کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2493773 1115528 2012 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Chronic treatment with the opioid antagonist naltrexone favours the coupling of spinal cord μ-opioid receptors to Gαz protein subunits
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب رفتاری
پیش نمایش صفحه اول مقاله
Chronic treatment with the opioid antagonist naltrexone favours the coupling of spinal cord μ-opioid receptors to Gαz protein subunits
چکیده انگلیسی

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 [35S]GTPγS binding and immunoprecipitation of [35S]GTPγS-labelled Gα subunits) as well as μ-opioid receptor-dependent inhibition of the adenylyl cyclase (AC) activity. Chronic naltrexone treatment augmented DAMGO-stimulated [35S]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 Gαz subunits. Immunoprecipitation assays confirmed the transduction switch from Gαi/o to Gαz proteins. The consequence was an enhancement of the antinociceptive response to sufentanil that, in consonance with the neurochemical data, was prevented by Gαz-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’.


► Chronic treatment with opioid antagonists increases agonist-mediated antinociception.
► We examine spinal cord changes in μ-opioid receptor signalling underlying this effect.
► Opioid receptor coupling to G-proteins and inhibition of cAMP pathway are enhanced.
► μ-opioid receptors experience a transduction shift from Gαi/o to Gαz proteins.
► The inverse agonist effect of naltrexone on cAMP accumulation is enhanced.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuropharmacology - Volume 62, Issue 2, February 2012, Pages 757–764
نویسندگان
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