Abstract
Studies demonstrated that cholecystokinin (CCK) system involved in morphine dependence and withdrawal. Our previous study showed that endogenous CCK system were up-regulated after chronic morphine exposure. Additionally, CCK1 receptor significantly blocked the inhibitory effect of exogenous CCK-8 on morphine dependence, but CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence. Therefore, CCK1R and CCK2R function differently in chronic morphine dependence, but the mechanism is still unclear. In this study, HEK-293 cells co-transfected with µ-opioid receptors (HEK293-hMOR) and CCK1R or CCK2R were established. Cells were treated with 10 µM morphine for 6, 12, 16, 24 h and 100 µM naloxone precipitation for 15 min. cAMP overshoot was appeared at 12 h and was increased time dependently after morphine exposure in HEK293-hMOR cells. The cAMP overshoot did not appear in CCK1R-overexpressing HEK293-hMOR cells, while still appeared in CCK2R-overexpressing HEK293-hMOR cells. Over-expression of CCK1R reversed CREB and ERK1/2 activation in HEK293-hMOR cells exposed to morphine. Our study identifies over-expression of CCK1R significantly blocked morphine dependence, which was related with phosphorylation of CREB, and ERK1/2 signaling activation. While over-expression of CCK2R promoted morphine dependence, which was related with phosphorylation of CREB but not ERK1/2 signaling activation.
Highlights
Opioids, such as morphine, are well known for their analgesic effects and addictive properties
Exposure to 10 μM morphine cAMP measurement is to investigate the function and signal transduction pathway of human μ-opioid receptor (hMOR) transfection in HEK293 compared to nontransfection (c–d). cAMP significantly increased in HEK293-hMOR cells treated by 10 μM morphine for 24 h followed by naloxone (100 μM) precipitation (d) but not in HEK293 cells (c)
Our previous study showed that cholecystokinin peptides (CCK)-8 significantly inhibited cAMP overshoot and measures of naloxone-precipitated withdrawal in vivo and in vitro (Wen et al 2012b), similar to CCK receptor antagonists
Summary
Opioids, such as morphine, are well known for their analgesic effects and addictive properties. Chronic use of opioids results in the development of dependence, leading to a withdrawal syndrome upon abrupt discontinuation (Williams et al 2013), which greatly limits their clinical use. The administration of CCK receptor antagonists can prevent or reverse tolerance to systemic exogenous opioids or electroacupuncture-induced analgesia, and suppress morphine withdrawal syndrome (Felicio et al 2001; Han et al 1985, 1986; Lu et al 2001; Mitchell et al 2006; Valverde and Roques 1998; Wen et al 2012a; Xiong and Yu 2006). CCK receptors are classified into two subtypes, CCK1R and CCK2R, based on their pharmacological properties and distribution of specific ligand binding sites. Previous studies have used different receptor antagonists to study the role of the two receptor subtypes and revealed they have different
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