和活性，以减少成瘾责任，从而改善丁丙诺啡作为镇痛作用的副作用，并可能作为药物滥用药物。这些化合物以及其他混合NOP/MU化合物将在体外表征具有结合亲和力和内在活性的体外，以及体内的抗伤害感受活性和滥用潜力。这些实验将极大地提高人们对NOP活性化合物介导抗伤害感受或抗合金反应的机制，以及进步的选择性NOP激动剂，以及混合的NOP/MU激动剂将临床用作临床用作作为镇痛学的临床用途，并减少了成瘾责任。