Spinal DN-9, a Peptidic Multifunctional Opioid/Neuropeptide FF Agonist Produced Potent Nontolerance Forming Analgesia With Limited Side Effects

JOURNAL OF PAIN

卷:21

Article

Wang, Zilong¹  Xu, Biao¹  Jiang, Changyu^2,3  Zhang, Ting¹  Zhang, Mengna¹  Li, Ning¹  Zhang, Qinqin¹  Xu, Kangtai¹  Chen, Dan¹  Xiao, Jian¹  Fang, Quan¹ 

[1] Lanzhou Univ, Sch Basic Med Sci, Key Lab Preclin Study New Drugs Gansu Prov, 199 Donggang West Rd, Lanzhou 730000, Peoples R China

[2] Shenzhen Univ, Shenzhen Nanshan Peoples Hosp, Shenzhen Municipal Key Lab Pain Med, Dept Pain Med,Hlth Sci Ctr, Shenzhen, Peoples R China

[3] Shenzhen Univ, Affiliated Hosp 6, Hlth Sci Ctr, Shenzhen, Peoples R China

关键词: Analgesic;    neuropeptide FF (NPFF);    opioid;    pain;    analgesic tolerance;    opioid dependence;   

DOI  :  10.1016/j.jpain.2019.08.016

来源: Elsevier

【 摘 要 】

The development of multitarget opioid drugs has emerged as an attractive therapeutic strategy to eliminate opioid-related side effects. Our previous study developed a series of opioid and neuropeptide FF pharmacophore-containing chimeric peptides, including DN-9 (Tyr-D.Ala-Gly-NMe. Phe-Gly-Pro-Gln-Arg-Phe-NH2), which produced potent nontolerance forming analgesia at the supraspinal level. In the present study, the antinociceptive effects of DN-9 in a series of preclinical pain models and the potential side-effects were investigated at the spinal level in mice. In the tail-flick test, intrathecal injection of DN-9 produced potent analgesia with an ED50 value at 1.33 pmol, and the spinal antinociception of DN-9 was mainly mediated by mu- and kappa-opioid receptors. In addition, DN-9-induced spinal antinociception was augmented by the neuropeptide FF receptors antagonist. Furthermore, DN-9 could decrease both the frequency and amplitude of sEPSCs in lamina IIo neurons of the spinal cord, which were mediated by opioid receptors. In contrast to morphine, chronic intrathecal treatments with DN-9 did not induce analgesic tolerance, c-Fos expression or microglial activation. Intrathecal injection of DN-9 showed potent analgesia with antinociceptive ED50 values between .66 and 55.04 pmol in different pain models, including the formalin test, acetic acid-induced writhing test, carrageenan-induced inflammatory pain and neuropathic pain. Moreover, DN-9 did not show side effects in locomotor function and coordination, gastrointestinal transit inhibition, the cardiovascular system, and body temperature regulation at antinociceptive doses. Taken together, the present study showed DN-9 produced effective, nontolerance forming analgesia with reduced side effects at the spinal level. DN-9 might be a promising compound for developing multifunctional opioid analgesics with limited adverse effects. Perspective: This article presents the potent and nontolerance forming analgesia effects of DN-9 in a series of preclinical pain models with less opioid related adverse effects at the spinal level in mice. This study also demonstrates that DN-9 has translational potential into an intrathecal analgesic. (C) 2020 U.S. Association for the Study of Pain. Published by Elsevier Inc. All rights reserved.

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