Mu-Opioid Receptors Expressed in Glutamatergic Neurons are Essential for Morphine Withdrawal
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ORIGINAL ARTICLE
Mu-Opioid Receptors Expressed in Glutamatergic Neurons are Essential for Morphine Withdrawal Xin-Yan Zhang1,2 • Qing Li1 • Ye Dong1 • Wei Yan1,2 • Kun Song1,2 Yong-Qin Lin1,2 • Yan-Gang Sun1
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Received: 29 November 2019 / Accepted: 11 February 2020 Ó Shanghai Institutes for Biological Sciences, CAS 2020
Abstract Although opioids still remain the most powerful pain-killers, the chronic use of opioid analgesics is largely limited by their numerous side-effects, including opioid dependence. However, the mechanism underlying this dependence is largely unknown. In this study, we used the withdrawal symptoms precipitated by naloxone to characterize opioid dependence in mice. We determined the functional role of mu-opioid receptors (MORs) expressed in different subpopulations of neurons in the development of morphine withdrawal. We found that conditional deletion of MORs from glutamatergic neurons expressing vesicular glutamate transporter 2 (Vglut2?) largely eliminated the naloxone-precipitated withdrawal symptoms. In contrast, conditional deletion of MORs expressed in GABAergic neurons had a limited effect on morphine withdrawal. Consistently, mice with MORs deleted from Vglut2? glutamatergic neurons also showed no morphine-induced locomotor hyperactivity. Furthermore, morphine withdrawal and morphine-induced hyperactivity were not significantly affected by conditional knockout of MORs from dorsal spinal neurons. Taken together, our data indicate that the development of
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12264-020-00515-5) contains supplementary material, which is available to authorized users. & Yan-Gang Sun [email protected] 1
Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
2
University of the Chinese Academy of Sciences, Beijing 100049, China
morphine withdrawal is largely mediated by MORs expressed in Vglut2? glutamatergic neurons. Keywords Morphine Mu-opioid receptor Naloxoneprecipitated withdrawal Dorsal spinal cord Locomotor hyperactivity
Introduction Opioids have been used in pain management for a long time, but their chronic use has been limited by numerous side-effects. Among these, opioid-induced dependence causes drug craving and prolongs medication, leading to a public health problem. Multiple maladaptive behaviors induced by the termination of opioid drugs, termed opioid withdrawal, are often used to characterize opioid dependence. Mu-opioid receptors (MORs), encoded by Oprm1 [1–3], are responsible for opioid withdrawal, as MORknockout mice do not express naloxone-precipitated opioid withdrawal behavior [4]. Like other opioid receptors, MORs are coupled with inhibitory G proteins, which in turn activate several intracellular effectors [5–7]. Repeated opioid administration impairs the homeostasis of the nervous system, as reflected by a
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