Potency of infused spinal antinociceptive agents is inversely related to magnitude of tolerance after continuous infusion

C. W. Stevens, T. L. Yaksh

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Abstract

By employing a constant-rate (1 μl/hr) constant-dose intrathecal infusion pump in rats, groups received a 7-day infusion of one of three concentrations (in nmol/hr) of each of the following receptor preferring ligands: morphine (mu: 2, 6, 20), sufentanil (mu: 0.06, 0.2, 0.6), DAMGO (mu: 0.1, 0.3, 1.0), DADLE (delta: 2, 6, 20) or ST-91 (alpha-2: 3, 10, 30). On day 7 the magnitude of tolerance was assessed by establishing i.t. dose-response curves for the effect of the chronic drug given as a bolus. Each infused animal was used for one bolus injection. It was observed that for all drugs, a parallel rightward shift in the dose-response curve was produced with the degree of shift proportional to the log of the infusion dose. Of particular significance was the finding that drugs differed significantly in the magnitude of the shift produced by the chronic infusion of equieffective concentrations. Thus, at the intermediate infusion dose, the degree of the shift in the bolus dose-response curve (i.e., magnitude of tolerance) for morphine, DADLE, ST-91, DAMGO and sufentanil was 55, 46, 29, 7 and 2, respectively. These data are interpreted to suggest that agents with high potency and a significant receptor reserve will produce a smaller shift in the dose-response curve (e.g., sufentanil and DAMGO) than the similar infusion of an equieffective dose of another agent with less potency and a smaller population of spare receptors (morphine).

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume250
Issue number1
StatePublished - 1 Jan 1989

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Ala(2)-MePhe(4)-Gly(5)-enkephalin
Sufentanil
Leucine-2-Alanine Enkephalin
Analgesics
Morphine
Pharmaceutical Preparations
Infusion Pumps
mu Opioid Receptor
Ligands
Injections
Population
ST 91

Cite this

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abstract = "By employing a constant-rate (1 μl/hr) constant-dose intrathecal infusion pump in rats, groups received a 7-day infusion of one of three concentrations (in nmol/hr) of each of the following receptor preferring ligands: morphine (mu: 2, 6, 20), sufentanil (mu: 0.06, 0.2, 0.6), DAMGO (mu: 0.1, 0.3, 1.0), DADLE (delta: 2, 6, 20) or ST-91 (alpha-2: 3, 10, 30). On day 7 the magnitude of tolerance was assessed by establishing i.t. dose-response curves for the effect of the chronic drug given as a bolus. Each infused animal was used for one bolus injection. It was observed that for all drugs, a parallel rightward shift in the dose-response curve was produced with the degree of shift proportional to the log of the infusion dose. Of particular significance was the finding that drugs differed significantly in the magnitude of the shift produced by the chronic infusion of equieffective concentrations. Thus, at the intermediate infusion dose, the degree of the shift in the bolus dose-response curve (i.e., magnitude of tolerance) for morphine, DADLE, ST-91, DAMGO and sufentanil was 55, 46, 29, 7 and 2, respectively. These data are interpreted to suggest that agents with high potency and a significant receptor reserve will produce a smaller shift in the dose-response curve (e.g., sufentanil and DAMGO) than the similar infusion of an equieffective dose of another agent with less potency and a smaller population of spare receptors (morphine).",
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