Received for publication July 28, 2004.
Revised September 16, 2004.
Accepted for publication September 21, 2004.

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, phenylalanine) of 14-O-methyloxymorphone. Their antinociceptive activities were compared to 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 intracerebroventricular (i.c.v.) administration, and 19- to 209-fold after subcutaneous (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. While 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.

Key words: Peripheral site of action, antinociception, formalin, opioids, quaternary opiate antagonists, tailflick

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