Journal
EUROPEAN JOURNAL OF PAIN
Volume 16, Issue 3, Pages 327-337Publisher
WILEY PERIODICALS, INC
DOI: 10.1002/j.1532-2149.2011.00022.x
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Funding
- Foundation for Alcohol Research/ABMRF (RMvR) Department of Defense [DAMD62-10-5-071]
- National Institute on Alcohol Abuse and Alcoholism [AA017072-03]
- National Institute on Drug Abuse [DA015232, DA019958]
- State of California for medical research on alcohol and substance abuse through the University of California, San Francisco
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Molecular cloning has identified three opioid receptors: mu (MOR), delta (DOR) and kappa (KOR). Yet, cloning of these receptor types has offered little clarification to the diverse pharmacological profiles seen within the growing number of novel opioid ligands, which has led to the proposal of multiple subtypes. In the present study, utilizing in vitro and in vivo methods including the use of opioid receptor knockout mice, we find that certain antinociceptive effects of the KOR-1 and KOR-2 subtype-selective ligands (+)-(5 alpha,7 alpha,8 beta)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzene-acetamide (U69, 593) and 4-[(3,4-Dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazine-carboxylic acid methyl ester fumarate (GR89, 696), respectively, are potentiated by antagonism of MOR and DOR receptors. We believe that our findings can be best explained by the existence of KOR-DOR and KOR-MOR heteromers. We only find evidence for the existence of these heteromers in neurons mediating mechanical nociception, but not thermal nociception. These findings have important clinical ramifications as they reveal new drug targets that may provide avenues for more effective pain therapies.
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