G-protein coupling of δ-opioid receptors in brains of μ-opioid receptor knockout mice

Oakley, Sarah M.; Tóth, Géza; Borsodi, Anna; Kieffer, Brigitte L.; Kitchen, Ian

doi:10.1016/s0014-2999(03)01531-0

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…However, in an analogous study of DOR using DPDPE as both radioligand and agonist, only a tenuous correspondence was seen (r ϭ 0.61, nonsignificant; Hyytia et al, 1999). In the present study, radioligand binding revealed a highly significant Third, efficiency of coupling between DOR and G-proteins may be regionally heterogeneous, as has been proposed for mouse DOR (Oakley et al, 2003) and for rat MOR (Sim-Selley et al, 2000). In this context, variations in [ 35 S]GTP␥S response may reflect signalling through G-proteins that are not readily detectable in this assay (Milligan, 2003).…”

Section: Delt-stimulated [ 35 S]gtp␥s Binding Vs Radioligand Bindingsupporting

confidence: 57%

Comparison between δ‐opioid receptor functional response and autoradiographic labeling in rat brain and spinal cord

Pradhan

Clarke

2004

J of Comparative Neurology

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The distribution of delta-opioid receptors (DORs) in the rat central nervous system has been previously characterized by radioligand binding and immunohistochemistry. However, the functional neuroanatomy of DORs has not been mapped in any detail; this is potentially important, because these receptors appear to be primarily cytosolic. Opioid receptors can couple to G(i/o) G proteins, a process that is detected by agonist-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]GTPgammaS) binding. The purpose of this study was therefore to determine the distribution of functional DORs, as assessed by [35S]GTPgammaS autoradiographic labeling in response to the DOR agonist deltorphin II. For comparison, adjacent sections were labeled with [125I]deltorphin II or the DOR antagonist [125I]AR-M100613. In all three assays, mu-opioid receptors were blocked pharmacologically. The distributions of [125I]deltorphin II and [125I]AR-M100613 were highly correlated but not identical. Deltorphin II increased [35S]GTPgammaS binding in a concentration-dependent and naltrindole-sensitive manner. The regional [35S]GTPgammaS response to deltorphin II was only moderately predicted by agonist or antagonist radioligand binding (r = 0.67 and 0.50, respectively). [35S]GTPgammaS responses to deltorphin II were strongest in the extended striatum (caudate putamen, nucleus accumbens, olfactory tubercle) and cerebral cortex. In contrast, some areas reported to mediate DOR analgesia (brainstem, spinal cord) possessed a much lower [35S]GTPgammaS response. These findings demonstrate the existence of a partial mismatch between DOR radioligand binding and [35S]GTPgammaS response. This divergence possibly reflects regional heterogeneity in G-protein receptor coupling, or in the subcellular localization of DOR.

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Section: Delt-stimulated [ 35 S]gtp␥s Binding Vs Radioligand Bindingsupporting

confidence: 57%

Comparison between δ‐opioid receptor functional response and autoradiographic labeling in rat brain and spinal cord

Pradhan

Clarke

2004

J of Comparative Neurology

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“…Compensatory mechanisms may have developed in some KO animals, but no systematic studies are available. Deletion of opioid receptors did not markedly modify the expression or activity of the other opioid receptors or the expression of opioid peptides as described by the initial characterizations of the distinct mutants lines (see references in Table 1 and Kitchen et al, 1997 ; Slowe et al, 1999 ; Oakley et al, 2003 ). A complete autoradiographic mapping of the delta KO mice indicated decreased binding levels of mu and kappa ligands in specific brain areas ( Goody et al, 2002 ).…”

Section: Generation Of Deficient Mice In Regards To Components Of Thementioning

confidence: 68%

Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies

Befort

2015

Front. Pharmacol.

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The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides (enkephalins, endorphins, and dynorphins). The endogenous cannabinoid system comprises lipid neuromodulators (endocannabinoids), enzymes for their synthesis and their degradation and two well-characterized receptors, cannabinoid receptors CB1 and CB2. These systems play a major role in the control of pain as well as in mood regulation, reward processing and the development of addiction. Both opioid and cannabinoid receptors are coupled to G proteins and are expressed throughout the brain reinforcement circuitry. Extending classical pharmacology, research using genetically modified mice has provided important progress in the identification of the specific contribution of each component of these endogenous systems in vivo on reward process. This review will summarize available genetic tools and our present knowledge on the consequences of gene knockout on reinforced behaviors in both systems, with a focus on their potential interactions. A better understanding of opioid–cannabinoid interactions may provide novel strategies for therapies in addicted individuals.

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“…Importantly, we show that delta receptor coupling to G proteins in the brain remains intact in the absence of either mu or kappa opioid receptors. Although subtle regional alterations of delta receptor coupling could occur in mu receptor knockout mice (Oakley et al ., 2003), our result suggests that delta receptor signalling overall is independent from mu or kappa receptors. The dramatic decrease of behavioural responses to delta agonists in mu knockout mice therefore is probably not due to a lack of delta receptor expression and coupling.…”

Section: Discussionmentioning

confidence: 99%

The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout mice

Scherrer¹,

Befort²,

Contet

et al. 2004

Eur J of Neuroscience

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Delta-selective agonists have been developed to produce potent analgesic compounds with limited side-effects. DPDPE and deltorphin II are considered prototypes, but their delta-selectivity in vivo and the true ability of delta receptors to produce analgesia remain to be demonstrated. Here we have performed a parallel analysis of mu, delta and combinatorial opioid receptor knockout mice, in which we found no obvious alteration of G-protein coupling for remaining opioid receptors. We compared behavioural responses in two models of acute thermal pain following DPDPE and deltorphin II administration by intracerebroventricular route. In the tail-immersion test, both compounds were fully analgesic in delta knockout mice and totally inactive in mu knockout mice. In the hotplate test, the two compounds again produced full analgesia in delta knockout mice. In mu knockout mice, there was significant, although much lower, analgesia. Furthermore, DPDPE analgesia in the delta knockout mice was fully reversed by the mu selective antagonist CTOP in both tests. Together, this suggests that mu rather than delta receptors are recruited by the two agonists for the tail withdrawal and the hotplate responses. Finally, deltorphin II slightly prolonged jump latencies in double mu/kappa knockout mice (delta receptors only) and this response was abolished in the triple knockout mice, demonstrating that the activation of delta receptors alone can produce weak but significant mu-independent thermal antinociception.

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G-protein coupling of δ-opioid receptors in brains of μ-opioid receptor knockout mice

Cited by 4 publications

References 25 publications

Comparison between δ‐opioid receptor functional response and autoradiographic labeling in rat brain and spinal cord

Comparison between δ‐opioid receptor functional response and autoradiographic labeling in rat brain and spinal cord

Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies

The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout mice

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