It had been proposed that different receptor sites in the CNS mediate opioid-related analgesia and respiratory impairment . Such difference has also been demonstrated for fentanyl-analogues in the animal , suggesting a clinical relevance for reversal of respiratory impairment, however at the same time maintaining antinoci-ception. Such connotation was further corroborated by experimental data where the selective antagonist naloxonazine was able to reverse opioid induced analgesia, but not respiratory impairment. This led to the assumption that ^-opioid subreceptors are involved in the mediation of opioid-induced respiratory depression (i.e. ^ and [55, 56]. Clinical data seem to underline this assumption, as low doses of sufentanil demonstrated a lesser respiratory depressive effect and a higher analgesic potency when compared to fentanyl. Such difference in action reportedly is due to a disparity in receptor affinity to ^-subsites, with a higher affinity to the and a lesser affinity to the ^-receptor .
Other experiments, however, suggest that the co-binding of ^-selective ligands to the 8-receptor results in respiratory impairment. Subanalgesic doses of the 8-selective ligand D-Ala2-D-Leu-Enkephalin, when co-administered with morphine, induced a potentiation of analgesia, while another 8-ligand D-Ala2-Met-Enkephalinamid produced a reduction in analgesia . Such 8-related differentiation in efficacy was also seen with the potent ligand sufentanil. There respiratory impairment was reversed while at the same time maintaining antinociception using the highly selective 8-antagonists naltrindol and naltribene respectively  (Figure II-38).
The implication of ^/8-receptor interaction is further supported by receptor binding studies, where sufentanil demonstrates higher 8-selectivity than fentanyl (Table II-9).
Such putative interaction between and 8-receptors is further corroborated when co-administering intrathecally a and a 8-selective ligand resulted in a potentiation of effects . From such data it can be concluded that a coupling mechanism between the and 8-opioid receptor not only seems to result in an increase in analgesia, but at the same time also seems to cause respiratory depression. Such coupling mechanisms may result in a modulation to potentiation of effects whereby it is still uncertain whether both sites independently operate from each other or whether the 8-receptor only accentuates the effects induced by ^-binding.
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