YFa, a chimeric opioid peptide, induces kappa-specific antinociception with no tolerance development during 6 days of chronic treatment
✍ Scribed by Ishwar Dutt Vats; Karamjit Singh Dolt; Krishan Kumar; Jayashree Karar; Mahendra Nath; Anita Mohan; M. A. Qadar Pasha; Santosh Pasha
- Book ID
- 102384557
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 321 KB
- Volume
- 86
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
Abstract
Our previous study showed that YGGFMKKKFMRFamide (YFa), a chimeric peptide of Met‐enkephalin, and Phe‐Met‐Arg‐Phe‐NH~2~ 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.