Selectivity of Ligands for Opioid Receptors

Corbett, A.D.; Paterson, S.J.; Kosterlitz, H. W.

doi:10.1007/978-3-642-77460-7_26

Cited by 154 publications

(97 citation statements)

References 94 publications

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“…Indeed, transgenic mice deficient in pre-proenkephalin have altered responses to noxious stimuli (Konig et al, 1996). Some of these inhibitory effects are exerted through activation of mOR, to which both met-enkephalin and endomorphin-2 bind with high affinity (Corbett et al, 1993;Zadina et al, 1997). We propose here that sustained stimulation of mOR by endogenous opioids may also result in increased trafficking of dOR to neuronal plasma membranes.…”

Section: Effect Of Mor Gene Knockout On Cfa-induced Up-regulation Of mentioning

confidence: 86%

Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain

Morinville

Cahill

Kieffer

et al. 2004

Pain

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Previous studies from our laboratory have demonstrated that both chronic inflammatory pain, induced by intraplantar injection of complete Freund's adjuvant (CFA), and prolonged (48 h) stimulation of mu-opioid receptors (mOR) by systemic administration of a variety of selective agonists, resulted in enhanced plasma membrane targeting of delta-opioid receptors (dOR) in neurons of the dorsal spinal cord. To determine whether dOR trafficking induced by chronic inflammation was dependent on the activation of mOR, we investigated by immunogold cytochemistry the effects of intraplantar CFA injection on the plasma membrane density of dOR in mOR knockout (KO) mice. In untreated wild-type (WT) mice, only a small proportion of dOR was associated with neuronal plasma membranes in the dorsal horn of the spinal cord. The CFA-induced inflammation produced a significantly higher ratio of plasma membrane to intracellular receptors, as well as a 75% increase in the membrane density of immunoreactive dOR, in dendrites of the ipsilateral dorsal horn as compared to untreated mice. This increase in the membrane density of dOR was likely due to a recruitment of receptors from intracellular stores since no difference in the overall dOR immunolabeling density was evident between CFA-treated and untreated mice. Most importantly, the CFA-induced changes in dOR plasma membrane insertion seen in WT animals were not present in the spinal cord of mOR KO mice. These results demonstrate that the integrity of mOR is necessary for CFA-induced changes in dOR trafficking to occur and suggest that these changes could be elicited by stimulation of mOR by endogenous opioids released in response to chronic inflammatory pain. q

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Section: Effect Of Mor Gene Knockout On Cfa-induced Up-regulation Of mentioning

confidence: 86%

Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain

Morinville

Cahill

Kieffer

et al. 2004

Pain

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“…High concentrations of morphine bind to δ and κ receptors [5]. Yet, the δ receptor antagonist naltrindole [29] was inactive in both non-tolerant and tolerant rats (Fig 4B).…”

Section: Behavioral Expression Of Morphine Tolerance In P17 Ratsmentioning

confidence: 95%

“…Involvement of κ and δ opioid receptors in mediating the antinociceptive effects of morphine in tolerant rat pups Higher doses of morphine have been demonstrated to bind not only μ opioid receptors, but to bind κ and δ opioid receptors as well [5]. This led to the hypothesis that the antinociceptive effects of morphine in tolerant rat pups is mediated by high doses of morphine acting on κ and/or δ opioid receptors.…”

Section: Influence Of Water Bath Temperature On the Efficacy Of Morphinementioning

confidence: 99%

“…If morphine was acting through κ receptors, this could explain why it was necessary to decrease the temperature of the water bath in order to demonstrate an increase in the efficacy of morphine. Interestingly, κ receptor agonists like U50,488 and dynorphin A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) are often tested at a tail-immersion temperature of 49 °C [13,35].…”

Section: Behavioral Expression Of Morphine Tolerance In P17 Ratsmentioning

confidence: 99%

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Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats

2007

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We have previously noted that the antinociceptive efficacy of morphine was significantly decreased in rat pups chronically infused with morphine from implanted osmotic minipumps. In this study, morphine was fully efficacious (i.e., 100% maximum possible effect, %MPE) in the 52 ºC tail-immersion test after a 72-h infusion from implanted saline-filled osmotic minipumps. However, administration of up to 1000 mg/kg s.c. morphine failed to elicit greater than a 27% MPE in rats infused with morphine at 2 mg/kg/h. Morphine was more efficacious when the water bath temperature was decreased to 49 ºC. Experiments were conducted to determine the mechanisms whereby chronic morphine administration leads to a decrease in antinociceptive efficacy. The kappa-opioid antagonist nor-binalorphimine completely blocked the antinociceptive effects of morphine in morphine-infused rat pups. The kappa agonist U50,488 elicited antinociception however, the requirement to use higher doses in morphine-than saline-infused rats indicates that kappa cross-tolerance was present. Thus, in tolerant rats the antinociceptive effects of high doses of morphine appear to be mediated through kappa-opioid receptors. The deltaopioid antagonist naltrindole was inactive in both treatment groups. DAMGO-stimulated [ 35 S]GTPγS and [ 3 H]naloxone binding reveal that the anatomical distribution of the mu-opioid receptor was consistent with that of the adult rat brain. In adult rats, the mu-opioid receptor is desensitized during morphine tolerance. However, desensitization was not evident in P17 rats based on the lack of significant decreases in [ 35 S]GTPγS binding. Furthermore, [ 3 H]naloxone binding indicated a lack of mu receptor downregulation in morphine-tolerant rat pups.

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“…Extensive physiological, behavioral, and pharmacological studies have defined three major types of opioid receptors, designated~.t, 6, and K (Wood and Iyengar, 1988;Corbett et al, 1993). The activation of all three opioid receptor types can inhibit adenylate cyclase.…”

Section: Introductionmentioning

confidence: 99%

Site Mutation in the Rat μ‐Opioid Receptor Demonstrates the Involvement of Calcium/Calmodulin‐Dependent Protein Kinase II in Agonist‐Mediated Desensitization

Koch

Kroslak

Mayer

et al. 1997

Journal of Neurochemistry

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The rat 1z-opioid receptor (rMOR1), expressed in human embryonic kidney 293 (HEK293) cells, showsa desensitization to the inhibitory effect of the js agonist DAMGO on adenylate cyclase activity within 4 h of DAMGO preincubation. To investigate the role of calcium/calmodulin-dependent protein kinase Il (CaM kinase Il) on 1s-opioid receptor desensitization, we coexpressed rMOR1 and constitutively active CaM kinase Il in HEK293 cells. This coexpression led to a faster time course of agonist-induced desensitization of the~-opioid receptor. The increase ofdesensitization could not be observed with a te-opioid receptor mutant (S261A!S266A) that lacks two putative CaM kinase Il phosphorylation sites in the third intracellular loop. In addition, injection of CaM kinase Il in Xenopus oocytes led only to desensitization of expressed rMOR1, but not of an S261 A! S266A receptor mutant. These results suggest that phosphorylation of Ser 251 and Ser266 by CaM kinase II is involved in the desensitization of the 1s-opioid receptor. Key Words:~t-Opioid receptor -Desensitization -Calcium! calmodulin -dependent protein kinase phosphorylation-G protein-activated channelXenopus oocytes. J. Neurochem. 69, 1767-1770 (1997).Extensive physiological, behavioral, and pharmacological studies have defined three major types of opioid receptors, designated~.t, 6, and K (Wood and Iyengar, 1988;Corbett et al., 1993). The activation of all three opioid receptor types can inhibit adenylate cyclase. In addition, opiates have been shown to open K~channels and to close Ca 2~channels (North, 1993).In Xenopus oocytes expressing opioid receptors and the G protein-gated, inwardly rectifying K channel (known as KGA or GIRK1), application of the~.t agonist [D-Ala2, MePhe4,G1y5-ol] enkephalin (DAMGO) evoked a dose-dependent increase in K + conductance (Chen and Yu, 1994). Chen and Yu (1994) demonstrated that repeated agonist stimulation of the~i-opioid receptor coexpressed with GIRK 1 in Xenopus oocytes resulted in desensitization of the u-activated current response. Using the Xenopus expression system, it has also been reported that phosphorylation by protein kinase C and Ca2~/calmodulin-dependentprotein kinase II (CaM kinase II) modulates desensitization of the human p~-opioidreceptor (Mestek et al., 1995), whereas receptor desensitization of the 6-opioidreceptor is influenced by protein kinase C (Ueda et al., 1994(Ueda et al., , 1995. Due to the experimental conditions, it is not clearly shown in these experiments whether the target of these kinases is the opioid receptor, the G protein, the K + channel, or some intermediary factors. Moreover, Kovoor et al. (1995) suggested that the desensitization of the rat~t-opioid receptor in the Xenopus oocyte system is receptor-independent and caused by an inactivation of the K + channel itself.To investigate further the role of CaM kinase II in opioid receptor desensitization, we used, in addition to the Xenopus oocyte expression system, the human embryonic kidney 293 (HEK293) cell line for expressing the ...

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Selectivity of Ligands for Opioid Receptors

Cited by 154 publications

References 94 publications

Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain

Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain

Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats

Site Mutation in the Rat μ‐Opioid Receptor Demonstrates the Involvement of Calcium/Calmodulin‐Dependent Protein Kinase II in Agonist‐Mediated Desensitization

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