Abstract
Cholecystokinin octapeptide (CCK-8), a gut-brain peptide, regulates a variety of physiological behavioral processes. Previously, we reported that exogenous CCK-8 attenuated morphine-induced conditioned place preference, but the possible effects of CCK-8 on aversively motivated drug seeking remained unclear. To investigate the effects of endogenous and exogenous CCK on negative components of morphine withdrawal, we evaluated the effects of CCK receptor antagonists and CCK-8 on the naloxone-precipitated withdrawal-induced conditioned place aversion (CPA). The results showed that CCK2 receptor antagonist (LY-288,513, 10 µg, i.c.v.), but not CCK1 receptor antagonist (L-364,718, 10 µg, i.c.v.), inhibited the acquisition of CPA when given prior to naloxone (0.3 mg/kg) administration in morphine-dependent rats. Similarly, CCK-8 (0.1–1 µg, i.c.v.) significantly attenuated naloxone-precipitated withdrawal-induced CPA, and this inhibitory function was blocked by co-injection with L-364,718. Microinjection of L-364,718, LY-288,513 or CCK-8 to saline pretreated rats produced neither a conditioned preference nor aversion, and the induction of CPA by CCK-8 itself after morphine pretreatments was not significant. Our study identifies a different role of CCK1 and CCK2 receptors in negative affective components of morphine abstinence and an inhibitory effect of exogenous CCK-8 on naloxone-precipitated withdrawal-induced CPA via CCK1 receptor.
Highlights
Chronic use of opioids such as morphine results in the development of physical and psychological dependence, characterized by the expression of withdrawal symptoms after abstinence of drug administration or treatment of opioid receptor antagonist for precipitation
The conditioned place aversion (CPA) score was 4016122 s, which was statistically significant compared to the saline control group (30685 s)
It has been reported that several CCK2 receptor antagonists such as L-365,260, PD134,308 and LY-288,513, but not CCK1 receptor antagonist such as L-364,718, attenuate the development of morphine dependence and naloxone-precipitated withdrawal symptoms [26,27]
Summary
Chronic use of opioids such as morphine results in the development of physical and psychological dependence, characterized by the expression of withdrawal symptoms after abstinence of drug administration or treatment of opioid receptor antagonist for precipitation The symptoms include both physical and affective components. CCK has been shown to participate in anxiety and stress- related behaviors which reflect the negative affect of morphine withdrawal and are the most important behavioral changes involved in CPA expression [11]. Based on this profile, the CCK system may be involved in the rewarding effects of opioids and aversively motivated drug seeking process
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