Abstract
Our laboratory demonstrated that morphine exhibits a modulatory control over the glyburide-binding site (sulfonylurea receptor) of the ATP-gated K+ channel. This study evaluated the effect of chronic morphine administration on the sulfonylurea receptor during tolerance and physical dependence. ICR and Swiss-Webster mice were rendered tolerant to morphine by pellet implantation and were withdrawn by pellet removal. Alterations in the Bmaxand KD were evaluated in mouse spinal cord using the radiolabeled ATP-gated K+ channel blocker glyburide. The ED50 for Swiss-Webster mice shifted from 13 to 451 mg/kg and thus they were more tolerant to morphine than ICR mice (ED50 shift from 12 to 120 mg/kg). Swiss-Webster mice were also dependent to morphine only when the morphine pellet was in place, unlike ICR mice, which were dependent for 48 h after morphine pellet removal. Glyburide binding increased during chronic morphine treatment in Swiss-Webster mice by over 2-fold (from 294 to 635 fmol/mg of protein). This was not observed in ICR mice. In Swiss-Webster mice, chronic morphine treatment also significantly increased theKD by 3-fold (from 0.38 to 1.1 nM), whereas there was no change in affinity for ICR mice. Both strains of mice remained tolerant for 2 days after spontaneous withdrawal from morphine. However, the only increases in theBmax and KD of glyburide were observed in Swiss-Webster mice that were highly tolerant to morphine. These results indicate that a high degree of tolerance is needed to alter ATP-gated potassium channels.
Footnotes
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Send reprint requests to: Sandra P. Welch, Ph.D., Department of Pharmacology, P.O. Box 980613, MCV Station, Richmond, VA 23298-0613. E-mail: swelch{at}hsc.vcu.edu
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↵1 This work was supported by the National Institute on Drug Abuse Grants KO2DA00186, DA01647, and T32DA07027.
- Abbreviations:
- KATP
- adenosine 5′-triphosphate-gated potassium channel
- i.t.
- intrathecal
- M6G
- morphine 6-β-d-glucuronide
- %MPE
- percentage of the maximum possible effect
- MOR-1
- μ-opioid receptor-1
- Received January 18, 2000.
- Accepted August 25, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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