Neutral antagonist activity of naltrexone and 6beta-naltrexol in naïve and opioid-dependent C6 cells expressing a mu-opioid receptor.
Br J Pharmacol
; 156(7): 1044-53, 2009 Apr.
Article
en En
| MEDLINE
| ID: mdl-19220294
ABSTRACT
BACKGROUND AND PURPOSE:
Adenylyl cyclase sensitization occurs on chronic agonist activation of mu-opioid receptors and is manifested by an increase in cAMP levels (overshoot) on challenge with antagonist. It has been proposed that a long lasting constitutively active receptor is formed on chronic mu-opioid exposure and that antagonists with inverse agonist activity rapidly return the receptor to a basal state causing a cAMP overshoot and a more severe withdrawal response in vivo. This hypothesis depends on an accurate characterization of neutral and inverse agonist properties of opioid antagonists. EXPERIMENTALAPPROACH:
C6 glioma and HEK293 cells expressing mu-opioid receptors were used. Opioid antagonists were examined for their ability to induce a cAMP overshoot following chronic treatment with the agonist DAMGO ([D-Ala(2),N-Me-Phe(4),Glyol(5)]-enkephalin). The compounds were also characterized as agonists, inverse agonists or neutral antagonists by using assays for competitive binding, [(35)S]GTPgammaS (guanosine-5'-O-(3-[(35)S]thio)triphosphate) binding and changes in cell surface receptor expression. KEYRESULTS:
Naltrexone, 6beta-naltrexol and naloxone were indistinguishable to the mu-opioid receptor in the opioid-naïve or dependent state and acted as neutral antagonists. The delta-opioid receptor inverse agonist RTI-5989-25 [(+)-N-[trans-4'-(2-methylphenyl)-2'-butenyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine], a 3,4-dimethyl-4-(3-hydroxyphenyl)-piperidine, was an inverse agonist at the mu-opioid receptor, and the peptide antagonist CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)) showed variable, assay-dependent properties. All the antagonists precipitated the same degree of cAMP overshoot in opioid-dependent cells. CONCLUSIONS AND IMPLICATIONS Antagonists at the mu-opioid receptor may be neutral or show inverse agonist activity. Formation of a constitutively active mu-opioid receptor is not a requirement for the development or expression of adenylyl cyclase sensitization.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores Opioides mu
/
Naltrexona
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Br J Pharmacol
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos