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BN-9, a chimeric peptide with mixed opioid and neuropeptide FF receptor agonistic properties, produces nontolerance-forming antinociception in mice.
Br J Pharmacol. 2016 06; 173(11):1864-80.BJ

Abstract

BACKGROUND AND PURPOSE

Neuropeptide FF (NPFF) behaves as an endogenous opioid-modulating peptide. In the present study, the opioid and NPFF pharmacophore-containing chimeric peptide BN-9 was synthesized and pharmacologically characterized.

EXPERIMENTAL APPROACH

Agonist activities of BN-9 at opioid and NPFF receptors were characterized in in vitro cAMP assays. Antinociceptive activities of BN-9 were evaluated in the mouse tail-flick and formalin tests. Furthermore, its side effects were investigated in rotarod, antinociceptive tolerance, reward and gastrointestinal transit tests.

KEY RESULTS

BN-9 acted as a novel multifunctional agonist at μ, δ, κ, NPFF1 and NPFF2 receptors in cAMP assays. In the tail-flick test, BN-9 produced dose-related antinociception and was approximately equipotent to morphine; this antinociception was blocked by μ and κ receptor antagonists, but not by the δ receptor antagonist. In the formalin test, supraspinal administration of BN-9 produced significant analgesia. Notably, repeated administration of BN-9 produced analgesia without loss of potency over 8 days. In contrast, repeated i.c.v. co-administration of BN-9 with the NPFF receptor antagonist RF9 produced significant antinociceptive tolerance. Furthermore, i.c.v. BN-9 induced conditioned place preference. When given by the same routes, BN-9 had a more than eightfold higher ED50 value for gastrointestinal transit inhibition compared with the ED50 values for antinociception.

CONCLUSIONS AND IMPLICATIONS

BN-9 produced a robust, nontolerance-forming analgesia with limited inhibition of gastrointestinal transit. As BN-9 is able to activate both opioid and NPFF systems, this provides an interesting approach for the development of novel analgesics with minimal side effects.

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, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27018797

Citation

Li, Ning, et al. "BN-9, a Chimeric Peptide With Mixed Opioid and Neuropeptide FF Receptor Agonistic Properties, Produces Nontolerance-forming Antinociception in Mice." British Journal of Pharmacology, vol. 173, no. 11, 2016, pp. 1864-80.
Li N, Han ZL, Wang ZL, et al. BN-9, a chimeric peptide with mixed opioid and neuropeptide FF receptor agonistic properties, produces nontolerance-forming antinociception in mice. Br J Pharmacol. 2016;173(11):1864-80.
Li, N., Han, Z. L., Wang, Z. L., Xing, Y. H., Sun, Y. L., Li, X. H., Song, J. J., Zhang, T., Zhang, R., Zhang, M. N., Xu, B., Fang, Q., & Wang, R. (2016). BN-9, a chimeric peptide with mixed opioid and neuropeptide FF receptor agonistic properties, produces nontolerance-forming antinociception in mice. British Journal of Pharmacology, 173(11), 1864-80. https://doi.org/10.1111/bph.13489
Li N, et al. BN-9, a Chimeric Peptide With Mixed Opioid and Neuropeptide FF Receptor Agonistic Properties, Produces Nontolerance-forming Antinociception in Mice. Br J Pharmacol. 2016;173(11):1864-80. PubMed PMID: 27018797.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BN-9, a chimeric peptide with mixed opioid and neuropeptide FF receptor agonistic properties, produces nontolerance-forming antinociception in mice. AU - Li,Ning, AU - Han,Zheng-Lan, AU - Wang,Zi-Long, AU - Xing,Yan-Hong, AU - Sun,Yu-Long, AU - Li,Xu-Hui, AU - Song,Jing-Jing, AU - Zhang,Ting, AU - Zhang,Run, AU - Zhang,Meng-Na, AU - Xu,Biao, AU - Fang,Quan, AU - Wang,Rui, Y1 - 2016/04/21/ PY - 2015/10/14/received PY - 2016/03/16/revised PY - 2016/03/22/accepted PY - 2016/3/29/entrez PY - 2016/3/29/pubmed PY - 2017/10/24/medline SP - 1864 EP - 80 JF - British journal of pharmacology JO - Br J Pharmacol VL - 173 IS - 11 N2 - BACKGROUND AND PURPOSE: Neuropeptide FF (NPFF) behaves as an endogenous opioid-modulating peptide. In the present study, the opioid and NPFF pharmacophore-containing chimeric peptide BN-9 was synthesized and pharmacologically characterized. EXPERIMENTAL APPROACH: Agonist activities of BN-9 at opioid and NPFF receptors were characterized in in vitro cAMP assays. Antinociceptive activities of BN-9 were evaluated in the mouse tail-flick and formalin tests. Furthermore, its side effects were investigated in rotarod, antinociceptive tolerance, reward and gastrointestinal transit tests. KEY RESULTS: BN-9 acted as a novel multifunctional agonist at μ, δ, κ, NPFF1 and NPFF2 receptors in cAMP assays. In the tail-flick test, BN-9 produced dose-related antinociception and was approximately equipotent to morphine; this antinociception was blocked by μ and κ receptor antagonists, but not by the δ receptor antagonist. In the formalin test, supraspinal administration of BN-9 produced significant analgesia. Notably, repeated administration of BN-9 produced analgesia without loss of potency over 8 days. In contrast, repeated i.c.v. co-administration of BN-9 with the NPFF receptor antagonist RF9 produced significant antinociceptive tolerance. Furthermore, i.c.v. BN-9 induced conditioned place preference. When given by the same routes, BN-9 had a more than eightfold higher ED50 value for gastrointestinal transit inhibition compared with the ED50 values for antinociception. CONCLUSIONS AND IMPLICATIONS: BN-9 produced a robust, nontolerance-forming analgesia with limited inhibition of gastrointestinal transit. As BN-9 is able to activate both opioid and NPFF systems, this provides an interesting approach for the development of novel analgesics with minimal side effects. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/27018797/BN_9_a_chimeric_peptide_with_mixed_opioid_and_neuropeptide_FF_receptor_agonistic_properties_produces_nontolerance_forming_antinociception_in_mice_ L2 - https://doi.org/10.1111/bph.13489 DB - PRIME DP - Unbound Medicine ER -