Knockdown of spinal opioid receptors by antisense targeting β-arrestin reduces morphine tolerance and allodynia in rat

Przewłocka, Barbara; Sieja, Agnieszka; Starowicz, Katarzyna; Maj, Marcin; Bilecki, Wiktor; Przewłocki, Ryszard

doi:10.1016/s0304-3940(02)00246-x

Cited by 39 publications

(33 citation statements)

References 13 publications

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“…Antinociceptive tolerance is also significantly attenuated in ␤arr2-KO mice in response to long-term morphine treatment in this same assay (Bohn et al, 2000(Bohn et al, , 2002Raehal and Bohn, 2011). Likewise, Li et al (2009) showed that siRNA inhibition of ␤-arrestin2 in periaqueductal gray matter in mice enhances morphine-induced antinociception and delays the development of antinociceptive tolerance in the hot (Przewlocka et al, 2002). These enhanced and prolonged antinociceptive responses to morphine in the absence of ␤-arrestin2 are consistent with the described role of ␤-arrestin2 as a desensitizing agent.…”

Section: B Biased Agonism and ␤-Arrestins In Antinociception And Antsupporting

confidence: 81%

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

et al. 2011

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Section: B Biased Agonism and ␤-Arrestins In Antinociception And Antsupporting

confidence: 81%

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

et al. 2011

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“…can activate the receptor may be therapeutically useful considering that suppression of the ␤-arrestin2-OR interaction attenuates morphine antinociceptive tolerance and morphine-induced side effects in genetically modified mouse models (Bohn et al, 2000b;Przewlocka et al, 2002;.…”

Section: Discussionmentioning

confidence: 99%

“…Although the morphinebound OR seems to be a poor substrate for ␤arr2 binding, a combination of both animal and cellular studies suggests that ␤arr2 is prominently involved in OR regulation. Mice that lack ␤arr2 display enhanced and prolonged morphine analgesia with limited development of tolerance (Bohn et al, 1999(Bohn et al, , 2000b(Bohn et al, , 2002Przewlocka et al, 2002). It is somewhat of a surprise that these animals are not as susceptible to the morphine-induced side effects, including constipation and respiratory suppression .…”

mentioning

confidence: 99%

An Opioid Agonist that Does Not Induce μ-Opioid Receptor—Arrestin Interactions or Receptor Internalization

Groer¹,

Tidgewell²,

Moyer³

et al. 2006

Mol Pharmacol

211

220

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G protein-coupled receptor desensitization and trafficking are important regulators of opioid receptor signaling that can dictate overall drug responsiveness in vivo. Furthermore, different -opioid receptor (OR) ligands can lead to varying degrees of receptor regulation, presumably because of distinct structural conformations conferred by agonist binding. For example, morphine binding produces a OR with low affinity for ␤-arrestin proteins and limited receptor internalization, whereas enkephalin analogs promote robust trafficking of both ␤-arrestins and the receptors. Here, we evaluate OR trafficking in response to activation by a novel -selective agonist derived from the naturally occurring plant product, salvinorin A. It is interesting that this compound, termed herkinorin, does not promote the recruitment of ␤-arrestin-2 to the OR and does not lead to receptor internalization. Moreover, whereas G protein-coupled receptor kinase overexpression can promote morphine-induced ␤-arrestin interactions and OR internalization, such manipulations do not promote herkinorin-induced trafficking. Studies in mice have shown that ␤-arrestin-2 plays an important role in the development of morphine-induced tolerance, constipation, and respiratory depression. Therefore, drugs that can activate the receptor without recruiting the arrestins may be a promising step in the development of opiate analgesics that distinguish between agonist activity and receptor regulation and may ultimately lead to therapeutics designed to provide pain relief without the adverse side effects normally associated with the opiate narcotics.

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“…Acute and chronic treatment with morphine variably regulates βarrestin-2 mRNA in several brain regions in rats (Fan et al 2003). Finally, an involvement of βarrestin-2 in modulating spinal antinociception induced by µOR agonists was demonstrated in mice recently by using intrathecally administered βarrestin-2 antibody (Ohsawa et al 2003) or by using antisense RNA to βarrestin-2 (Przewlocka et al 2002).…”

Section: β-Arrestinsmentioning

confidence: 99%

Desensitization of G Protein–coupled Receptors and Neuronal Functions

Gainetdinov

Premont

Bohn

et al. 2004

Annu. Rev. Neurosci.

765

692

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I Abstract G protein-coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modern pharmacology. Over 90% of nonsensory GPCRs are expressed in the brain, where they play important roles in numerous neuronal functions. GPCRs can be desensitized following activation by agonists by becoming phosphorylated by members of the family of G protein-coupled receptor kinases (GRKs). Phosphorylated receptors are then bound by arrestins, which prevent further stimulation of G proteins and downstream signaling pathways. Discussed in this review are recent progress in understanding basics of GPCR desensitization, novel functional roles, patterns of brain expression, and receptor specificity of GRKs and βarrestins in major brain functions. In particular, screening of genetically modified mice lacking individual GRKs or βarrestins for alterations in behavioral and biochemical responses to cocaine and morphine has revealed a functional specificity in dopamine and µ-opioid receptor regulation of locomotion and analgesia. An important and specific role of GRKs and βarrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules in certain brain disorders, such as addiction, Parkinson's disease, mood disorders, and schizophrenia. Furthermore, the utility of a pharmacological strategy aimed at targeting this GPCR desensitization machinery to regulate brain functions can be envisaged.

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Knockdown of spinal opioid receptors by antisense targeting β-arrestin reduces morphine tolerance and allodynia in rat

Cited by 39 publications

References 13 publications

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

An Opioid Agonist that Does Not Induce μ-Opioid Receptor—Arrestin Interactions or Receptor Internalization

Desensitization of G Protein–coupled Receptors and Neuronal Functions

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