TY - JOUR
T1 - Guanine nucleotide-binding protein-coupled and -uncoupled states of opioid receptors and their relevance to the determination of subtypes
AU - Richardson, A.
AU - Demoliou-Mason, C.
AU - Barnard, E. A.
PY - 1992
Y1 - 1992
N2 - Opioid receptors are currently classified as μ, δ, and κ types, but various subtypes have also been proposed. We have investigated whether subtypes exist by using [
3H]bremazocine. [
3H]Bremazocine binds to twice as many naloxone-sensitive sites as other nonselective opioid agonists, as shown in four membrane types that have very different ratios of μ, δ, and κ receptor types. [
3H]Bremazocine binding is completely inhibited by an excess (in unlabeled form) of other opioid ligands, with Hill coefficients of 0.8- 0.95. These paradoxes can be explained if there are high- and low-affinity states of the μ, δ, and κ receptors and bremazocine binds with similar affinities to both states. We propose that these states are the guanine nucleotide-binding protein (G-protein)-coupled form and the uncoupled form of each receptor. As evidence for this proposal, the [
3H]bremazocine binding suffered little or no loss with G-protein-uncoupling treatments, whereas binding of other opioid agonists was fully sensitive. We conclude that [
3H]bremazocine offers a tool for the measurement of the total pools of coupled and uncoupled opioid receptors and that much of the previous characterization of opioid receptor subtypes reflects, instead, a significant pool of G-protein-uncoupled opioid receptors.
AB - Opioid receptors are currently classified as μ, δ, and κ types, but various subtypes have also been proposed. We have investigated whether subtypes exist by using [
3H]bremazocine. [
3H]Bremazocine binds to twice as many naloxone-sensitive sites as other nonselective opioid agonists, as shown in four membrane types that have very different ratios of μ, δ, and κ receptor types. [
3H]Bremazocine binding is completely inhibited by an excess (in unlabeled form) of other opioid ligands, with Hill coefficients of 0.8- 0.95. These paradoxes can be explained if there are high- and low-affinity states of the μ, δ, and κ receptors and bremazocine binds with similar affinities to both states. We propose that these states are the guanine nucleotide-binding protein (G-protein)-coupled form and the uncoupled form of each receptor. As evidence for this proposal, the [
3H]bremazocine binding suffered little or no loss with G-protein-uncoupling treatments, whereas binding of other opioid agonists was fully sensitive. We conclude that [
3H]bremazocine offers a tool for the measurement of the total pools of coupled and uncoupled opioid receptors and that much of the previous characterization of opioid receptor subtypes reflects, instead, a significant pool of G-protein-uncoupled opioid receptors.
KW - κ receptors
KW - arylacetamides
KW - bremazocine
UR - http://www.scopus.com/inward/record.url?scp=0026498187&partnerID=8YFLogxK
U2 - 10.1073/pnas.89.21.10198
DO - 10.1073/pnas.89.21.10198
M3 - Article
C2 - 1332034
AN - SCOPUS:0026498187
SN - 0027-8424
VL - 89
SP - 10198
EP - 10202
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -