Peripheral and central sites of action for anti-allodynic activity induced by the bifunctional opioid/NPFF receptors agonist BN-9 in inflammatory pain model

Abstract

The activation of opioid and neuropeptide FF (NPFF) receptors plays important roles to modulate nociceptive signal in inflammatory pain states. Recently, BN-9 (Tyr-D. Ala-Gly-Phe-Gln-Pro-Gln-Arg-Phe-NH₂) was pharmacologically characterized as a novel bifunctional agonist at both opioid and NPFF receptors. In the present study, the anti-allodynic activity and site(s) of action of BN-9 were assessed in a mouse model of carrageenan-induced inflammatory pain. In mice, BN-9 induced a dose-dependent anti-allodinic effect through opioid receptor at supraspinal or spinal level, and this effect was augmented by pretreatment with the NPFF receptor antagonist at the same level. In contrast, peripheral administration of BN-9 produced opioid receptor-mediated anti-allodynia, which was insensitive of the NPFF receptor antagonist. In addition, systemic BN-9 produced anti-allodynic effect via opioid receptors, independent of NPFF system. Therefore, these data indicate that central, peripheral or systemic administrations of BN-9 exert potent analgesic activities in inflammatory pain model via opioid receptor, and central effects of BN-9 are associated with NPFF system. Interestingly, systemic anti-allodynia of BN-9 was blocked by intraperitoneal administration of the opioid receptor antagonists, naloxone and naloxone methiodide, but not by intracerebroventricular injection of the peripherally acting opioid antagonist naloxone methiodide. Furthermore, BN-9-induced systemic anti-allodynia was reversed by intraplantar administration of naloxone, but not by peripheral administration of the NPFF receptor antagonist. Taken together, our data further suggest that systemic BN-9-induced anti-allodynic effect is mainly mediated by peripheral opioid receptors, independent of NPFF receptors.

Keywords: BN-9; Bifunctional agonist; Inflammatory pain; NPFF (PubChem CID: 9854861); NPVF (PubChem CID: 71451611); Neuropeptide FF; Opioid; RF9 (PubChem CID: 53320361); TY005 (PubChem CID: 16737673); carrageenan (PubChem CID: 91972149); endomorphin-2 (PubChem CID: 5311081); morphine (PubChem CID: 5464110); naloxone (PubChem CID: 5284596); naloxone methiodide (PubChem CID: 16219719); pentobarbital sodium (PubChem CID: 23676152).