Mu-Opioid Receptors Expressed in Glutamatergic Neurons are Essential for Morphine Withdrawal
Xin-Yan Zhang 1,2 • Qing Li1 • Ye Dong1 • Wei Yan 1,2 • Kun Song 1,2 • Yong-Qin Lin 1,2 • Yan-Gang Sun 1
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
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 morphine withdrawal is largely mediated by MORs expressed in Vglut2+ glutamatergic neurons.
Keywords
Morphine; Mu-opioid receptor; Naloxone precipitated withdrawal; Dorsal spinal cord; Locomotor hyperactivity
