Dual effects of [Tyr(6)]-gamma2-MSH(6-12) on pain perception and in vivo hyperalgesic activity of its analogues.
[Tyr(6)]-gamma2-MSH(6-12) with a short effecting time of about 20 min is one of the most potent rMrgC receptor agonists. To possibly increase its potency and metabolic stability, a series of analogues were prepared by replacing the Tyr(6) residue with the non-canonical amino acids 3-(1-naphtyl)-L-alanine, 4-fluoro-L-phenylalanine, 4-methoxy-L-phenylalanine and 3-nitro-L-tyrosine. Dose-dependent nociceptive assays performed in conscious rats by intrathecal injection of the MSH peptides showed [Tyr(6)]-gamma2-MSH(6-12) hyperalgesic effects at low doses (5-20 nmol) and analgesia at high doses (100-200 nmol). This analgesic activity is fully reversed by the kyotorphin receptor-specific antagonist Leu-Arg. For the two analogues containing in position 6, 4-fluoro-L-phenylalanine and 3-nitro-L-tyrosine, a hyperalgesic activity was not observed, while the 3-(1-naphtyl)-L-alanine analogue at 10 nmol dose was found to induce hyperalgesia at a potency very similar to gamma2-MSH(6-12), but with longer duration of the effect. Finally, the 4-methoxy-L-phenylalanine analogue (0.5 nmol) showed greatly improved hyperalgesic activity and prolonged effects compared to the parent [Tyr(6)]-gamma2-MSH(6-12) compound.
Wei
Chunnan
C
Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, 222 Tianshui South Road, Lanzhou 730000, China.
Huang
Wenmin
W
Xing
Xiaoting
X
Dong
Shouliang
S
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced*; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019825:gamma-MSH / Q000008:administration & dosage / Q000494:pharmacology*
D000700:Analgesics; D004151:Dipeptides; D010446:Peptide Fragments; D019825:gamma-MSH; C553734:gamma2-MSH (6-12), Tyr(6)-; C078789:leucylarginine; D009270:Naloxone