Analgesic Mechanism of Opioid Analgesics at the Spinal Level. 1. Investigation of the Role of Opiate Receptor Subtypes

This study was undertaken to examine the antinociceptive role of mu, delta and kappa opiate receptor subtypes which could be involved in spinal morphine suppression of noxiously evoked activity of spinal wide dynamic range （WDR） neurons. We extracellularly recorded the activity of a single WDR neuron evoked by noxious radiant heat （51℃） in decerebrate, spinally transected cats. In the first study, spinally administered morphine （n=22）, DAGO （selective mu agonist, n=28）, DADL （delta/mu agonist, n=17） and DPDPE （selective delta agonist, n=25）, but not U-50,488H （selective kappa agonist, n=11）, produced a significant suppression of the evoked activity in time and dose-dependent manners. In addition, intravenous naloxone （non-selective opiate antagonist） reversed the suppressive effects of all opiates studied. Intravenous ICI174,864 （selective delta antagonist） reversed the effect of DPDPE. The purpose of the second study was to evaluate the relative role of mu and delta opiate receptors in morphine suppression of noxiously evoked activity. Pretreatment with spinal β-FNA （selective mu antagonist） antagonized the suppressive effects of spinal DAGO, but not that of DPDPE. Following β-FNA pretreatment, the suppression of morphine （200 or 400 μg） was partially antagonized, however, when ICI174,864 was co-administered with morphine in β-FNA pretreated animals, there was even greater antagonism of the neuronal suppression by morphine at these dosages. In the third study, we investigated the interaction between mu and delta receptors at the spinal level. Ineffective and effective dosage of DAGO （1 or 1.5 μg, respectively） were combined with an ineffective dosage of DPDPE （30 μg）. The spinal combination of DAGO and DPDPE produced synergistic suppressive effects. These results indicate that both mu and delta opiate receptors can modulate the input of somatic nociceptive information in the spinal dorsal horn and that morphine is capable of suppressing the evoked activity of WDR neurons as a result of interaction with delta receptors in addition to mu ?receptors at the spinal level. Furthermore, the synergism of mu and delta agonist suggests that the antinociceptive effects of morphine, which possess both mu and delta receptor agonists, could be a result of this synergism due to activation of both mu and delta receptors.departmental bulletin pape