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Chronic treatment with the opioid antagonist naltrexone favours the coupling of spinal cord µ-opioid receptors to Ga z protein subunits

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'.

 Autoría: 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

 Editorial: Elsevier

 Año de publicación: 2012

 Nº de páginas: 8

 Tipo de publicación: Artículo de Revista

 DOI: 10.1016/j.neuropharm.2011.08.029

 ISSN: 0028-3908,1873-7064

 Proyecto español: SAF2007/65451

 Url de la publicación: https://www.doi.org/10.1016/j.neuropharm.2011.08.029

Autoría

ELSA MARIA VALDIZAN RUIZ

MARIA FUENCISLA PILAR CUELLAR

LANTERO, AQUILINO

MOSTANY, RICARDO

LAORDEN, MARÍA L.