title: Chronic treatment with the opioid antagonist naltrexone favours the coupling of spinal cord μ-opioid receptors to Gαz protein subunits.
abstract: Sustained administration of opioid antagonists to rodents results in an enhanced antinociceptive response to agonists. We investigated the changes in spinal μ-opioid receptor signalling underlying this phenomenon. Rats received naltrexone (120 μg/h; 7 days) via osmotic minipumps. The antinociceptive response to the μ-agonist sufentanil was tested 24 h after naltrexone withdrawal. In spinal cord samples, we determined the interaction of μ-receptors with Gα proteins (agonist-stimulated [(35)S]GTPγS binding and immunoprecipitation of [(35)S]GTPγS-labelled Gα subunits) as well as μ-opioid receptor-dependent inhibition of the adenylyl cyclase (AC) activity. Chronic naltrexone treatment augmented DAMGO-stimulated [(35)S]GTPγS 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 μ-receptors to PTX-insensitive Gα(z) subunits. Immunoprecipitation assays confirmed the transduction switch from Gα(i/o) to Gα(z) proteins. The consequence was an enhancement of the antinociceptive response to sufentanil that, in consonance with the neurochemical data, was prevented by Gα(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'.
authors: Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Cantabria, Spain.
authors: Elsa M
authors: EM
authors: Valdizán
authors: Alvaro
authors: A
authors: Díaz
authors: Fuencisla
authors: F
authors: Pilar-Cuéllar
authors: Aquilino
authors: A
authors: Lantero
authors: Ricardo
authors: R
authors: Mostany
authors: Ana V
authors: AV
authors: Villar
authors: María L
authors: ML
authors: Laorden
authors: María A
authors: MA
authors: Hurlé
mesh_terms: D000818:Animals; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone