Abstract:
RATIONALE:In cell culture systems, agonists can promote the phosphorylation and internalization of receptors coupled to G proteins (GPCR), leading to their desensitization. However, in the CNS opioid agonists promote a profound desensitization of their analgesic effects without diminishing the presence of their receptors in the neuronal membrane. Recent studies have indicated that CNS proteins of the RGS family, specific regulators of G protein signalling, may be involved in mu-opioid receptor desensitization in vivo. OBJECTIVE:In this work we review the role played by RGS proteins in the intensity and duration of the effects of mu-opioid receptor agonists, and how they influence the delayed tolerance that develops in response to specific doses of opioids. RESULTS:RGS proteins are GTPase-activating proteins (GAP) that accelerate the hydrolysis of GalphaGTP to terminate signalling at effectors. The GAP activity of RGS-R4 and RGS-Rz proteins restricts the amplitude of opioid analgesia, and the efficient deactivation of GalphazGTP subunits by RGS-Rz proteins prevents mu receptor desensitization. However, RGS-R7 proteins antagonize effectors by binding to and sequestering mu receptor-activated Galphai/o/z subunits. Thus, they reduce the pool of receptor-regulated G proteins and hence, the effects of agonists. The delayed tolerance observed following morphine administration correlates with the transfer of Galpha subunits from mu receptors to RGS-R7 proteins and the subsequent stabilization of this association. CONCLUSION:In the CNS, the RGS proteins control the activity of mu opioid receptors through GAP-dependent (RGS-R4 and RGS-Rz) as well as by GAP-independent mechanisms (RGS-R7). As a result, they can both antagonize effectors and desensitize receptors under certain circumstances.
journal_name
Psychopharmacology (Berl)journal_title
Psychopharmacologyauthors
Garzón J,Rodríguez-Muñoz M,de la Torre-Madrid E,Sánchez-Blázquez Pdoi
10.1007/s00213-005-2248-9subject
Has Abstractpub_date
2005-06-01 00:00:00pages
1-11issue
1eissn
0033-3158issn
1432-2072journal_volume
180pub_type
杂志文章,评审abstract::The present report investigated several parametric and pharmacological aspects of the enhanced self-grooming behavior of rats following systemic administration of the selective D1 dopamine (DA) receptor agonist SKF 38393. The amount of time that rats spent grooming themselves was measured continuously for 30 min follo...
journal_title:Psychopharmacology
pub_type: 杂志文章
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abstract:RATIONALE:Multiple low doses of cocaine (COC) may cause intermittent vasoconstriction and reperfusion, leading to elevations in damaging reactive oxygen species, such as hydroxyl free radicals (*OH). Salicylate may offer protection because it reacts with *OH and/or because of its anti-inflammatory actions. OBJECTIVE:T...
journal_title:Psychopharmacology
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pub_type: 临床试验,杂志文章,随机对照试验
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pub_type: 临床试验,杂志文章
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更新日期:2007-01-01 00:00:00
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pub_type: 杂志文章,随机对照试验
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更新日期:2006-08-01 00:00:00