Cholecystokinin receptor-1 mediates the inhibitory effects of exogenous cholecystokinin octapeptide on cellular morphine dependence

Abstract

BackgroundCholecystokinin octapeptide (CCK-8), the most potent endogenous anti-opioid peptide, has been shown to regulate the processes of morphine dependence. In our previous study, we found that exogenous CCK-8 attenuated naloxone induced withdrawal symptoms. To investigate the precise effect of exogenous CCK-8 and the role of cholecystokinin (CCK) 1 and/or 2 receptors in morphine dependence, a SH-SY5Y cell model was employed, in which the μ-opioid receptor, CCK1/2 receptors, and endogenous CCK are co-expressed.ResultsForty-eight hours after treating SH-SY5Y cells with morphine (10 μM), naloxone (10 μM) induced a cAMP overshoot, indicating that cellular morphine dependence had been induced. The CCK receptor and endogenous CCK were up-regulated after chronic morphine exposure. The CCK2 receptor antagonist (LY-288,513) at 1–10 μM inhibited the naloxone-precipitated cAMP overshoot, but the CCK1 receptor antagonist (L-364,718) did not. Interestingly, CCK-8 (0.1-1 μM), a strong CCK receptor agonist, dose-dependently inhibited the naloxone-precipitated cAMP overshoot in SH-SY5Y cells when co-pretreated with morphine. The L-364,718 significantly blocked the inhibitory effect of exogenous CCK-8 on the cAMP overshoot at 1–10 μM, while the LY-288,513 did not. Therefore, the CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence in SH-SY5Y cells. An additional inhibitory effect of CCK-8 at higher concentrations appears to involve the CCK1 receptor.ConclusionsThis study reveals the difference between exogenous CCK-8 and endogenous CCK effects on the development of morphine dependence, and provides the first evidence for the participation of the CCK1 receptor in the inhibitory effects of exogenous CCK-8 on morphine dependence.

The role of reactive oxygen species in morphine addiction of SH-SY5Y cells

“…Next, we aimed to investigate the change of cAMP accumulation in acute/chronic morphine administration and morphine withdrawal cells, as well as to further prove that morphine addiction cell model could be utterly competent for our subsequent assays. It has been reported that the level of cAMP was closely associated with the cellular opioid-dependent state [18,22]. After differentiated SH-SY5Y cells were treated with morphine (10 μM) for 10 min (acute morphine administration), cAMP level significantly decreased (**P b 0.01) compared with that of control group.…”

“…It has been already reported that the SH-SY5Y cell can be induced to a differentiated cell line which displays an in vitro opioid-dependent state through the up-regulation of the adenylate cyclase effector system [17,18,19]. The morphology of SH-SY5Y cells was captured after the treatment with RA for 6 days.…”

Over-expression of CCK1 Receptor Reverse Morphine Dependence

“…Our previous study showed that 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. We hypothesized that this phenomenon was related to the different functions of CCK receptor subtypes.…”

“…Lu et al concluded that CCK1R present in discrete regions of the brain has a low affinity for central CCK and is not involved in the development of morphine tolerance and dependence (Lu et al 2001 ). However, we previously found that chronic pretreatment with exogenous CCK-8 significantly inhibited morphine dependence, and that activation of central CCK1R by exogenous CCK-8 did attenuate opioid dependence in vivo and in vitro (Wen et al 2012a , b ). Several studies have revealed that the two different CCK receptor subtypes have opposing influences on behavioral actions(Lu et al 2001 ; Potter et al 2012 ).…”

Unexpected development of tongue squamous cell carcinoma after sclerotherapy for the venous malformation: a unique case report and literature review

“…To our best knowledge, this is the first study to document the development of oral SCC after sclerotherapy. Nevertheless, several sporadic cases of esophageal cancer development following sclerotherapy have been reported for esophageal varices [4-9], and most of the carcinomas are SCC. Moreover, in 2012, Hashimoto et al also reported a unique case of papillary renal cell carcinoma after sclerotherapy for simple renal cyst [10].…”