title: Antinociception by a peripherally administered novel endomorphin-1 analogue containing beta-proline.
abstract: We previously described a novel endomorphin-1 analogue (Tyr-L-beta-Pro-Trp-Phe-NH(2); Endo1-beta-Pro) more resistant to enzymatic hydrolysis than endomorphin-1 that acts as a mu-opioid receptor agonist. In this study we report that Endo1-beta-Pro, s.c. injected in the mouse, is an effective antinociceptive agent in the tail flick (ED(50)=9.2 mg/kg) and acetic acid-induced abdominal constriction (ED(50)=1.2 mg/kg) tests. Moreover, s.c. Endo1-beta-Pro significantly decreases, in the mouse, the gastrointestinal propulsion measured as transit of an orally administered charcoal meal (ED(50)=10.0 mg/kg). Subcutaneous beta-funaltrexamine or a high dose of the mu(1)-opioid receptor-selective antagonist naloxonazine (50 mg/kg) prevents the antinociceptive and antitransit action of Endo1-beta-Pro; moreover, these effects are partially blocked by i.c.v. naloxone or by i.p. naloxone methiodide, this latter does not readily cross the blood-brain barrier. On the contrary, the kappa-opioid receptor antagonist nor-binaltorphimine or the delta-opioid receptor antagonist naltrindole are ineffective Thus, Endo1-beta-Pro may act, preferentially, through central and peripheral mu(2)-opioid receptors to produce antinociception and to inhibit gastrointestinal transit. Endo1-beta-Pro is among the first endomorphin-1 analogues showing antinociceptive activity after systemic administration. This compound will be extremely useful for exploring the pharmacological profile of endomorphins in vivo and confirms the potential therapeutic interest of endomorphin derivatives as novel analgesic agents.
authors.affiliation: Department of Pharmacology, University of Bologna, Irnerio 48, 40126 Bologna, Italy. spampi@biocfarm.unibo.it
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
authors.forename: Ahmed R
authors.initials: AR
authors.lastname: Qasem
authors.forename: Maria
authors.initials: M
authors.lastname: Calienni
authors.forename: Giovanna
authors.initials: G
authors.lastname: Murari
authors.forename: Luca
authors.initials: L
authors.lastname: Gentilucci
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tolomelli
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cardillo
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D009842:Oligopeptides; C105293:endomorphin 1; D011392:Proline; C072401:beta-proline