Document Detail

Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain.
MedLine Citation:
PMID:  18246198     Owner:  NLM     Status:  MEDLINE    
Although opioids are highly effective analgesics, they are also known to induce cellular adaptations resulting in tolerance. Experimental studies are often performed in the absence of painful tissue injury, which precludes extrapolation to the clinical situation. Here we show that rats with chronic morphine treatment do not develop signs of tolerance at peripheral mu-opioid receptors (micro-receptors) in the presence of painful CFA-induced paw inflammation. In sensory neurons of these animals, internalization of mu-receptors was significantly increased and G protein coupling of mu-receptors as well as inhibition of cAMP accumulation were preserved. Opioid receptor trafficking and signaling were reduced, and tolerance was restored when endogenous opioid peptides in inflamed tissue were removed by antibodies or by depleting opioid-producing granulocytes, monocytes, and lymphocytes with cyclophosphamide (CTX). Our data indicate that the continuous availability of endogenous opioids in inflamed tissue increases recycling and preserves signaling of mu-receptors in sensory neurons, thereby counteracting the development of peripheral opioid tolerance. These findings infer that the use of peripherally acting opioids for the prolonged treatment of inflammatory pain associated with diseases such as chronic arthritis, inflammatory neuropathy, or cancer, is not necessarily accompanied by opioid tolerance.
Christian Zöllner; Shaaban A Mousa; Oliver Fischer; Heike L Rittner; Mohammed Shaqura; Alexander Brack; Mehdi Shakibaei; Waltraud Binder; Florian Urban; Christoph Stein; Michael Schäfer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  118     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-04     Completed Date:  2008-04-22     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1065-73     Citation Subset:  AIM; IM    
Klinik für Anaesthesiologie und operative Intensivmedizin, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
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MeSH Terms
Cells, Cultured
Cyclophosphamide / pharmacology
Drug Tolerance
Fentanyl / therapeutic use
Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
Inflammation / physiopathology
Morphine / therapeutic use*
Neurons, Afferent / pathology
Pain / drug therapy*
Rats, Wistar
Receptors, Opioid, mu / metabolism
beta-Endorphin / physiology
Reg. No./Substance:
0/Receptors, Opioid, mu; 37589-80-3/Guanosine 5'-O-(3-Thiotriphosphate); 437-38-7/Fentanyl; 50-18-0/Cyclophosphamide; 57-27-2/Morphine; 60617-12-1/beta-Endorphin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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