Spinal infusion of opiate and alpha-2 agonists in rats: Tolerance and cross-tolerance studies

Craig Stevens, M. S. Monasky, T. L. Yaksh

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Intrathecal morphine or ST-91, an alpha-2 agonist, produce potent antinocicpetion in a number of animal models. Using osmotic minipumps and a new Y-catheter technique, we show that chronic intrathecal (i.t.) infusion of morphine (2, 6 or 20 nmol/μl/hr) or ST-91 (3, 10 or 30 nmol/μl/hr) in rats produces a dose-dependent increase in hot-plate latency 1 day after pump implant. By 4 to 5 days after initiation of chronic infusion of either drug, hot-plate latencies do not differ from saline-infused controls. Rats rendered tolerant to one of the three chronic i.t. morphine doses (2, 6 or 20 nmol/μl/hr) and tested at 7 days after initiation of infusion with a bolus i.t. dose of morphine, show a dose-dependent rightward shift in hot-plate dose-response curves. The two lower doses of chronic i.t. infusions of morphine produce parallel shifts of the subsequent i.t. administered morphine dose-response curves, but the highest chronic i.t. dose of morphine (20 nmol/μl/hr) produces a significantly greater slope of the subsequent i.t. administered morphine dose-response curve. Animals exposed to chronic i.t. infusion of one of three doses of ST-91 (3, 10 or 30 nmol/μl/hr) display a parallel, dose-dependent rightward shift to a subsequent bolus i.t. injection of ST-91. Rats rendered tolerant to chronic i.t. infusions of ST-91 showed no difference in the response to i.t. administered morphine hot-plate dose-response curves as compared to saline infused controls. Surprisingly, however, animals rendered tolerant to i.t. infusions of morphine show a parallel, dose-dependent rightward shift to i.t. administration of ST-91. Thus, an asymmetrical cross-tolerance is demonstrated whereby rats tolerant to ST-91 show no cross-tolerance to morphine, but animals tolerant to morphine show considerable cross-tolerance to ST-91. Double-reciprocal (Lineweaver-Burk) plots reveal that dose-response curves from tolerant animals exhibit a competitive antagonistic profile.

Original languageEnglish
Pages (from-to)63-70
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume244
Issue number1
StatePublished - 1 Jan 1988

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