Changes Of Protein Kinase A And Kappa Opioid Receptor Expressions In Selected Brain Regions During The Process Of Chronic Morphine-induced Place Aversion In Rats

BackgroundDrug addiction is a chronic and relapsing brain disease that leads to a series of serious social and economic problems. Repeated exposures to addictive drugs can result in psychological and physical dependence. Withdrawal symptoms make substance addicts extremely disgusted, and thus negative reinforce impulsive drug seeking behavior and relapse. Considering those, we focus on the neurobiological mechanism underpinning the withdrawal-induced aversion in our study, using the rat’s conditioned place aversion (CPA) model induced by naloxone-precipitated withdrawal from chronic morphine dependence.ObjectivesTo explore neurobiological mechanisms of the withdrawal-induced aversion, the changes of protein kinase A and Kappa opioid receptors were measured in the shell of nucleus accumbens(AcbSH), central amygdaloid nucleis (CeA) and ventral tegmental area (VTA)of CPA model rats.Methods1All72male SD rats were randomly divided into three groups, model group (MN group), and control group (MS group and SN group). MN group was injected with morphine for6.5days,10mg/kg, intraperitoneally (IP), twice per day, naloxone injection,0.3mg/kg, IP, along with conditioned place aversion training, to develop the CPA model. The MS group was administrated equivalent volume of morphine and saline. Also the SN group was injected with equivalent volume of saline and naloxone. 2. During the process of morphine-induced CPA, the expression of protein kinase A was assayed with immunohistochemistry in the AcbSH, CeA and VTA.Results1. Before the development of CPA, PKA and kappa opiate receptors expressions were no significant differences between the model group and control group in the AcbSH, CeA and VTA. After development of CPA, PKA expressions showed significant differences between the model group and control group in the AcbSH (F=36.516, P=0.000) and VTA (F=9.853, P=0.018).The average gray intensity of MN group in the AcbSH (109.50±4.661) was apparently higher than the MS group (126.50±3.697, P<0.001, and the SN group (133.50±6.364, P<0.001). Similarly, kappa opiate receptors expressions also showed significant differences between the model group and control group in the CeA(F=27.833, P=0.000). The average gray intensity of MN group(99.56±7.667)was higher than SN group(118.25±1.708; P<0.001).2. In the MN group, Protein kinase A and kappa opiate receptors expressions occurred adaptive changes at different points of CPA. For example, protein kinase A expressions in the AcbSH (F=5.321, P=0.004) and CeA (F=7.256, P=0.029) showed significant differences. Similarly, kappa opiate receptors expressions in the AcbSH (F=3.820, P=0.016), CeA (F=3.153, P=0.039) and VTA (F=10.216, P=0.004) However, PKA and kappa opiate receptors expressions were no significant differences both MS group and SN group.Conclusion1. The neuroadaptation mediated by protein kinase A and kappa-opiate receptors may be the important molecular biology foundation of CPA.2. The upregulation of AC-cAMP-PKA-CREB signaling pathway, in the AcbSH and VTA probably participate in the process of CPA.