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Title: | Supersensitivity to μ-opioid receptor-mediated inhibition of the adenylyl cyclase pathway involves pertussis toxin-resistant Gα protein subunits |
Authors: | Mostany, Ricardo; Díaz, Álvaro ![]() ![]() ![]() |
Issue Date: | 2008 |
Publisher: | Elsevier |
Citation: | Neuropharmacology 54(6): 989- 997 (2008) |
Abstract: | Sustained administration of opioids leads to antinociceptive tolerance, while prolonged association of L-type Ca2+ channel blockers (e.g. nimodipine) with opioids results in increased antinociceptive response. Herein, we investigated the changes in μ-opioid receptor signalling underlying this shift from analgesic tolerance to supersensitivity. Thus, the interaction of μ-opioid receptors with G proteins and adenylyl cyclase was examined in lumbar spinal cord segments of rats. In control animals, the μ-opioid selective agonists, sufentanil and DAMGO, stimulated [35S]5′-(gamma-thio)-triphosphate ([35S]GTPγS) binding and inhibited forskolin-stimulated adenylyl cyclase activity, through a mechanism involving pertussis toxin (PTX) sensitive Gαi/o subunits. Seven days of chronic sufentanil treatment developed antinociceptive tolerance associated with a reduction in μ-agonist-induced [35S]GTPγS binding, μ-agonist-induced adenylyl cyclase inhibition, and co-precipitation of Gαo, Gαi2 Gαz and Gαq11 subunits with μ-opioid receptors. In contrast, combined nimodipine treatment with sufentanil over the same period increased the sufentanil analgesic response. This antinociceptive supersensitivity was accompanied by a significant increase of μ-agonist-induced inhibition of adenylyl cyclase that was resistant to the antagonism by PTX. In good agreement, co-precipitation of the PTX-resistant, Gαz and Gαq/11 subunits with μ-opioid receptors was not lowered. On the other hand, the PTX-sensitive subunits, Gαi2 and Gαo, as well as agonist-stimulated [35S]GTPγS binding were still reduced. Our results demonstrate that μ-opioid analgesic tolerance follows uncoupling of spinal μ-opioid receptors from their G proteins and linked effector pathways. Conversely, the enhanced analgesic response following combined nimodipine treatment with sufentanil is associated with adenylyl cyclase supersensitivity to the opioid inhibitory effect through a mechanism involving PTX-resistant G protein subunits. © 2008 Elsevier Ltd. All rights reserved. |
URI: | http://hdl.handle.net/10261/63435 |
DOI: | 10.1016/j.neuropharm.2008.02.004 |
Identifiers: | doi: 10.1016/j.neuropharm.2008.02.004 issn: 0028-3908 |
Appears in Collections: | (IC) Artículos (IBBTEC) Artículos |
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