Spinal administration of the multi-functional opioid/neuropeptide FF agonist BN-9 produced potent antinociception without development of tolerance and opioid-induced hyperalgesia.
Spinal administration of the multi-functional opioid/neuropeptide FF agonist BN-9 produced potent antinociception without development of tolerance and opioid-induced hyperalgesia.
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DOI：
10.1016/j.ejphar.2020.173169
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发表时间：
2020-05
影响因子：
5
通讯作者：
Run Zhang;Biao Xu;Qinqin Zhang;Dan Chen;Meng‐na Zhang;Guang‐hai Zhao;Kangtai Xu;Jian Xiao;Hanwen Zhu;Jiandong Niu;Ning Li;Quan Fang
中科院分区：
文献类型：
--
作者：
Run Zhang;Biao Xu;Qinqin Zhang;Dan Chen;Meng‐na Zhang;Guang‐hai Zhao;Kangtai Xu;Jian Xiao;Hanwen Zhu;Jiandong Niu;Ning Li;Quan Fang
慢性阿片类药物治疗是阻碍发展的镇痛耐受性和阿片类药物引起的痛觉过敏。最近的研究表明，多功能阿片化合物具有镇痛活性，副作用有限。我们开发了一种新的靶向阿片样物质和神经肽FF受体的多功能肽BN-9，在棘上和全身给药后产生了强效和非耐受性的抗感觉性作用。本研究在一系列临床前啮齿类动物模型中研究鞘内BN-9的镇痛特性和潜在副作用。在完全的Freund佐剂诱导的炎性疼痛模型中，鞘内BN-9通过阿片受体剂量依赖性地产生镇痛作用，脊髓抗痛觉作用被神经肽FF受体拮抗剂RF9增强。相比之下，在足底切口术后疼痛模型中，BN-9通过阿片受体和神经肽FF受体表现出强大的抗异动作用。在醋酸致内脏痛和福尔马林痛小鼠模型中，bn -9诱导的脊髓抗痛觉主要由阿片受体介导，不依赖于神经肽FF受体。此外，在脊柱水平，BN-9慢性治疗不导致镇痛耐受和吗啡交叉耐受。此外，反复给药吗啡后观察到阿片类药物引起的痛觉过敏，而BN-9则没有。综上所述，我们目前的研究表明鞘内BN-9产生强效和非耐受性形成抗痛觉，并且不会引起阿片类药物诱导的痛觉过敏。因此，BN-9可能成为开发副作用最小的多功能阿片类镇痛药的先导化合物。
Chronic opioids treatment is impeded by the development of analgesic tolerance and opioid-induced hyperalgesia. Recent studies have shown that multi-functional opioid compounds produce analgesic activities with limited side effects. We developed a novel multi-functional peptide targeting opioid and neuropeptide FF receptors named BN-9, which produced potent and non-tolerance forming antinociceptive effect after supraspinal and systemic administrations. In the present study, the analgesic properties and potential side effects of intrathecal BN-9 were investigated in a range of preclinical rodent models. In complete Freund's adjuvant-induced inflammatory pain model, intrathecal BN-9 dose-dependently produced analgesic effect via opioid receptors, and the spinal antinociceptive effect was augmented by the neuropeptide FF receptor antagonist RF9. In contrast, in plantar incision-induced postoperative pain model, BN-9 exhibited potent anti-allodynic effect via opioid receptors and, at least partially, neuropeptide FF receptors. In mouse models of acetic acid-induced visceral pain and formalin pain, BN-9-induced spinal antinociception was mainly mediated by opioid receptors, independent of neuropeptide FF receptors. Furthermore, at the spinal level, chronic treatments with BN-9 did not lead to analgesic tolerance and cross-tolerance to morphine. Moreover, opioid-induced hyperalgesia was observed after repeated administration of morphine, but not BN-9. Taken together, our present study suggests that intrathecal BN-9 produces potent and non-tolerance forming antinociception, and does not cause opioid-induced hyperalgesia. Thus, BN-9 might serve as a promising lead compound in the development of multi-functional opioid analgesics with minimized side effects.