Effect of chronic intra-peritoneally administered chimeric peptide of met-enkephalin and FMRFa-[d-Ala2]YFa-on antinociception and opioid receptor regulation

The physiological role of NPFF/FMRFa family of peptides is complex and exact mechanism of action of these peptides is not yet completely understood. In same line of scrutiny, previously we reported an enzymatically stable chimeric analog of YGGFMKKKFMRFamide (YFa) i.e., [d-Ala2]YAGFMKKKFMRFamide ([d-Ala2]YFa) which have a role in antinociception and modulatory effect on opioid analgesia. In continuation, presently we investigated using tail-flick test whether [d-Ala2]YFa on systemic administration induced any antinociception in rats and if so then which specific opioid receptor(s) μ, δ or κ mediated it. Further, the antinociceptive effect of [d-Ala2]YFa on 6 days chronic intra-peritoneal (i.p.) treatment in rats was examined and finally, effect of this chronic treatment on the differential expression of opioid receptors was assessed.

[d-Ala2]YFa on i.p. administration induced dose dependent antinociception which was mainly mediated by δ (DOR) and partially by μ (MOR) and κ (KOR) opioid receptors. Moreover, its antinociceptive effect remained comparable throughout the chronic treatment even during insufficient availability of DOR1. Importantly, during this treatment the mRNA expression of all three opioid receptors (MOR1, KOR1 and DOR1) was increased as assessed by real-time RTPCR though subsequent western blot analysis revealed a selective increase in the protein level of DOR1, only.

Thus, pharmacological behavior of [d-Ala2]YFa suggests that competency of an opioid agonist to bind with multiple opioid receptors may enhance its potency to induce tolerance free analgesia.