Distinctive roles of L-type calcium channels subtypes within the dorsal hippocampus in formation of morphine withdrawal-induced aversion in rats.

Although the negative effects coming along with opiate withdrawal are in part modulated by L-type calcium channels (LTCCs), the distinctive physiological properties and functions of LTCCs subtypes suggest differential roles of subtypes during withdrawal. The present study aimed to examine the contributions of LTCC subtypes, Ca1.2 and Ca1.3, within the dorsal hippocampus (DH) in naloxone-precipitated morphine withdrawal using the conditioned place aversion (CPA) paradigm. Firstly, we injected the non-specific LTCCs antagonist verapamil into the DH of morphine-dependent rats before conditioning an environment with naloxone-precipitated withdrawal. Our results showed that verapamil blocked the acquisition of CPA. Then, to explore the molecular mechanisms of LTCCs subtypes during withdrawal, we measured the protein expression of Ca1.2 and Ca1.3 in morphine-dependent rats under different conditions. In morphine-dependent rats, conditioning with withdrawal increased Ca1.2 expression in the membrane, while only acute naloxone injection increased the membrane expression of Ca1.3. To further determine the causal roles of LTCCs subtypes in the withdrawal process, we used Ca1.2 siRNA or Ca1.3 shRNA to knock down the expression of subtypes and detected the effects on CPA and somatic withdrawal signs in morphine-dependent rats. Ca1.2 siRNA, but not Ca1.3 shRNA, inhibited the acquirement of CPA and relieved somatic withdrawal symptoms. Together, our findings reveal that Ca1.2, but not Ca1.3 plays an important role in mediating morphine withdrawal, suggesting this subtype may serve as a potential therapeutic target for the treatment of negative effects in opiate dependence.