A novel spinal analgesic with mixed MOP/NOP actions in primates

 描述（由申请方提供）：尽管μ阿片受体（MOP）激动剂是临床上治疗中度至重度疼痛最常用的阿片类药物，但MOP激动剂的几种副作用限制了其作为脊髓镇痛剂的价值。研究确定具有较少副作用的新型镇痛剂对于促进人类的医疗保健至关重要。科学家们发现了N/OFQ，这是一种十七肽，是新型阿片受体（现在称为NOP受体）的内源性配体。特别是，鞘内施用NOP激动剂在不同疼痛模式下的动物中产生强烈的抗伤害感受作用。更重要的是，我们发现MOP激动剂和NOP激动剂的组合在猴伤害感受模型中具有协同的抗伤害感受作用。这些令人兴奋的结果促使本提案评估一种新的类似物BU 10038，该类似物已由Husbands博士在恒河猴的许多试验中与吗啡进行了并排比较。BU 10038对MOP和NOP受体都具有结合亲和力，并对两种受体都显示出部分激动剂作用。已专门建立这些猴试验，以反映阿片类药物的治疗（脊髓镇痛）和副作用（瘙痒、呕吐、呼吸抑制、便秘、体温过低和便秘）特征。在本建议的第一个目的中，将用MOP和NOP拮抗剂评价和确定鞘内给药后BU 10038的抗伤害感受作用。在第二个目的中，将进行几种测定以建立与吗啡相比鞘内注射BU 10038的副作用/安全性概况。在两种受体上具有激动剂作用的药物将是强效和有效的脊髓镇痛剂，副作用减少，这一可能性鼓励了我们对BU 10038的药理学研究。我们在植入鞘内导管的清醒恒河猴中进行的一组独特的生理和行为测定，结合新型双功能MOP/NOP激动剂的可用性，为在未来临床应用中确定有效和安全的脊髓内注射的突破奠定了基础。 相关性：这项拟议的研究与公共卫生有关，因为它可能导致确定一种具有前景的治疗概况的脊髓镇痛药。寻找一种副作用少的脊髓镇痛药一直是疼痛治疗的目标。这种药物可能会深刻影响脊髓镇痛的实践，并大大降低目前可用的μ阿片类镇痛药带来的风险和担忧。

 DESCRIPTION (provided by applicant): Although mu opioid receptor (MOP) agonists are the most commonly used opioids for the treatment of moderate to severe pain in the clinic, several side effects of MOP agonists limit their value as spinal analgesics. Research to identify novel analgesics with fewer side effects is pivotal to advancing the health care of humans. Scientists have discovered N/OFQ, a heptadecapeptide that is an endogenous ligand for the novel opioid receptors (now named NOP receptors). In particular, intrathecal administration of NOP agonists produced robust antinociceptive effects in animals under different pain modalities. More importantly, we have found that combinations of MOP agonists and NOP agonists have synergistic antinociceptive effects in the monkey nociceptive models. These exciting results prompt this proposal to evaluate a novel analog, BU10038, that has been developed and synthesized by Dr. Husbands in side-by-side comparisons with morphine in a number of assays in rhesus monkeys. BU10038 has binding affinities on both MOP and NOP receptors and displays partial agonist actions on both receptors. These monkey assays have been established specifically to reflect the therapeutic (spinal analgesia) and side effect (pruritus, vomitting, respiratory depression, hypotention, hypothermia and constipation) profile of opioid analgeiscs. In the first aim of this proposal, antinociceptive effects of BU10038 following intrathecal administration will be evaluated and determined with MOP and NOP antagonists. In the second aim, several assays will be conducted to establish the side effect/safety profile of intrathecal BU10038 as compared with that of morphine. The possibility that drugs with agonist actions at both receptors will be potent and effective spinal analgesics with reduced side effects encourages our pharmacological studies of BU10038. Our unique set of physiological and behavioral assays in conscious rhesus monkeys implanted with intrathecal catheters, in combination with the availability of a novel bifunctional MOP/NOP agonist, sets the stage for the identification of a breakthrough in the effective and safe spinal analgeisc in the future clinical application. RELEVANCE: The proposed research is relevant to public health because it could result in the identification of a spinal analgesic with promising therapeutic profile. Identification of a superir spinal analgesic with fewer side effects has long been a goal of pain management. Such a drug could profoundly impact the practice of spinal analgesia as well as substantially reduce the risks and concerns posed by the currently available mu opioid analgesics.