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.