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Differential noxious and motor tolerance of chronic delta opioid receptor agonists in rodents.

ABSTRACT: In the present study, we asked whether multiple intrathecal injections of deltorphin II, a selective delta opioid receptor (DOPR) agonist, induced DOPR tolerance in three behavioral assays. Unilateral inflammation caused by complete Freund's adjuvant (CFA) injection into the rat or mouse hind paw (CFA model) induced thermal hyperalgesic response that was transiently and dose-dependently reduced by intrathecal administration of deltorphin II or morphine. In both rodent species, the effect of deltorphin II was not modified by a single prior administration of deltorphin II, suggesting an absence of acute tolerance in this paradigm. Repeated administration of intrathecal deltorphin II or s.c. SB-235863 (five consecutive injections over 60 h) also failed to impair the antihyperalgesic response to delta opioid receptor agonist, whereas repeated intrathecal or s.c. injections of morphine induced a significant decrease in the subsequent thermal antihyperalgesic response to morphine. In mice, deltorphin II also induced a rapid, transient motor incoordination/ataxia-like behavior as tested with the accelerating rotarod. In contrast to the antihyperalgesic responses, tolerance to the motoric effect of deltorphin II was evident in mice previously exposed to multiple intrathecal agonist injections, but not multiple saline administrations. Using the tail flick antinociceptive test, we found that DOPR-mediated analgesia was significantly reduced by repeated exposure to deltorphin II. Altogether, these observations suggest that repeated injections of DOPR agonists induce differential tolerance effects on antihyperalgesic, antinociceptive, and motor incoordination/ataxia-like behaviors related to DOPR activation by deltorphin II.

SUBMITTER: Beaudry H

PROVIDER: S-EPMC3727641 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Differential noxious and motor tolerance of chronic delta opioid receptor agonists in rodents.

Beaudry H H Proteau-Gagné A A Li Shuang S Dory Y Y Chavkin C C Gendron L L

Neuroscience 20090327 2

In the present study, we asked whether multiple intrathecal injections of deltorphin II, a selective delta opioid receptor (DOPR) agonist, induced DOPR tolerance in three behavioral assays. Unilateral inflammation caused by complete Freund's adjuvant (CFA) injection into the rat or mouse hind paw (CFA model) induced thermal hyperalgesic response that was transiently and dose-dependently reduced by intrathecal administration of deltorphin II or morphine. In both rodent species, the effect of delt ...[more]

PMID: 19328839

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Project description:BackgroundGPCRs regulate a remarkable diversity of biological functions, and are thus often targeted for drug therapies. Stimulation of a GPCR by an extracellular ligand triggers receptor signaling via G proteins, and this process is highly regulated. Receptor activation is typically accompanied by desensitization of receptor signaling, a complex feedback regulatory process of which receptor internalization is postulated as a key event. The in vivo significance of GPCR internalization is poorly understood. In fact, the majority of studies have been performed in transfected cell systems, which do not adequately model physiological environments and the complexity of integrated responses observed in the whole animal.Methods and findingsIn this study, we used knock-in mice expressing functional fluorescent delta opioid receptors (DOR-eGFP) in place of the native receptor to correlate receptor localization in neurons with behavioral responses. We analyzed the pain-relieving effects of two delta receptor agonists with similar signaling potencies and efficacies, but distinct internalizing properties. An initial treatment with the high (SNC80) or low (AR-M100390) internalizing agonist equally reduced CFA-induced inflammatory pain. However, subsequent drug treatment produced highly distinct responses. Animals initially treated with SNC80 showed no analgesic response to a second dose of either delta receptor agonist. Concomitant receptor internalization and G-protein uncoupling were observed throughout the nervous system. This loss of function was temporary, since full DOR-eGFP receptor responses were restored 24 hours after SNC80 administration. In contrast, treatment with AR-M100390 resulted in retained analgesic response to a subsequent agonist injection, and ex vivo analysis showed that DOR-eGFP receptor remained G protein-coupled on the cell surface. Finally SNC80 but not AR-M100390 produced DOR-eGFP phosphorylation, suggesting that the two agonists produce distinct active receptor conformations in vivo which likely lead to differential receptor trafficking.ConclusionsTogether our data show that delta agonists retain full analgesic efficacy when receptors remain on the cell surface. In contrast, delta agonist-induced analgesia is abolished following receptor internalization, and complete behavioral desensitization is observed. Overall these results establish that, in the context of pain control, receptor localization fully controls receptor function in vivo. This finding has both fundamental and therapeutic implications for slow-recycling GPCRs.

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Differential noxious and motor tolerance of chronic delta opioid receptor agonists in rodents.

Publications

Differential noxious and motor tolerance of chronic delta opioid receptor agonists in rodents.

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