Biochemical demonstration of mu-opioid receptor association with Gsα: enhancement following morphine exposure

Chakrabarti, Swapan; Regec, Annette L.; Gintzler, Alan R.

doi:10.1016/j.molbrainres.2004.12.016

Cited by 74 publications

(106 citation statements)

References 33 publications

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“…The EC 50 for morphine-induced down-regulation was 205±0.3 nM and receptor binding decreased to 63±3.7% of control. These data are consistent with previously published results from different laboratories in various cell lines (Chakrabarti et al, 2005;Chaturvedi et al, 2001;Horner and Zadina, 2004). In contrast, in M2 cells lacking filamin A, chronic morphine treatment induced a marked concentration-dependent increase in MOP binding sites to 188±4.8 % of control (Fig.…”

Section: Regulation Of Mop Binding In Melanoma Cellssupporting

confidence: 93%

Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

Onoprishvili

Simon

2007

Brain Research

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We investigated the effects of morphine and other agonists on the human mu opioid receptor (MOP) expressed in M2 melanoma cells, lacking the actin cytoskeleton protein filamin A and in A7, a sub clone of the M2 melanoma cells, stably transfected with filamin A cDNA. The results of binding experiments showed, that after chronic morphine treatment (24 hr) of A7 cells, MOP binding sites were down-regulated to 63% of control, whereas, unexpectedly, in M2 cells, MOP binding was upregulated to 188% of control naïve cells. Similar up-regulation was observed with the agonists methadone and levorphanol. The presence of antagonists (naloxone or CTAP) during chronic morphine treatment inhibited MOP down-regulation in A7 cells. In contrast, morphine-induced upregulation of MOP in M2 cells was further increased by these antagonists. Chronic morphine desensitized MOP in A7 cells, i.e. it decreased DAMGO-induced stimulation of GTPγS binding. In M2 cells DAMGO stimulation of GTPγS binding was significantly greater than in A7 cells and was not desensitized by chronic morphine. Pertussis toxin treatment abolished morphine-induced receptor up-regulation in M2 cells, whereas it had no effect on morphine-induced down-regulation in A7 cells. These results indicate that, in the absence of filamin A, chronic treatment with morphine, methadone or levorphanol leads to up-regulation of MOP, to our knowledge, the first instance of opioid receptor up-regulation by agonists in cell culture.

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Section: Regulation Of Mop Binding In Melanoma Cellssupporting

confidence: 93%

Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

Onoprishvili

Simon

2007

Brain Research

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“…The MOR-G s coupling may also contribute to the development of opioid analgesic tolerance, opioid-induced hyperalgesia, and differences in μ-opioid efficacy. 19,24,38,67,74,76 Although the ultra-low-dose NTX attenuation of injury-induced MOR-G s coupling was mild compared with the suppression of chronic opioid-induced MOR-G s coupling in intact animals, oxycodone plus ultra-low-dose NTX produced profound and significant antihypersensitivities in the L 5 /L 6 SNL model. These data suggest a common mechanism of action for certain ultra-low-dose opioid antagonist/opioid combinations in preventing analgesic tolerance and in alleviating hypersensitivities in SNL rats.…”

Section: Discussionmentioning

confidence: 96%

“…6,23,28,30,32,51,54,65,71 Prolonged opioid treatment has also been shown to alter the function of Gβγ-subunits of G proteins coupling to MORs, resulting in multiplicative excitatory effects such as phosphorylation of Gβ and enhanced Gβγ stimulation of adenylyl cyclase, phosphorylation of G protein receptor kinase 2/3 and Gβ via protein kinase C, and increased activity of PKA, which can also be activated by G s stimulation of adenylyl cyclase. [15][16][17][18][19][20]37,57 The Gβγ that associates with adenylyl cyclases during opioid tolerance has now been shown to originate from the G s protein coupling to MOR. 72 In conjunction with increased excitatory signaling via MOR-associated Gα s in an injury state, the Gβγ released by these G s heterotrimeric proteins may further enhance the analgesic tolerance and hyperalgesia observed clinically.…”

Section: Author Manuscript Author Manuscriptmentioning

confidence: 99%

“…24,41,42,45,[47][48][49]58 Chronic opioid use has been shown paradoxically to cause excitatory rather than inhibi tory effects on the cell, stimulating pain propagation. 11,14,26,27,31,40,67,76 This enhanced pain and the underlying excitatory signaling have been proposed to be mediated by opioid receptors preferentially coupling to G s proteins, 19,60 or alternatively, via the Gβγ dimer of the G i/o proteins native to opioid receptors. 36,76 More recent data have shown that chronic opioid administration leads to a shift in G protein coupling by μ-opioid receptors (MOR) from G i/o to G s, 74 with the Gβγ of this MOR-associated G s protein also contributing to the excitatory signaling.…”

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confidence: 99%

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Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

Largent-Milnes

Guo

Wang

et al. 2008

The Journal of Pain

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Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)-G protein coupling from G i/o to G s that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L 5 /L 6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G s in the damaged (ipsilateral) spinal dorsal horn. This MOR-G s coupling occurred without changing G i/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G s coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G s coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G s coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G s coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. KeywordsNeuropathic pain; G protein coupling; tolerance; opioids; hyperalgesia; allodynia; μ-opioid receptor Patients who have diseases such as cancer, arthritis, and diabetes often have development of painful neuropathies due to disease progression or medical treatment. HHS Public AccessAuthor manuscript J Pain. Author manuscript; available in PMC 2017 June 13. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript approaches used in the clinic to treat these neuropathies include tricyclic antidepressants, dual-acting reuptake inhibitors, and anticonvulsants (eg, gabapentin) or combinations of these with nonsteroidal anti-flammatory drugs (NSAIDs) and opioids. However, these options often cause side effects such as dizziness and sedation and may not treat the various classifications of neuropathic pain states with comparable efficacy. 30,32,55,77 Treatment of neuropathic pain that is not responsive to first-line therapies is often limited to opioids, which can be effective acutely but have decreased efficacy after chronic exposure, leading to the use of higher doses to achieve the same level of pain relief and often resulting in opioidinduced mechanical and thermal hypersensitivities. 5,7,9,29,30,32,[69][70][71]79,81 For patients taking higher doses of opioids to achieve pain relief, the presence of unwanted side effects including tolerance, dependence, respiratory depression, and constipation furthe...

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“…Increased agonist potency may simply increase the number of bg subunits after activation of the G i -protein. In addition, several studies have also provided evidence that the m-opioid receptor couples to the G as subtype after chronic morphine pretreatment (Chakrabarti et al, 1998(Chakrabarti et al, , 2005Wang and Burns, 2006). GIRK channels are directly activated by bg subunits (Huang et al, 1995), so an increase in bg release after increased excitatory G as signaling mediated by m-opioid receptors could also increase activation of GIRK channels.…”

Section: Discussionmentioning

confidence: 99%

Tolerance to Repeated Morphine Administration Is Associated with Increased Potency of Opioid Agonists

Ingram

Macey

Fossum

et al. 2007

Neuropsychopharmacol

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Tolerance to the pain-relieving effects of opiates limits their clinical use. Although morphine tolerance is associated with desensitization of m-opioid receptors, the underlying cellular mechanisms are not understood. One problem with the desensitization hypothesis is that acute morphine does not readily desensitize m-opioid receptors in many cell types. Given that neurons in the periaqueductal gray (PAG) contribute to morphine antinociception and tolerance, an understanding of desensitization in PAG neurons is particularly relevant. Opioid activity in the PAG can be monitored with activation of G-protein-mediated inwardly rectifying potassium (GIRK) currents. The present data show that opioids have a biphasic effect on GIRK currents in morphine tolerant rats. Opioid activation of GIRK currents is initially potentiated in morphine (EC 50 ¼ 281 nM) compared to saline (EC 50 ¼ 8.8 mM) pretreated rats as indicated by a leftward shift in the concentration-response curve for met-enkephalin (ME)-induced currents. These currents were inhibited by superfusion of the m-opioid receptor antagonist b-funaltrexamine (b-FNA) suggesting that repeated morphine administration enhances agonist stimulation of m-opioid receptor coupling to G-proteins. Although supersensitivity of m-opioid receptors in the PAG is counterintuitive to the development of tolerance, peak GIRK currents from tolerant rats desensitized more than currents from saline pretreated rats (56% of peak current after 10 min compared to 15%, respectively). These data indicate that antinociceptive tolerance may be triggered by enhanced agonist potency resulting in increased desensitization of m-opioid receptors.

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Biochemical demonstration of mu-opioid receptor association with Gsα: enhancement following morphine exposure

Cited by 74 publications

References 33 publications

Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

Tolerance to Repeated Morphine Administration Is Associated with Increased Potency of Opioid Agonists

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