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

• 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
• 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

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）：Nociceptin/Orphanin 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，参与大量生理过程。在涉及伤害性反应的大脑区域，脊髓背角和背根神经节中的高表达水平强烈建议将其作为疼痛治疗的靶点。然而，在啮齿动物急性疼痛模型中，激动剂和拮抗剂似乎都没有显著的抗痛觉性。而不是使用选择性的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。这些化合物，如SR14150，已被证明具有抗伤感受活性，而不诱导条件位置偏好。此外，最近的实验表明，NOP激动剂在慢性疼痛模型中具有抗变动力活性，这表明选择性NOP激动剂治疗慢性疼痛的潜力要大得多，而不是急性疼痛。在Specific Aim 1中描述的实验将验证NOP受体和/或N/OFQ在遭受脊髓神经结扎（SNL）或糖尿病性神经病变的大鼠的选定脑区、脊髓和DRG中上调，从而诱导慢性疼痛的假设。这将通过定量rtPCR检测mRNA水平，Western分析检测蛋白水平，在SNL、糖尿病大鼠和对照大鼠中检测[35S]GTP S在脑区和脊髓中的结合，以及在SNL、糖尿病大鼠和对照大鼠中测定灌注和给药后NOP激动剂抗异动活性的效力来检验。特异性目的2将确定NOP激动剂的作用是由于选择性抑制c -纤维还是A初级传入。使用高或低加热速率，C-或A -纤维可以独立激活。此外，SNL和糖尿病性神经病变诱导了这些传入神经的不同敏感性。NOP激动剂阻断机械异位痛、冷异位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 -纤维过敏的能力，并更好地了解NOP激动剂对不同慢性疼痛状态的潜在临床用途。最后，将为Specific Aim 3合成新的丁丙诺啡类似物。这些化合物将被设计成比丁丙诺啡具有更高的NOP亲和力和活性，以减少成瘾性，从而改善丁丙诺啡作为止痛药和潜在的药物滥用药物的副作用。这些化合物以及其他混合NOP/mu化合物将在体外进行结合亲和力和内在活性的表征，在体内进行抗伤害性活性和滥用潜力的表征。这些实验将极大地提高对NOP活性化合物介导抗痛觉性或抗异动性反应的机制的理解，并将选择性NOP激动剂和混合NOP/mu激动剂作为减少成瘾倾向的镇痛药用于临床。