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

 描述(申请人提供)：尽管MU阿片受体(MOP)激动剂是临床上治疗中重度疼痛最常用的阿片类药物，但MOP激动剂的几个副作用限制了其作为脊椎止痛药的价值。寻找副作用更少的新型镇痛剂的研究对于促进人类的健康保健至关重要。科学家们发现了N/OFQ，这是一种十七肽，是新型阿片受体(现在被称为NOP受体)的内源性配体。特别是，鞘内注射NOP激动剂在不同疼痛模式的动物身上产生了强大的抗伤害效应。更重要的是，我们发现MOP激动剂和NOP激动剂在猴伤害性模型中具有协同的抗伤害性作用。这些令人兴奋的结果促使这项建议对一种新的类似物BU10038进行评估，这种类似物是由霍班兹博士开发和合成的，在恒河猴的许多试验中与吗啡进行了并列比较。BU10038在MOP和NOP受体上都有结合亲和力，并在这两种受体上表现出部分激动剂作用。这些猴子试验专门用来反映阿片类止痛剂的疗效(脊椎止痛)和副作用(瘙痒、呕吐、呼吸抑制、低血压、体温过低和便秘)。在这项提案的第一个目标中，鞘内给药后BU10038的抗伤害效应将与MOP和NOP拮抗剂一起评估和确定。在第二个目标中，将进行几项测试，以建立鞘内注射BU10038与吗啡相比的副作用/安全性概况。在两个受体上都有激动剂作用的药物可能是有效的脊椎止痛剂，副作用减少，这鼓励了我们对BU10038的药理学研究。我们在清醒恒河猴身上植入鞘内导管的独特的生理和行为分析，结合一种新型的双功能MOP/NOP激动剂的可获得性，为在未来的临床应用中确定有效和安全的脊髓镇痛的突破奠定了基础。 相关性：这项拟议的研究与公共健康相关，因为它可能导致一种具有良好治疗前景的脊椎止痛药的鉴定。长期以来，寻找副作用较少的高级脊椎止痛药一直是疼痛治疗的目标。这种药物可能会对脊椎止痛的实践产生深远的影响，并大大减少目前可用的MU阿片类止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.