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IRAS Modulates Opioid Tolerance and Dependence by Regulating μ Opioid Receptor Trafficking

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Abstract

Imidazoline receptor antisera-selected (IRAS) protein, the mouse homologue named Nischarin, was found to target to early endosomes with properties of sorting nexins in vitro. Recently, we generated IRAS knockout mice and found IRAS deficiency exacerbated the analgesic tolerance and physical dependence caused by opioids, suggesting that IRAS plays a role in regulating μ opioid receptor (MOR) functions. In the present study, we found that IRAS interacts with MOR and regulates MOR trafficking in vitro. In the CHO or HEK293 cells co-expressing MOR and IRAS, IRAS, through its PX domain, interacted with MOR. The interaction facilitated the recycling of internalized MOR and prevented MOR downregulation induced by DAMGO, the MOR agonist. Functionally, IRAS accelerated MOR resensitization and attenuated DAMGO-induced MOR desensitization, which is believed as one of mechanisms mediating opioid tolerance and dependence. Taken together, we propose that IRAS is a new MOR interacting protein and regulates agonist-induced trafficking of MOR via sorting internalized MOR to the recycling pathway, which may be a molecular mechanism underlying IRAS modulating opioid tolerance and dependence.

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Acknowledgments

The authors would like to express their gratitude to Dr. Lee-Yuan Liu-Chen (School of Medicine, Temple University, USA) for giving the advice and revising this manuscript. This work was supported by the Key Project of National Natural Science Foundation of China (No. 30930040), the National Basic Research Program of China (No. 2009CB522008 and No. 2015CB553504), and the Beijing Natural Science Foundation of China (No. 7122137).

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We declare that there is no conflict of interest.

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  1. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China

    Fei Li, Hao Ma, Ning Wu & Jin Li

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  1. Fei Li
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Correspondence to Ning Wu or Jin Li.

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Li, F., Ma, H., Wu, N. et al. IRAS Modulates Opioid Tolerance and Dependence by Regulating μ Opioid Receptor Trafficking. Mol Neurobiol 53, 4918–4930 (2016). https://doi.org/10.1007/s12035-015-9417-6

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