oxymorphone and Inflammation

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.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Hyperalgesia; Inflammation; Male; Morphine; Naloxone; Neuralgia; Oxymorphone; Pain; Rats; Rats, Wistar; Structure-Activity Relationship

1. Our recent studies in rats have demonstrated that the small-fiber excitant and inflammatory irritant mustard oil injected into the temporomandibular joint (TMJ) region can evoke a sustained and reversible increase of electromyographic (EMG) activity in jaw muscles and an acute inflammatory response. The aim of the present study was to test if opioid mechanisms are involved in modulating the EMG increase evoked by mustard oil. 2. Mustard oil injected into the rat TMJ region evoked significant increases of jaw muscle EMG activity; the vehicle mineral oil had no such effect. The increased EMG activity lasted up to 20 min, and by 30 min after the mustard oil injection had returned to control (preinjection) levels, at which time administration of the opiate antagonist naloxone (1.3 mg/kg i.v.) induced a significant recurrence of the increase in EMG activity. This "rekindling" of EMG activity appeared at 5 to 10 min after the naloxone administration and lasted for 10 to 20 min. In contrast, naloxone administration in the animals receiving mineral oil injection into the TMJ region did not "rekindle" the EMG activity, nor did the administration of the peripherally acting opiate antagonist methylnaloxone or the vehicle of naloxone. 3. These findings reveal that the application of the opiate antagonist naloxone produces a recurrence of increased jaw muscle activity reflexively evoked by mustard oil injection into the rat TMJ region. They suggest that central opioid depressive mechanisms activated by the mustard oil-induced afferent barrage limit the duration of the evoked EMG changes.

Topics: Afferent Pathways; Animals; Electromyography; Inflammation; Male; Masticatory Muscles; Mustard Plant; Naloxone; Narcotic Antagonists; Nociceptors; Oxymorphone; Plant Extracts; Plant Oils; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Recurrence; Temporomandibular Joint