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

Abstract

BACKGROUND AND PURPOSENeuropeptide 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 APPROACHAgonist 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 RESULTSBN-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 ED 50 value for gastrointestinal transit inhibition compared with the ED 50 values for antinociception. CONCLUSIONS AND IMPLICATIONSBN-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.

GpTx‐1 and [Ala5, Phe6, Leu26, Arg28]GpTx‐1, two peptide NaV1.7 inhibitors: analgesic and tolerance properties at the spinal level

“…Our data show that antinociceptive tolerance developed to the i.t. injection of morphine (2 nmol) on day 4 based on a tail‐flick test (Li et al ., ). In contrast, the increased flick latency induced by both GpTx‐1 and GpTx‐1‐71 remained unchanged during the observation period (Figure A).…”

“…Previous data have shown that spinal morphine produces antinociceptive tolerance on day 4 in an acute pain model (Li et al ., ). In contrast to opioids, this study indicated that spinal administration of GpTx‐1 and GpTx‐1‐71 induced equivalent analgesia during the 8 days of dosing in acute, inflammatory or neuropathic pain models, which is consistent with the previous data that repeated i.v.…”

“…I.c.v. injections were performed via a permanent guide cannula embedded into the lateral ventricle (Li et al ., ). Briefly, the mice were anaesthetized with pentobarbital sodium (80 mg·kg −1 , i.p.)…”

“…Nociceptive responses in mice were confirmed using the tailflick test as previously described (Li et al, 2016a). Briefly, the tail of the mouse was positioned in a groove underneath a radiant heat source.…”

Heteromerization of μ-opioid receptor and cholecystokinin B receptor through the third transmembrane domain of the μ-opioid receptor contributes to the anti-opioid effects of cholecystokinin octapeptide

“…The cAMP concentrations of the samples were calculated according to the equation. The Prism program (GraphPad Software) was used to analyze the differences in forskolin responses 22 between MOR alone and MOR–CCKBR-co-expressing cells treated with each concentration of DAMGO.…”