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Systemic administration of the bifunctional opioid/neuropeptide FF receptors agonist BN-9 produced peripheral antinociception in preclinical mouse models of pain.
Eur J Pharmacol. 2018 Oct 15; 837:53-63.EJ

Abstract

We recently characterized a novel bifunctional agonist for opioid and neuropeptide FF receptors, named BN-9, which exhibited potent analgesia in the mouse tail-flick test when given centrally. To further evaluate its potential therapeutic efficacy for translational-medical development, the current work was performed to explore the antinociceptive activities of intraperitoneal (i.p.) administration of BN-9 in mouse models of tail-flick assay, formalin pain, visceral pain and post-operative pain. In the tail-flick test, BN-9 induced a dose-related antinociceptive effect, which was fully blocked by systemic pretreatment with the peripheral acting opioid receptor antagonist naloxone methiodide, but not supraspinal naloxone methiodide, implying the involvement of the peripheral opioid receptors. In addition, the systemic antinociception of BN-9 was antagonized by the selective antagonists of the μ- and κ-opioid receptors, independently of the δ-opioid and neuropeptide FF receptors. Similarly, dose-dependent analgesia was also produced by systemic BN-9 in different pain models via the peripheral opioid receptors, independently of the neuropeptide FF receptors. Furthermore, the side-effects of systemic BN-9 on motor performance, tolerance development and gastrointestinal transit inhibition were also evaluated. Repeated systemic injection of BN-9 produced non-tolerance analgesia over 8 days. Compared with morphine, intraperitoneal administration of BN-9 exerted less inhibition of gastrointestinal transit. These data show that BN-9 induced systemic analgesia with reduced side-effects on tolerance and constipation. This article suggests that systemic injection of BN-9 causes effective antinociception in different preclinical pain models via the peripheral opioid receptors, providing an attractive approach to develop peripherally acting opioid analgesics with multiple targeting properties.

Authors+Show Affiliations

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China. Electronic address: fangq@lzu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30172787

Citation

Li, Ning, et al. "Systemic Administration of the Bifunctional Opioid/neuropeptide FF Receptors Agonist BN-9 Produced Peripheral Antinociception in Preclinical Mouse Models of Pain." European Journal of Pharmacology, vol. 837, 2018, pp. 53-63.
Li N, Han ZL, Xu B, et al. Systemic administration of the bifunctional opioid/neuropeptide FF receptors agonist BN-9 produced peripheral antinociception in preclinical mouse models of pain. Eur J Pharmacol. 2018;837:53-63.
Li, N., Han, Z. L., Xu, B., Zhang, M. N., Zhang, T., Shi, X. R., Zhao, W. D., Guo, Y. Y., Zhang, Q. Q., & Fang, Q. (2018). Systemic administration of the bifunctional opioid/neuropeptide FF receptors agonist BN-9 produced peripheral antinociception in preclinical mouse models of pain. European Journal of Pharmacology, 837, 53-63. https://doi.org/10.1016/j.ejphar.2018.08.039
Li N, et al. Systemic Administration of the Bifunctional Opioid/neuropeptide FF Receptors Agonist BN-9 Produced Peripheral Antinociception in Preclinical Mouse Models of Pain. Eur J Pharmacol. 2018 Oct 15;837:53-63. PubMed PMID: 30172787.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Systemic administration of the bifunctional opioid/neuropeptide FF receptors agonist BN-9 produced peripheral antinociception in preclinical mouse models of pain. AU - Li,Ning, AU - Han,Zheng-Lan, AU - Xu,Biao, AU - Zhang,Meng-Na, AU - Zhang,Ting, AU - Shi,Xue-Rui, AU - Zhao,Wei-Dong, AU - Guo,Yuan-Yuan, AU - Zhang,Qin-Qin, AU - Fang,Quan, Y1 - 2018/08/30/ PY - 2018/04/27/received PY - 2018/08/22/revised PY - 2018/08/29/accepted PY - 2018/9/3/pubmed PY - 2019/2/14/medline PY - 2018/9/3/entrez KW - Antinociception KW - BN-9 KW - Intraperitoneal injection KW - Neuropeptide FF KW - Opioid SP - 53 EP - 63 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 837 N2 - We recently characterized a novel bifunctional agonist for opioid and neuropeptide FF receptors, named BN-9, which exhibited potent analgesia in the mouse tail-flick test when given centrally. To further evaluate its potential therapeutic efficacy for translational-medical development, the current work was performed to explore the antinociceptive activities of intraperitoneal (i.p.) administration of BN-9 in mouse models of tail-flick assay, formalin pain, visceral pain and post-operative pain. In the tail-flick test, BN-9 induced a dose-related antinociceptive effect, which was fully blocked by systemic pretreatment with the peripheral acting opioid receptor antagonist naloxone methiodide, but not supraspinal naloxone methiodide, implying the involvement of the peripheral opioid receptors. In addition, the systemic antinociception of BN-9 was antagonized by the selective antagonists of the μ- and κ-opioid receptors, independently of the δ-opioid and neuropeptide FF receptors. Similarly, dose-dependent analgesia was also produced by systemic BN-9 in different pain models via the peripheral opioid receptors, independently of the neuropeptide FF receptors. Furthermore, the side-effects of systemic BN-9 on motor performance, tolerance development and gastrointestinal transit inhibition were also evaluated. Repeated systemic injection of BN-9 produced non-tolerance analgesia over 8 days. Compared with morphine, intraperitoneal administration of BN-9 exerted less inhibition of gastrointestinal transit. These data show that BN-9 induced systemic analgesia with reduced side-effects on tolerance and constipation. This article suggests that systemic injection of BN-9 causes effective antinociception in different preclinical pain models via the peripheral opioid receptors, providing an attractive approach to develop peripherally acting opioid analgesics with multiple targeting properties. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/30172787/Systemic_administration_of_the_bifunctional_opioid/neuropeptide_FF_receptors_agonist_BN_9_produced_peripheral_antinociception_in_preclinical_mouse_models_of_pain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(18)30502-8 DB - PRIME DP - Unbound Medicine ER -