TY - JOUR
T1 - N-naphthoyl-β-naltrexamine (NNTA), a highly selective and potent activator of μ/κ-opioid heteromers
AU - Yekkirala, Ajay S.
AU - Lunzer, Mary M.
AU - McCurdy, Christopher R.
AU - Powers, Michael D.
AU - Kalyuzhny, Alexander E.
AU - Roerig, Sandra C.
AU - Portoghese, Philip S.
PY - 2011/3/22
Y1 - 2011/3/22
N2 - Numerous G protein-coupled receptors (GPCRs) have been shown to form heteromeric receptors in cell-based assays. Among the many heteromers reported in the opioid receptor family are μ/κ, κ/δ, and μ/δ. However, the in vivo physiological and behavioral relevance for the proposed heteromers have not yet been established. Here we report a unique example of a ligand, N-naphthoyl-β-naltrexamine (NNTA) that selectively activates heteromeric μ/κ-opioid receptors in HEK-293 cells and induces potent antinociception in mice. NNTA was an exceptionally potent agonist in cells expressing μ/κ-opioid receptors. Intriguingly, it was found to be a potent antagonist in cells expressing only μ-receptors. In the mouse tail-flick assay, intrathecal (i.t.) NNTA produced antinociception that was ∼100-fold greater than by intracerebroventricular (i.c.v.) administration. The κ-antagonist, norBNI, decreased the i.t. potency, and the activity was virtually abolished in μ-opioid receptor knockout mice. No tolerance was induced i.t., but marginal tolerance (3-fold) was observed via the i.c.v. route. Moreover, NNTA produced neither significant physical dependence nor place preference in the ED50 dose range. Taken together, this work provides an important pharmacologic tool for investigating the in vivo functional relevance of heteromeric μ/κ-opioid receptors and suggests an approach to potent analgesics with fewer deleterious side effects.
AB - Numerous G protein-coupled receptors (GPCRs) have been shown to form heteromeric receptors in cell-based assays. Among the many heteromers reported in the opioid receptor family are μ/κ, κ/δ, and μ/δ. However, the in vivo physiological and behavioral relevance for the proposed heteromers have not yet been established. Here we report a unique example of a ligand, N-naphthoyl-β-naltrexamine (NNTA) that selectively activates heteromeric μ/κ-opioid receptors in HEK-293 cells and induces potent antinociception in mice. NNTA was an exceptionally potent agonist in cells expressing μ/κ-opioid receptors. Intriguingly, it was found to be a potent antagonist in cells expressing only μ-receptors. In the mouse tail-flick assay, intrathecal (i.t.) NNTA produced antinociception that was ∼100-fold greater than by intracerebroventricular (i.c.v.) administration. The κ-antagonist, norBNI, decreased the i.t. potency, and the activity was virtually abolished in μ-opioid receptor knockout mice. No tolerance was induced i.t., but marginal tolerance (3-fold) was observed via the i.c.v. route. Moreover, NNTA produced neither significant physical dependence nor place preference in the ED50 dose range. Taken together, this work provides an important pharmacologic tool for investigating the in vivo functional relevance of heteromeric μ/κ-opioid receptors and suggests an approach to potent analgesics with fewer deleterious side effects.
KW - Pain
UR - http://www.scopus.com/inward/record.url?scp=79953191134&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953191134&partnerID=8YFLogxK
U2 - 10.1073/pnas.1016277108
DO - 10.1073/pnas.1016277108
M3 - Article
C2 - 21385944
AN - SCOPUS:79953191134
SN - 0027-8424
VL - 108
SP - 5098
EP - 5103
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 - 12
ER -