BN‐9, a chimeric peptide with mixed opioid and neuropeptide FF receptor agonistic properties, produces nontolerance‐forming antinociception in mice

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.

DOI: 10.1111/bph.13489

View this article

• Full article (html)
• Enhanced article (html)
• PDF
• References