TY - JOUR
T1 - Standard opioid agonists activate heteromeric opioid receptors
T2 - Evidence for morphine and [ d -Ala2-MePhe4-Glyol 5]enkephalin as selective μ-delta; Agonists
AU - Yekkirala, Ajay S.
AU - Kalyuzhny, Alexander E.
AU - Portoghese, Philip S.
PY - 2010
Y1 - 2010
N2 - Research in the opioid field has relied heavily on the use of standard agonist ligands such as morphine, [D-Ala2-MePhe4- Glyol5]enkephalin (DAMGO), U69593, bremazocine, [D-Pen 2d-Pen5]enkephalin (DPDPE), and deltorphin-II as tools for investigating the three major types of opioid receptors, MOP (μ), KOP (κ), and DOP (δ), that mediate antinociception. The functional selectivity of these ligands has been based on the assumption that opioid receptors exist as homomers. As numerous studies in cultured cells have suggested that opioid receptors can associate both as homomers and heteromers, we have investigated the selectivity of these standard ligands using intracellular calcium release and [35S]GTPγS assays in HEK-293 cells that contain singly and coexpressed opioid receptors. The present study reveals that morphine and DAMGO, traditionally classified as μ selective agonists, selectively activate μ-δ heteromeric opioid receptors with greater efficacy than homomeric opioid receptors. Moreover, standard ligands that have been widely employed as κ- and δ-selective agonists display little or no differences in the activation of homomeric and heteromeric opioid receptors. The far-reaching implications of these results are discussed.
AB - Research in the opioid field has relied heavily on the use of standard agonist ligands such as morphine, [D-Ala2-MePhe4- Glyol5]enkephalin (DAMGO), U69593, bremazocine, [D-Pen 2d-Pen5]enkephalin (DPDPE), and deltorphin-II as tools for investigating the three major types of opioid receptors, MOP (μ), KOP (κ), and DOP (δ), that mediate antinociception. The functional selectivity of these ligands has been based on the assumption that opioid receptors exist as homomers. As numerous studies in cultured cells have suggested that opioid receptors can associate both as homomers and heteromers, we have investigated the selectivity of these standard ligands using intracellular calcium release and [35S]GTPγS assays in HEK-293 cells that contain singly and coexpressed opioid receptors. The present study reveals that morphine and DAMGO, traditionally classified as μ selective agonists, selectively activate μ-δ heteromeric opioid receptors with greater efficacy than homomeric opioid receptors. Moreover, standard ligands that have been widely employed as κ- and δ-selective agonists display little or no differences in the activation of homomeric and heteromeric opioid receptors. The far-reaching implications of these results are discussed.
KW - Heterodimers
KW - Heteromers
KW - Morphine
KW - Opioid
KW - Receptors
KW - Standard opioids
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U2 - 10.1021/cn9000236
DO - 10.1021/cn9000236
M3 - Article
C2 - 22816017
AN - SCOPUS:77952949502
SN - 1948-7193
VL - 1
SP - 146
EP - 154
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 2
ER -