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Abstract: Sustained administration of opioid antagonists to rodents results in an enhanced antinociceptive response to agonists. We investigated the changes in spinal ?-opioid receptor signalling underlying this phenomenon. Rats received naltrexone (120 ?g/h; 7 days) via osmotic minipumps. The antinociceptive response to the ?-agonist sufentanil was tested 24 h after naltrexone withdrawal. In spinal cord samples, we determined the interaction of ?-receptors with G? proteins (agonist-stimulated [(35)S]GTP?S binding and immunoprecipitation of [(35)S]GTP?S-labelled G? subunits) as well as ?-opioid receptor-dependent inhibition of the adenylyl cyclase (AC) activity. Chronic naltrexone treatment augmented DAMGO-stimulated [(35)S]GTP?S binding, potentiated the inhibitory effect of DAMGO on the AC/cAMP pathway, and increased the inverse agonist effect of naltrexone on cAMP accumulation. In control rats, the inhibitory effect of DAMGO on cAMP production was antagonized by pertussis toxin (PTX) whereas, after chronic naltrexone, the effect became resistant to the toxin, suggesting a coupling of ?-receptors to PTX-insensitive G?(z) subunits. Immunoprecipitation assays confirmed the transduction switch from G?(i/o) to G?(z) proteins. The consequence was an enhancement of the antinociceptive response to sufentanil that, in consonance with the neurochemical data, was prevented by G?(z)-antisense oligodeoxyribonucleotides but not by PTX. Such changes in opioid receptor signalling can be a double-edged sword. On the one hand, they may have potential applicability to the optimisation of the analgesic effects of opioid drugs for the control of pain. On the other hand, they represent an important homeostatic dysregulation of the endogenous opioid system that might account for undesirable effects in patients chronically treated with opioid antagonists. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
Authorship: Valdizán E.M., Díaz A., Pilar-Cuéllar F., Lantero A., Mostany R., Villar A.V., Laorden M.L., Hurlé M.A.,
Fuente: Neuropharmacology 2012 Feb;62(2):757-64
Publisher: Elsevier
Year of publication: 2012
No. of pages: 8
Publication type: Article
DOI: 10.1016/j.neuropharm.2011.08.029
ISSN: 0028-3908,1873-7064
Spanish project: SAF2007/65451
Publication Url: https://www.doi.org/10.1016/j.neuropharm.2011.08.029
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ELSA MARIA VALDIZAN RUIZ
ALVARO MARCELINO DIAZ MARTINEZ
MARIA FUENCISLA PILAR CUELLAR
LANTERO, AQUILINO
MOSTANY, RICARDO
ANA VICTORIA VILLAR RAMOS
LAORDEN, MARÍA L.
MARIA AMOR HURLE GONZALEZ
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