The fact that 5-opioid receptors act at spinal and supraspinal sites increases the possibility that, like morphine, 5-opioid agonists may exhibit a synergistic interaction between the spinal and supraspinal sites of action. It has been clearly established that the concurrent administration of ICV and ITH morphine results in a multiplicative antinociceptive interaction [130,131]. It is this supraspinal/spinal multiplicative nature of morphine and its clinical analgesic utility at tolerable doses. Early studies with mice indicated only an additive interaction between ICV and ITH DPDPE against thermal endpoints in mice . In contrast, however, the concomitant ICV and ITH administration of DPDPE in rats demonstrated a synergistic interaction against mechanical nociception [132,133]. However, one difficulty with these studies was that either the ITH or ICV dose was held constant while the doses given at the alternate site were altered to produce dose-effect curves [132,133]. This paradigm would cause changes in dose ratio, possibly complicating the data interpretation. More recently, fixed ratios of agonists given spinally and suprsapinally were employed to allow for rigorous isobolo-graphic interpretation of additivity or synergy [134-136]. It was found that over low dose ranges, the interaction between [D-Ala2,Glu4]deltorphin given ITH and into the RVM was synergistic, and became additive at higher dose ranges . Because of its relative lack of efficacy, a dose-effect curve for RVM DPDPE was not constructed in these studies, although an additive interaction was surmised based on a modeling isobolograms when a single component is effective [134,137]. More detailed results were obtained when less intense noxious stimuli were applied (e.g., 52EC vs. 55EC hot plate, 52EC hot water vs. radiant heat tail flick; radiant heat paw withdrawal test) . A synergistic interaction was detected between RVM and spinal [D-Ala2, Glu4]deltorphin in all tests and between spinal and RVM DPDPE in all tests, with the exception of the hot plate test . The synergistic interaction between RVM and ITH [D-Ala2,Glu4]deltorphin was abolished by the ITH administration of the a2-adrenergic antagonist yohimbine . Furthermore, the concomitant spinal injection of [D-Ala2,Glu4]deltorphin with the a2-adrenergic dexmedetomidine produced a synergistic antinociceptive interaction . It was hypothesized that activation of the supraspinal 52-opioid receptors resulted in a spinal release of endogenous norepinephrine, which acts to enhance the inhibition of nociceptive inputs. Interestingly, mice made tolerant to morphine lost A-opioid spinal/supraspinal synergy, while DADLE, a relatively selective 5-opioid agonist, actually developed a multiplicative interaction, leading to the speculation that 5-opioid agonists may be clinically useful in conditions of opioid tolerance .
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