Continuous intrathecal opioid analgesia: Tolerance and cross-tolerance of mu and delta spinal opioid receptors

R. D. Russell, J. B. Leslie, Y. F. Su, W. D. Watkins, K. J. Chang

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)150-158
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume240
Issue number1
StatePublished - 1987
Externally publishedYes

Fingerprint

delta Opioid Receptor
Analgesia
Opioid Analgesics
mu Opioid Receptor
Analgesics
Ala(2)-enkephalinamide-met

ASJC Scopus subject areas

  • Pharmacology

Cite this

Continuous intrathecal opioid analgesia : Tolerance and cross-tolerance of mu and delta spinal opioid receptors. / Russell, R. D.; Leslie, J. B.; Su, Y. F.; Watkins, W. D.; Chang, K. J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 240, No. 1, 1987, p. 150-158.

Research output: Contribution to journalArticle

Russell, R. D. ; Leslie, J. B. ; Su, Y. F. ; Watkins, W. D. ; Chang, K. J. / Continuous intrathecal opioid analgesia : Tolerance and cross-tolerance of mu and delta spinal opioid receptors. In: Journal of Pharmacology and Experimental Therapeutics. 1987 ; Vol. 240, No. 1. pp. 150-158.
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