Tolerance to repeated morphine administration is associated with increased potency of opioid agonists

Susan L Ingram; Tara A Macey; Erin N Fossum; Michael M Morgan

doi:10.1038/sj.npp.1301634

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Tolerance to repeated morphine administration is associated with increased potency of opioid agonists

Journal article

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Peer reviewed

Tolerance to repeated morphine administration is associated with increased potency of opioid agonists

Susan L Ingram, Tara A Macey, Erin N Fossum and Michael M Morgan

Neuropsychopharmacology (New York, N.Y.), Vol.33(10), pp.2494-2504

09/2008

DOI: https://doi.org/10.1038/sj.npp.1301634

Handle:

https://hdl.handle.net/2376/107982

PMCID: PMC5688517

PMID: 18046309

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https://doi.org/10.1038/sj.npp.1301634View

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Abstract

Brain Chemistry - drug effects

Naltrexone - analogs & derivatives

Receptors, Opioid - agonists

G Protein-Coupled Inwardly-Rectifying Potassium Channels - drug effects

Periaqueductal Gray - drug effects

Analgesics, Opioid - pharmacology

Drug Tolerance - physiology

Male

Enkephalin, Methionine - pharmacology

Dose-Response Relationship, Drug

Morphine Dependence - physiopathology

Naltrexone - pharmacology

G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism

Disease Models, Animal

Receptors, Opioid - metabolism

Receptors, Opioid, mu - metabolism

Rats

Receptors, Opioid, mu - antagonists & inhibitors

Rats, Sprague-Dawley

Periaqueductal Gray - metabolism

Brain Chemistry - physiology

Periaqueductal Gray - physiopathology

Morphine Dependence - metabolism

Animals

Narcotic Antagonists - pharmacology

Tolerance to the pain-relieving effects of opiates limits their clinical use. Although morphine tolerance is associated with desensitization of mu-opioid receptors, the underlying cellular mechanisms are not understood. One problem with the desensitization hypothesis is that acute morphine does not readily desensitize mu-opioid receptors in many cell types. Given that neurons in the periaqueductal gray (PAG) contribute to morphine antinociception and tolerance, an understanding of desensitization in PAG neurons is particularly relevant. Opioid activity in the PAG can be monitored with activation of G-protein-mediated inwardly rectifying potassium (GIRK) currents. The present data show that opioids have a biphasic effect on GIRK currents in morphine tolerant rats. Opioid activation of GIRK currents is initially potentiated in morphine (EC(50)=281 nM) compared to saline (EC(50)=8.8 microM) pretreated rats as indicated by a leftward shift in the concentration-response curve for met-enkephalin (ME)-induced currents. These currents were inhibited by superfusion of the mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) suggesting that repeated morphine administration enhances agonist stimulation of mu-opioid receptor coupling to G-proteins. Although supersensitivity of mu-opioid receptors in the PAG is counterintuitive to the development of tolerance, peak GIRK currents from tolerant rats desensitized more than currents from saline pretreated rats (56% of peak current after 10 min compared to 15%, respectively). These data indicate that antinociceptive tolerance may be triggered by enhanced agonist potency resulting in increased desensitization of mu-opioid receptors.

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Title: Tolerance to repeated morphine administration is associated with increased potency of opioid agonists
Creators: Susan L Ingram - Department of Psychology, WSU Vancouver, Vancouver, WA 98686, USA. ingram@vancouver.wsu.edu
Tara A Macey
Erin N Fossum
Michael M Morgan
Publication Details: Neuropsychopharmacology (New York, N.Y.), Vol.33(10), pp.2494-2504
Academic Unit: Psychology, Department of
Publisher: England
Grant note: R21 DA019879 / NIDA NIH HHS R01 DA015498 / NIDA NIH HHS DA015498 / NIDA NIH HHS
Identifiers: 99900546757001842
Language: English
Resource Type: Journal article