Role of nucleus accumbens μ opioid receptors in the effects of morphine on ERK1/2 phosphorylation

Rosas, Michela; Porru, Simona; Fenu, Sandro; Ruiu, Stefania; Peana, Alessandra Tiziana; Papale, Alessandro; Brambilla, Riccardo; Chiara, G. Di; Acquas, Elio

doi:10.1007/s00213-016-4340-8

Cited by 10 publications

(13 citation statements)

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“…The results of the present study also confirm that both ethanol (Porru et al 2020(Porru et al , 2021Rosas et al 2017) and morphine (Rosas et al 2016;Valjent et al 2004) activate ERKs phosphorylation in the AcbSh of CD1 mice and show for the first time that both WSE (50 mg/kg) and DF (2 mg/ kg) are able to prevent these increases. The acute effects of WSE and DF in the prevention of either ethanol-or morphine-induced ERKs phosphorylation in the AcbSh was assessed, in distinct cohorts of animals, to better define the molecular mechanisms leading to WSE's and DF's prevention of the acquisition of ethanol-or morphine-elicited CPP.…”

Section: Discussionsupporting

confidence: 87%

Effects of docosanyl ferulate, a constituent of Withania somnifera, on ethanol- and morphine-elicited conditioned place preference and ERK phosphorylation in the accumbens shell of CD1 mice

et al. 2022

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Background Docosanyl ferulate (DF) is a behaviourally active GABAA receptor complex (GABAAR) agonist, recently isolated from the standardized methanolic extract of Withania somnifera Dunal (WSE) root. Previous studies have shown that WSE prevents both ethanol- and morphine-dependent acquisition and expression of conditioned place preference (CPP) and stimulation of dopamine release in the nucleus accumbens shell (AcbSh). Aims The study aimed at determining (a) whether DF contributes to WSE’s ability to affect the acquisition and expression of ethanol- and morphine-elicited CPP and, given that phosphorylation of extracellular signal-regulated kinase (pERK) in the AcbSh is involved in associative learning and motivated behaviours, (b) whether WSE and DF may affect ethanol- and morphine-induced ERKs phosphorylation in the AcbSh. Methods In adult male CD1 mice, DF’s effects on the acquisition and expression of ethanol- and morphine-elicited CPP were evaluated by a classical place conditioning paradigm, whereas the effects of WSE and DF on ethanol- and morphine-elicited pERK in the AcbSh were evaluated by immunohistochemistry. Results and conclusions The study shows that DF, differently from WSE, affects only the acquisition but not the expression of ethanol- and morphine-induced CPP. Moreover, the study shows that both WSE and DF can prevent ethanol- and morphine-elicited pERK expression in the AcbSh. Overall, these results highlight subtle but critical differences for the role of GABAARs in the mechanism by which WSE affects these ethanol- and morphine-dependent behavioural and molecular/cellular responses and support the suggestion of WSE and DF for the control of different components of drug addiction.

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Section: Discussionsupporting

confidence: 87%

Effects of docosanyl ferulate, a constituent of Withania somnifera, on ethanol- and morphine-elicited conditioned place preference and ERK phosphorylation in the accumbens shell of CD1 mice

et al. 2022

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“…Their activation by either non-contingent (Acquas et al, 2007; Ibba et al, 2009; Lin et al, 2010; Valjent et al, 2004) or contingent (Faccidomo et al, 2015; Peana et al, 2013; Radwanska et al, 2008) drug exposure represents a critical biochemical event that bridges drug exposure to long-term behavioral consequences (Shiflett and Balleine, 2011; Sweatt, 2001). Accordingly, the role of MEK was shown to be critical for the acquisition of place preference conditioned by d-amphetamine (Gerdjikov et al, 2004), ecstasy (Salzmann et al, 2003), morphine (Lin et al, 2010; Mazzucchelli et al, 2002; Rosas et al, 2016; Spina et al, 2010) and cocaine (Valjent et al, 2000); with the exception, to the best of our knowledge, of ethanol (Groblewski et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of the MEK inhibitor SL327 on the acquisition and expression of ethanol-elicited conditioned place preference and aversion in mice

et al. 2016

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The involvement of mitogen-activating extracellular kinase (MEK) in place conditioning may vary depending on the motivational sign (positive or negative) and nature (pharmacological or nociceptive) of the unconditioned stimulus (US) and on the phase (acquisition or expression) of the learning process. This study investigated the role of MEK on the acquisition and expression of ethanol-elicited (given 2 g/kg) backward (preference, CPP) and forward (aversion, CPA) place conditioning. The MEK inhibitor SL327 (50 mg/kg for CPP, and 50 and 100 mg/kg for CPA) was administered to CD-1 mice 60 minutes before an ethanol dose (acquisition) or 60 minutes before the post-conditioning tests (expression). Ethanol significantly elicited CPP and CPA; SL327 (50 mg/kg) significantly blocked the acquisition of ethanol-elicited CPP, but not that of CPA. Moreover, SL327 (50 and 100 mg/kg) significantly reduced the expression of ethanol-elicited CPP, but not that of CPA. Finally, SL327 also prevented ethanol-elicited (given 2 g/kg) increases of phosphorylated extracellular signal regulated kinase (pERK)-positive neurons in the nucleus accumbens and other nuclei of the extended amygdala. Overall, these results confirmed the differential involvement of MEK in the acquisition and expression of drug-elicited place conditioning and suggested its differential involvement in distinct behavioral outcomes, depending on the motivational sign of the (same) US and on the significance of the experimental phase of the learning process.

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“…Interestingly, the current data indicates that high levels of ERK phosphorylation, irrespective of activation time, is associated with negative physiological outcomes. For example, high levels of pERK are typically seen within the shell of the nucleus accumbens (early and late phase) and the VTA (early phase) (mesolimbic system) following the administration of morphine and fentanyl and is associated with preference for drug paired chambers in mice and rats using the conditioned place preference assay (Lesscher et al, 2003, Rosas et al, 2016. While in the dorsal horn of the spinal cord, high levels of pERK are associated with antinociceptive tolerance and hyperalgesia (Bobeck et al, 2016, Deng et al, 2019.…”

Section: Kurkinol and Kurkinorin Are Potent Activators Of Erkmentioning

confidence: 99%

“…A further limitation of this study is that the dose response effects on ERK phosphorylation at early and late time points were never assessed due to time restrictions. As previously discussed, the biphasic nature of ERK activation is thought to play a role in the different physiological effect of μ receptor agonists, with late-phase (or β-arrestin2 dependent) believed to be involved with abuse liability, tolerance, and hyperalgesia (Lesscher et al, 2003, Rosas et al, 2016. The dose response analysis of ERK phosphorylation at these time points would further add to the accuracy of the bias calculations and provide a better understanding of the role ERK in the behavioural effects of μ receptor agonists.…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

“…However, either i.c.v or injection into the 4 th ventricle may be optimized to result in knockdown in the pre-Bötzinger. Other downstream kinases of MAPK have also been associated with behavioural effects, such as pERK1/2 that is associated with the abuse liability (Lesscher et al, 2003, Rosas et al, 2016 and induction of hyperalgesia by μ receptor agonists (Bobeck et al, 2016, Deng et al, 2019. While the activation of p38 is linked to the induction of anti-nociceptive tolerance (Koch et al, 2004, Yang et al, 2010.…”

Section: The Role Of Other Subcellular Pathways and Regulatory Proteinsmentioning

confidence: 99%

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Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

Alder¹

2021

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Chronic pain is a major problem worldwide, affecting 1 in 5 New Zealanders resulting in a decreased quality of life for the patient and a large socioeconomic problem costing an estimated $13-$14.5 billion a year. Current therapeutics target the mu opioid receptor (μ receptor) and include drugs such as morphine and fentanyl. While these drugs are highly effective in the treatment of strong acute pain, their long-term use is associated with tolerance to the analgesic effects and increasing rates of side effects such as respiratory depression and constipation. Due to their high abuse liability, they are also known to cause dependence and addiction when prescribed for extended periods. This is believed to have played a role in the opioid crisis in the United States and highlights the need for improved therapeutics for the treatment of chronic pain. One mechanism that has been proposed to generate μ receptor agonists for the treatment of chronic pain with reduced analgesic tolerance and safer side effects is the development of G-protein biased agonists. Such agonists selectively activate the canonical G-protein signalling to a greater extent than the non-canonical β-arrestin2 pathway. This is based on previous work in β-arrestin2 knockout mice where the antinociceptive effects were increased, while side effects, including respiratory depression, tolerance, and constipation are reduced, increasing the therapeutic window. In this thesis, we aimed to assess the anti-nociceptive and side effect behavioural profiles of two novel μ receptor agonists, kurkinol (bias = 0.14) and kurkinorin (bias = 0.57), with a varying bias for the G-protein pathway to assess the role of this paradigm. Evaluation of the behavioural profile of kurkinol and kurkinorin revealed that G-protein bias was correlated to increased anti-nociceptive potency and reduced tolerance in wildtype C57BL/6J mice. Furthermore, the anti-nociceptive potency of morphine was increased, and tolerance decreased in in β-arrestin2 knockout mice. While the level of tolerance was reduced for kurkinorin. However, in the chemotherapy-induced model of neuropathic pain, tolerance to kurkinol and kurkinorin developed at the same rate as morphine. Overall this work showed a poor correlation between G-protein bias and therapeutic window. With the G-protein selective kurkinol inducing worse respiratory depression, constipation, and motor coordination impairment compared to kurkinorin. Interestingly, respiratory depressive and constipation effects of kurkinol were not prevented in the β-arrestin2 knockout mice indicating that they are induced through the G-protein pathway. These results highlight the change that has occurred in the biased agonism field over the last 4 years, with the lack of reproducibility of key experiments and poor translation of G-protein biased μ receptor agonists resulting in improved therapeutic windows both clinically and pre-clinically. Moreover, recent research has shown that pathway efficacy (i.e. partial agonism) and not G-protein bias is responsible for the behavioural profiles of compounds previously identified as G-protein biased. We, therefore, decided to further investigate the cell signalling profiles of our two novel agonists to assess them for partial agonism and to assess downstream signalling molecules activated by G-protein and β-arrestin2. <div> </div> This revealed cell-specific inhibition of membrane hyperpolarisation in Hek293 and CHO cells stably expressing the human μ receptor, with kurkinol found to be the most potent in both cell lines, followed by kurkinorin, morphine, and [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO). However, no differences were identified between the μ receptor agonists in the activation of the inwardly rectifying channels in the CHO cell line. The assessment of pCREB (phosphorylated cAMP response-element binding protein) as a β-arrestin2 dependent pathway revealed poor activation by kurkinorin while kurkinol was a potent activator. Bias factors generated from this data showed poor correlations to therapeutic windows. While the differences om CREB phosphorylation was shown to have a stronger correlation to therapeutic windows generated from the behavioural data. Overall this thesis has identified kurkinorin as a μ receptor agonist that induces potent anti-nociception with reduced side effects, without strong-G-protein bias. We also show that the highly selective μ receptor agonist kurkinol has improved anti-nociception with a worse side effect profile adding to the growing body of literature showing bias is not a good predictor in its current state. Furthermore, the discrepancies between cell lines, differential activation of subcellular pathways, and lack of reproducibility between bias equations indicate that the field has massively oversimplified a complex system. Which has, most likely, resulted in the poor translation of in vitro bias factors to clinically available μ receptor agonists for chronic pain.

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Role of nucleus accumbens μ opioid receptors in the effects of morphine on ERK1/2 phosphorylation

Cited by 10 publications

References 47 publications

Effects of docosanyl ferulate, a constituent of Withania somnifera, on ethanol- and morphine-elicited conditioned place preference and ERK phosphorylation in the accumbens shell of CD1 mice

Effects of docosanyl ferulate, a constituent of Withania somnifera, on ethanol- and morphine-elicited conditioned place preference and ERK phosphorylation in the accumbens shell of CD1 mice

Differential effects of the MEK inhibitor SL327 on the acquisition and expression of ethanol-elicited conditioned place preference and aversion in mice

Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

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