The tolerance effects of continuous intrathecal infusions of opioids at mu and delta receptors were studied in rats. These effects were compared to those of chronic systemic morphine. A chronic intrathecal infusion of the relatively selective delta agonist, [D-Ala2, D-Leu5]enkephalin (DADLE), produced a larger degree of tolerance to DADLE than to the highly specific mu-activating morphiceptin analog [N-methyl-Phe3, D-Pro4] morphiceptin (PL017). The slope of the analgesic dose-response curve for the highly specific delta agonist, cyclic [D-Penicillamine2, D-Penicillamine5]enkephalin (DPDPE), was significantly different (flatter) from those of mu agonists or DADLE. High-dose infusion of PL017 induced a 61-fold parallel shift of the dose-response curve for PL017. This same treatment also induced a corresponding flattened, nonparallel change of the dose-response curve for DADLE. This altered curve for DADLE was very similar in slope to that of DPDPE. Pretreatment with the irreversible mu antagonist, β-funaltrexamine, caused a parallel rightward shift of the dose-response curve for PL017 but did not affect DPDPE activity. β-Funaltrexamine treatment induced a nonparallel rightward shift of the dose-response curve for DADLE with a change of slope similar to that of DPDPE. These findings demonstrate a mixed mu-delta analgesic activity for the compound DADLE, which is often referred to as a prototypic delta agonist. These interactions differ from prior reports of none or minimal mu-ligand interactions with DADLE. Despite the cross-reactivity of DADLE to mu receptors, DADLE remains a more effective analgesic than do mu agonists in states of mu receptor tolerance. Furthermore, we showed a 6-fold parallel rightward shift of the dose-response curve for DPDPE after our highest dose PL017 infusion. In view of the high degrees of distinct receptor-selectivities of PL017 and DPDPE, this finding seems to support the hypothesis of some direct mu-delta receptor interactions.
|Number of pages
|Journal of Pharmacology and Experimental Therapeutics
|Published - Jun 25 1987
ASJC Scopus subject areas
- Molecular Medicine