title: Peripheral antinociceptive effects of the cyclic endomorphin-1 analog c[YpwFG] in a mouse visceral pain model.
abstract: We previously described a novel cyclic endomorphin-1 analog c[Tyr-D-Pro-D-Trp-Phe-Gly] (c[YpwFG]), acting as a mu-opioid receptor (MOR) agonist. This study reports that c[YpwFG] is more lipophilic and resistant to enzymatic hydrolysis than endomorphin-1 and produces preemptive antinociception in a mouse visceral pain model when injected intraperitoneally (i.p.) or subcutaneously (s.c.) before 0.6% acetic acid, employed to evoke abdominal writhing (i.p. ED(50)=1.24 mg/kg; s.c. ED(50)=2.13 mg/kg). This effect is reversed by the selective MOR antagonist β-funaltrexamine and by a high dose of the mu(1)-opioid receptor-selective antagonist naloxonazine. Conversely, the kappa-opioid receptor antagonist nor-binaltorphimine and the delta-opioid receptor antagonist naltrindole are ineffective. c[YpwFG] produces antinociception when injected i.p. after acetic acid (ED(50)=4.80 mg/kg), and only at a dose of 20mg/kg did it elicit a moderate antinociceptive response in the mouse, evaluated by the tail flick assay. Administration of a lower dose of c[YpwFG] (10mg/kg i.p.) apparently produces a considerable part of antinociception on acetic acid-induced writhes through peripheral opioid receptors as this action is fully prevented by i.p. naloxone methiodide, which does not readily cross the blood-brain barrier; whereas this opioid antagonist injected intracerebroventricularly (i.c.v.) is not effective. Antinociception produced by a higher dose of c[YpwFG] (20mg/kg i.p.) is partially reversed by naloxone methiodide i.c.v. administered. Thus, only at the dose of 20mg/kg c[YpwFG] can produce antinociception through both peripheral and central opioid receptors. In conclusion, c[YpwFG] displays sufficient metabolic stability to be effective after peripheral administration and demonstrates the therapeutic potential of endomorphin derivatives as novel analgesic agents to control visceral pain.
authors: Department of Pharmacology, University of Bologna, Irnerio 48, 4126 Bologna, Italy.
authors: Andrea
authors: A
authors: Bedini
authors: Monica
authors: M
authors: Baiula
authors: Luca
authors: L
authors: Gentilucci
authors: Alessandra
authors: A
authors: Tolomelli
authors: Rossella
authors: R
authors: De Marco
authors: Santi
authors: S
authors: Spampinato
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D051379:Mice; D009270:Naloxone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000517:prevention & control*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: D000700:Analgesics; D009292:Narcotic Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017450:Receptors, Opioid, mu; C492968:cyclo(tyrosyl-prolyl-tryptophyl-phenylalanyl-glycyl); C105293:endomorphin 1; D009270:Naloxone; D009271:Naltrexone; C024524:beta-funaltrexamine; C034643:naloxonazine