Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat

S. Fürst, P. Riba, Tamas Friedmann, Julia Tímar, M. Al-Khrasani, Ilona Obara, Wioletta Makuch, Mariana Spetea, Johannes Schütz, Ryszard Przewlocki, Barbara Przewlocka, Helmut Schmidhammer

Research output: Contribution to journalArticle

57 Citations (Scopus)

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 μ-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 antihyperalgesic 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.

Original languageEnglish
Pages (from-to)609-618
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume312
Issue number2
DOIs
Publication statusPublished - Feb 2005

Fingerprint

Acute Pain
Opioid Analgesics
Morphine
Amino Acids
Fentanyl
Tail
Central Nervous System
Narcotic Antagonists
Opioid Receptors
Pain Measurement
Phenylalanine
Alanine
Glycine
Analgesics
Safety
Pain
14-O-methyloxymorphone
N-methylnaloxone
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat. / Fürst, S.; Riba, P.; Friedmann, Tamas; Tímar, Julia; Al-Khrasani, M.; Obara, Ilona; Makuch, Wioletta; Spetea, Mariana; Schütz, Johannes; Przewlocki, Ryszard; Przewlocka, Barbara; Schmidhammer, Helmut.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 312, No. 2, 02.2005, p. 609-618.

Research output: Contribution to journalArticle

Fürst, S. ; Riba, P. ; Friedmann, Tamas ; Tímar, Julia ; Al-Khrasani, M. ; Obara, Ilona ; Makuch, Wioletta ; Spetea, Mariana ; Schütz, Johannes ; Przewlocki, Ryszard ; Przewlocka, Barbara ; Schmidhammer, Helmut. / Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat. In: Journal of Pharmacology and Experimental Therapeutics. 2005 ; Vol. 312, No. 2. pp. 609-618.
@article{092ce663e2d04dce9ce8402858b8dc00,
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 μ-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 antihyperalgesic 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.",
author = "S. F{\"u}rst and P. Riba and Tamas Friedmann and Julia T{\'i}mar and M. Al-Khrasani and Ilona Obara and Wioletta Makuch and Mariana Spetea and Johannes Sch{\"u}tz and Ryszard Przewlocki and Barbara Przewlocka and Helmut Schmidhammer",
year = "2005",
month = "2",
doi = "10.1124/jpet.104.075176",
language = "English",
volume = "312",
pages = "609--618",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat

AU - Fürst, S.

AU - Riba, P.

AU - Friedmann, Tamas

AU - Tímar, Julia

AU - Al-Khrasani, M.

AU - Obara, Ilona

AU - Makuch, Wioletta

AU - Spetea, Mariana

AU - Schütz, Johannes

AU - Przewlocki, Ryszard

AU - Przewlocka, Barbara

AU - Schmidhammer, Helmut

PY - 2005/2

Y1 - 2005/2

N2 - 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 μ-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 antihyperalgesic 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.

AB - 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 μ-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 antihyperalgesic 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.

UR - http://www.scopus.com/inward/record.url?scp=19944432736&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=19944432736&partnerID=8YFLogxK

U2 - 10.1124/jpet.104.075176

DO - 10.1124/jpet.104.075176

M3 - Article

C2 - 15383636

AN - SCOPUS:19944432736

VL - 312

SP - 609

EP - 618

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -