Chronic morphine acts via a protein kinase Cγ–Gβ–adenylyl cyclase complex to augment phosphorylation of Gβ and Gβγ stimulatory adenylyl cyclase signaling

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

doi:10.1016/j.molbrainres.2005.04.004

Cited by 31 publications

(40 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Introductionmentioning

confidence: 53%

“…We hypothesized that the strategies that cells use to rescue themselves from the sustained activation of opioid receptors would depend on the consequences of their short-term activation in the opioid-naive state. This formulation predicts that previously demonstrated sequelae of longterm morphine treatment [e.g., augmented phosphorylation of AC (Chakrabarti et al, 1998b) and the G␤ subunit of G proteins (Chakrabarti et al, 2001(Chakrabarti et al, , 2005bChakrabarti and Gintzler, 2003], increased membrane translocation of protein kinase C␥ (PKC␥) Zeitz et al, 2001;Chakrabarti et al, 2005b), increased MOR G␣ s association (Chakrabarti et al, 2005a), all of which shift short-term MOR-coupled signaling from AC inhibitory to stimulatory (Gintzler and Chakrabarti, 2006), are not hard-wired and in fact will be negated, or reversed, in opioid-naive cells manifesting short-term stimulatory responsiveness to MOR activation.…”

mentioning

confidence: 53%

“…This antibody recognizes 23 amino acids of the second cytoplasmic domain (KGPVVAGVI-GARKPQYDIVVGNT; S. Mollner, personal communication). PKC␥ was immunoprecipitated using a mouse monoclonal antibody (6 l/ 600 g of protein; Sigma Chemical, St. Louis, MO), generated against rat PKC␥ 684 to 697 amino acid residues (Chakrabarti et al, 2005b). G␣ s was immunoprecipitated from solubilized membrane using a rabbit anti-G␣ s (bovine) polyclonal affinity-purified antibody generated against the C terminus of the G␣ s subunit (385-394 amino acids; U.S. Biologicals, Swampscott, MA; 1 l/100 g of protein) (Chakrabarti et al, 2005b;Chakrabarti and Gintzler, 2007).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Plasticity of Adenylyl Cyclase-Related Signaling Sequelae after Long-Term Morphine Treatment

Shy¹,

Chakrabarti²,

Gintzler³

2007

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

Adaptations to long-term morphine treatment resulting in tolerance are protective by counteracting the consequences of sustained opioid receptor activation. Consequently, the manifestation of specific adenylyl cyclase (AC)-related neurochemical sequelae of long-term morphine treatment should depend on the consequences of short-term -opioid receptor (MOR) activation. We tested this by comparing complementary chemical sequelae of long-term morphine treatment among cells in which short-term MOR activation inhibited instead of stimulated AC activity. Short-term activation of MOR in Chinese hamster ovary (CHO) cells stably transfected with MOR (MOR-CHO) inhibits AC activity. Long-term morphine treatment of these cells increased AC and G␤ phosphorylation, membrane protein kinase C␥ (PKC␥) translocation, and MOR G s association. All converge, shifting the consequences of short-term MOR activation from G␣ i /G␣ o inhibitory to AC stimulatory signaling. In contrast, overexpression of the G␤␥-stimulated AC isoform AC2 (which converted MOR-coupled inhibition to stimulation of AC) eliminated or reversed these adaptations to long-term morphine treatment; it negated the increase in G␤ phosphorylation and PKC␥ translocation while reversing the increase in AC phosphorylation and MOR G s association. These adaptations greatly attenuated MOR-coupled stimulation of AC activity. Altered overexpression of AC protein per se was not a confounding factor because MOR-CHO overexpressing AC1, which is inhibited by short-term MOR activation, manifested adaptations to long-term morphine treatment qualitatively identical with those of MOR-CHO. These results reveal that adaptations elicited by long-term morphine treatment depend on the effects of short-term MOR activation. This dynamic and pliable nature of tolerance mechanisms could represent a new paradigm for pharmacotherapeutics.All formulations of opioid tolerance are based on the tenet that it is adaptive. All identified neurochemical adaptations to long-term morphine enable cell survival by reinstating initial steady-state conditions. For example, up-regulation of the adenylyl cyclase (AC) system, believed to underlie the AC "superactivation" that is manifest upon short-term precipitated opioid withdrawal of long-term opioid-treated tissue (Chavkin and Goldstein, 1984;Chakrabarti et al., 1995;Cox and Crowder, 2004), would neutralize the persistent ongoing opioid receptor-coupled inhibition of AC. Opioid receptor uncoupling and its arrestin-mediated internalization that has been demonstrated in some preparations after persistent opioid exposure (Appleyard et al., 1999;Bohn et al., 2000) has been postulated to compensate for the sustained inhibitory action of drugs like morphine that are resistant to proteolytic degradation and thus persist in the extracellular milieu. Augmented AC stimulatory signaling via G␤␥ (Chakrabarti et al., 1998a(Chakrabarti et al., ,b, 2005bChakrabarti and Gintzler, 2003) and increased interaction of the -opioid receptor (MOR) with G s (Chakrabarti et ...

show abstract

Section: Introductionmentioning

confidence: 53%

mentioning

confidence: 53%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Plasticity of Adenylyl Cyclase-Related Signaling Sequelae after Long-Term Morphine Treatment

Shy¹,

Chakrabarti²,

Gintzler³

2007

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

show abstract

“…GluA4 can also be phosphorylated at Ser842 by PKC-g (Gomes et al, 2007;Zheng and Keifer, 2008). Deletion of the gene encoding PKC-g abolishes opioid-induced hypersensitivity (Célérier et al, 2004), whereas repeated administration of m-opioid agonists increases PKC-g activity (Chakrabarti et al, 2005;Narita et al, 2001). Thus, PKC-g may represent an additional key player in the regulation of trafficking of GluA4-containing AMPAR by opioids.…”

Section: Discussionmentioning

confidence: 99%

Pain after Discontinuation of Morphine Treatment Is Associated with Synaptic Increase of GluA4-Containing AMPAR in the Dorsal Horn of the Spinal Cord

Cabañero

Baker

Zhou

et al. 2013

Neuropsychopharmacol

View full text Add to dashboard Cite

Withdrawal from prescribed opioids results in increased pain sensitivity, which prolongs the treatment. This pain sensitivity is attributed to neuroplastic changes that converge at the spinal cord dorsal horn. We have recently reported that repeated morphine administration triggers an insertion of GluA2-lacking (Ca 2 þ -permeable) a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) in the hippocampus. This finding together with the reported involvement of AMPAR in the mechanisms underlying inflammatory pain led us to hypothesize a role for spinal AMPAR in opioid-induced pain behavior. Mice treated with escalating doses of morphine showed hypersensitivity to mechanical stimulation. Intrathecal administration of a Ca 2 þ -permeable AMPAR selective blocker disrupted morphine-induced mechanical sensitivity. Analysis of the expression and phosphorylation levels of AMPAR subunits (GluA1/2/3/4) in homogenates and in postsynaptic density fractions from spinal cord dorsal horns showed an increase in GluA4 expression and phosphorylation in the postsynaptic density after morphine. Co-immunoprecipitation analyses suggested an increase in GluA4 homomers (Ca 2 þ -permeable AMPAR) and immunohistochemical staining localized the increase in GluA4 levels in laminae III-V. The excitatory postsynaptic currents (EPSCs) recorded in laminae III-V showed enhanced sensitivity to Ca 2 þ -permeable AMPAR blockers in morphinetreated mice. Furthermore, current-voltage relationships of AMPAR-mediated EPSCs showed that rectification index (an indicator of Ca 2 þ -permeable AMPAR contribution) is increased in morphine-treated but not in saline-treated mice. These effects could be reversed by infusion of GluA4 antibody through patch pipette. This is the first direct evidence for a role of GluA4-containing AMPAR in morphineinduced pain and highlights spinal GluA4-containing AMPAR as targets to prevent the morphine-induced pain sensitivity.

show abstract

“…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: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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...

show abstract

Chronic morphine acts via a protein kinase Cγ–Gβ–adenylyl cyclase complex to augment phosphorylation of Gβ and Gβγ stimulatory adenylyl cyclase signaling

Cited by 31 publications

References 42 publications

Plasticity of Adenylyl Cyclase-Related Signaling Sequelae after Long-Term Morphine Treatment

Plasticity of Adenylyl Cyclase-Related Signaling Sequelae after Long-Term Morphine Treatment

Pain after Discontinuation of Morphine Treatment Is Associated with Synaptic Increase of GluA4-Containing AMPAR in the Dorsal Horn of the Spinal Cord

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

Contact Info

Product

Resources

About