YFa, a chimeric opioid peptide, induces kappa‐specific antinociception with no tolerance development during 6 days of chronic treatment

Our previous study showed that YGGFMKKKFMRFamide (YFa), a chimeric peptide of Met-enkephalin, and Phe-Met-Arg-Phe-NH2 induced naloxone-reversible antinociception and attenuated the development of tolerance to morphine analgesia. In continuation, the present study investigated which specific opioid receptors—μ, δ or κ—mediate the observed YFa antinociception pharmacologically using specific antagonists and whether chronic administration of YFa at 26.01 μmol/kg per day induces tolerance and its effect on the expression of μ and κ opioid receptors from day 4 to day 6, with endomorphine-1 (EM-1) and saline taken as positive and negative controls, respectively. Quantitative differential expression analysis was carried out by real-time reverse-transcriptase polymerase chain reaction, and the corresponding changes in protein levels were assessed by Western blot. A pharmacological investigation revealed that nor-binaltorphimine, a specific κ opioid receptor–1 (KOR1) antagonist, completely antagonized the antinociception induced by 39.01 μmol/kg of YFa. Importantly, its chronic intraperitoneal administration did not result in significant tolerance over 6 days, whereas EM-1 induced significant tolerance after day 4. Differential expression analysis revealed that EM-1 caused up-regulation of μ opioid receptor–1 on day 4, followed by down-regulation on later days. Interestingly, YFa treatment caused a decrease on day 4, followed by an increase in the expression of KOR1 from day 5 onward. In conclusion, YFa induces kappa-specific antinociception, with no development of tolerance during 6 days of chronic treatment, which further articulates new directions for improved designing of peptide-based analgesics that may be devoid of adverse effects like tolerance. © 2008 Wiley-Liss, Inc.