Antinociception achieved after peripheral administration of
opioids has opened a new approach to the treatment of severe and
chronic pain. Additionally,
opioid analgesics with restricted access to the central nervous system could improve safety of
opioid drugs used in clinical practice. In the present study, peripheral components of antinociceptive actions of 6-amino
acid-substituted derivatives of
14-O-methyloxymorphone were investigated after local intraplantar (i.pl.) administration in rat models of inflammatory and
neuropathic pain. Their antinociceptive activities were compared with those of
morphine, the classical
mu-opioid receptor agonist. Intraplantar administration of
morphine and the 6-amino
acid derivatives produced dose-dependent reduction of
formalin-induced flinching of the inflamed paw, without significant effect on the paw
edema. Local i.pl. administration of the new derivatives in rats with
neuropathic pain induced by sciatic nerve
ligation produced antiallodynic and antihyperalgesic effects; however, the antinociceptive activity was lower than that observed in inflammatory
pain. In both models, the 6-amino
acid derivatives and
morphine at doses that produced
analgesia after i.pl. administration were systemically (s.c.) much less active indicating that the antinociceptive action is due to a local effect. Moreover, the local
opioid antinociceptive effects were significantly attenuated by
naloxone methiodide, a peripherally acting
opioid receptor antagonist, demonstrating that the effect was mediated by peripheral
opioid receptors. The present data indicate that the peripherally restricted 6-amino
acid conjugates of
14-O-methyloxymorphone elicit antinociception after local administration, being more potent in inflammatory than in
neuropathic pain.
Opioid drugs with peripheral site of action can be an important target for the treatment of long lasting
pain.