Co-administration of δ- and μ-opioid receptor agonists promotes peripheral opioid receptor function

Enhancement of peripheral opioid analgesia following tissue injury or inflammation in animal models is well-documented, but clinical results of peripheral opioid therapy remain inconsistent. Previous studies in the central nervous system have shown that co-administration of mu- and delta-opioid receptor agonists can enhance analgesic outcomes; however, less is known about the functional consequences of opioid receptor interactions in the periphery. The present study examines the effects of intraplantar injection of the mu- and delta-opioid receptor agonists, morphine and deltorphin, alone and in combination on behavioral tests of nociception in naive rats and on potassium-evoked release of CGRP from sciatic nerves of naive rats. Neither drug alone affected nociceptive behaviors or CGRP release. Two separate measures of mechanical nociceptive sensitivity remained unchanged after co-administration of the two drugs. In contrast, when deltorphin was co-injected with morphine, dose-dependent and peripherally restricted increases in paw withdrawal latencies to radiant heat were observed. Similarly, concentration-dependent inhibition of CGRP release was observed when deltorphin and morphine were administered in sequence prior to potassium stimulation. However, no inhibition was observed when morphine was administered prior to deltorphin. All combined opioid effects were blocked by co-application of antagonists. Deltorphin exposure also enhanced the in vivo and in vitro effects of another mu-opioid receptor agonist, DAMGO. Together, these results suggest that under normal conditions, delta-opioid receptor agonists enhance the effect of mu-opioid receptor agonists in the periphery, and local co-administration of delta- and mu-opioid receptor agonists may improve results of peripheral opioid therapy for the treatment of pain. (C) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.