title: Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat.
abstract: Opioid analgesics with restricted access to the central nervous system represent a new approach to the treatment of severe pain with an improved safety profile. The objective of this study was to investigate the peripheral and central components of the antinociceptive actions of the 6-amino acid conjugates (glycine, alanine, and phenylalanine) of 14-O-methyloxymorphone. Their antinociceptive activities were compared with those of the centrally penetrating mu-opioid agonists morphine, fentanyl, and 14-O-methyloxymorphone. In the tail-flick test in rats, the 6-amino acid conjugates were 45- to 1170-fold more potent than morphine after i.c.v. administration and 19- to 209-fold after s.c. administration. They showed potencies similar to fentanyl after s.c. administration and were more potent after i.c.v. application. The time course of action was different between s.c. and i.c.v. administration, with significant long-lasting effects after i.c.v. administration. Systemic administration of the peripherally selective opioid antagonist naloxone methiodide antagonized the effects after s.c. but not after i.c.v. administration in the tail-flick test. Subcutaneous 6-amino acid derivatives also elicited antihyper-analgesic effects in the formalin test in rats, which were reversed by systemically administered naloxone methiodide. Although morphine exerts its analgesic effects by central and peripheral mechanisms, the investigated new opioids interact primarily with peripheral opioid receptors after s.c. administration. The present data indicate that the 6-amino acid conjugates of 14-O-methyloxymorphone have limited access to the central nervous system and can mediate antinociception at peripheral sites. Also, they might find clinical application when the central actions of opioids are unwanted.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical Faculty, Semmelweis University, Nagyvarad ter 4, P.O. Box 370, H-1445 Budapest, Hungary. furzsu@pharma.sote.hu
authors.forename: Susanna
authors.initials: S
authors.lastname: Fürst
authors.forename: Pal
authors.initials: P
authors.lastname: Riba
authors.forename: Tamas
authors.initials: T
authors.lastname: Friedmann
authors.forename: Julia
authors.initials: J
authors.lastname: Tímar
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Khrasani
authors.forename: Ilona
authors.initials: I
authors.lastname: Obara
authors.forename: Wioletta
authors.initials: W
authors.lastname: Makuch
authors.forename: Mariana
authors.initials: M
authors.lastname: Spetea
authors.forename: Johannes
authors.initials: J
authors.lastname: Schütz
authors.forename: Ryszard
authors.initials: R
authors.lastname: Przewlocki
authors.forename: Barbara
authors.initials: B
authors.lastname: Przewlocka
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidhammer
mesh_terms: D000208:Acute Disease; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000494:pharmacology; D005557:Formaldehyde; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D017933:Peripheral Nervous System / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects
chemical_list: D000700:Analgesics; D009022:Morphine Derivatives; D005557:Formaldehyde; D009020:Morphine; D005283:Fentanyl