Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

Xu, Jin; Lu, Zhigang; Narayan, Ankita; Rouzic, Valerie P. Le; Xu, Mingming; Hunkele, Amanda; Brown, Taylor G.; Hoefer, William F.; Rossi, Grace C.; Rice, Richard C.; Martínez-Rivera, Arlene; Rajadhyaksha, Anjali M.; Cartegni, Luca; Bassoni, Daniel L.; Pasternak, Gavril W.; Pan, Ying Xian

doi:10.1172/jci88760

Cited by 57 publications

(71 citation statements)

References 75 publications

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“…1a), i.e., female mice were more sensitive to the noxious heat stimulus. Next, we investigated sex differences in the antinociceptive potency of systemic morphine of different doses (1 mg/kg, 3 mg/kg and 10 mg/kg) in accordance with previous studies (the curve of tail-flick test is gradually ascending [22] and morphine ED50 is in the range of 2.3 ± 0.2mg/kg ~ 2.9 ± 0.3mg/kg [38]), since morphine predominantly targets the opioid receptor. As shown in Fig.…”

Section: Sex Differences In Baseline Responses Morphine-induced Analmentioning

confidence: 91%

“…To explore sex differences of sensibility, we picked out adult male and female mice randomly and the pain threshold (baseline latency) was determined and recorded using a radiant-heat tail-flick assay, with a maximal latency of 10 seconds (the heat intensity was set to 26 watt so that the baseline latencies were 2.0 -4.0 seconds) to minimize tissue damage, as previously described [18,22,38,39]. Tolerance in the targeted mice was induced by twice-daily injections with morphine (1, 3, 10 mg/kg, s.c., respectively) for 5 days and the results were calculated as the percentage of maximum possible effect (% MPE) as follows: [(latency after drug -baseline latency) / (10 -baseline latency) × 100].…”

Section: Painful Sensibility Morphine Analgesia Tolerance and Physimentioning

confidence: 99%

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Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

Liu

Zhang

Qin

et al. 2018

Cell Physiol Biochem

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Background/Aims: Opiates are potent analgesics but their clinical use is limited by sex-associated side effects, such as drug tolerance, opioid-induced hyperalgesia and withdrawal reaction. OPRM1, as the main receptor of opioids, plays an important role in the pharmacological process of opioids in rodents and human. We have previously investigated OPRM1, the μ opioid receptor gene, which have dozens of alternatively spliced variants probably correlating with opioid-induced effects in brain regions of four inbred mouse strains and demonstrated the strain-specific expressions of these splice variants. Also, within a strain, the regional expression patterns of some of the variants were similar while others were opposite. Thus, we are aiming to seek out the relationship between sex differences and these alternatively spliced variants. Methods: The present studies follow a SYBR green quantitative PCR (qPCR) which we had used before to examine the expression of OPRM1 splice variant mRNAs in selected brain regions of male and female C57BL/6 mice. Sex-associated differences in baseline latency, opioid-induced tolerance, analgesia and addiction were examined and determined by Tail-flick test, jumps and statistical analysis. Results: The mRNA levels of opioid receptor gene splice variants in male and female mice showed significant differences among the brain regions, implying region-specific alternative splicing of the OPRM1 gene, which was consistent with our previous study. More importantly, the complete mRNA expression profiles of the OPRM1 splice variants was also gender-specific, suggesting a sexual influence on OPRM1 alternative splicing. Conclusion: In brief, we put forward that the distinctions among baseline latency, opioid-induced tolerance, analgesia and physical dependence in male and female mice might correlate with sex associated differential expressions of OPRM1 gene.

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Section: Sex Differences In Baseline Responses Morphine-induced Analmentioning

confidence: 91%

Section: Painful Sensibility Morphine Analgesia Tolerance and Physimentioning

confidence: 99%

Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

Liu

Zhang

Qin

et al. 2018

Cell Physiol Biochem

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“…In conclusion, this study by Xu and colleagues (25) establishes the importance of considering the diversity of MOR alternative splice variants and their distinct signaling responses to our understanding of the mechanisms that underlie opioidinduced side effects. The work constitutes morphine-induced catalepsy, suggesting that the entire MOR C-terminus could play a role in mediating this effect.…”

Section: The Mor C Terminus and Opioid Side Effectsmentioning

confidence: 72%

“…Remarkably, they significance of these variants has not been explored. In this issue, Xu et al (25) address this important point by generating 3 different congenic strains of mice on two genetic backgrounds (C57/BL6 and Sv129 mice) that are known to have different behavioral responses to opioids. Each congenic strain had a different truncation in the C-terminal tail of the MOR.…”

Section: The Mor C Terminus and Opioid Side Effectsmentioning

confidence: 99%

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A “tail” of opioid receptor variants

Puig¹,

Gutstein²

2017

Journal of Clinical Investigation

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Photo‐affinity and Metabolic Labeling Probes Based on the Opioid Alkaloids

Duque,

Vallavoju,

Zhang

et al. 2024

ChemBioChem

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The opioids are powerful analgesics but carry many contingencies that can lead to opioid‐use disorder. Chemical probes derived from the opioid alkaloids can provide deeper insight into the molecular interactions in a cellular context. Here, we designed and developed photo‐click morphine (PCM‐2) as a photo‐affinity probe based on morphine and dialkynyl‐acetyl morphine (DAAM) as a metabolic acetate reporter based on heroin. Application of these probes to SH‐SY5Y, HEK293T, and U2OS cells revealed that PCM‐2 and DAAM primarily localize to the lysosome amongst other locations inside the cell by confocal microscopy and chemical proteomics. Interaction site identification by mass spectrometry revealed the mitochondrial phosphate carrier protein, solute carrier family 25 member 3, SLC25A3, and histone H2B as acylation targets of DAAM. These data illustrate the utility of chemical probes to measure localization and protein interactions in a cellular context and will inform the design of probes based on the opioids in the future.

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Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

Cited by 57 publications

References 75 publications

Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

A “tail” of opioid receptor variants

Photo‐affinity and Metabolic Labeling Probes Based on the Opioid Alkaloids

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