Inhibition of orexin receptor 1 contributes to the development of morphine dependence via attenuation of cAMP response element-binding protein and phospholipase Cβ3

Abstract

Noradrenergic neurons of the locus coeruleus (LC) receive projection from hypothalamus orexinergic neurons and express orexin 1 receptor (Orx1). Orx in the locus coeruleus nucleus is involved in the development of morphine dependence. The downstream signaling of Orx contribution to the development of morphine dependence in LC neurons of morphine-dependent rats was studied. Therefore, we evaluated cyclic adenosine monophosphate (cAMP), cAMP response element-binding protein (CREB) and phospholipase Cβ3 (PLCβ3) levels by the application of immunohistochemistry. Results showed that cAMP, CREB and PLCβ3 levels were suppressed by the application of SB-334867 (as a selective Orx1 antagonist) in morphine-dependent rats. Our results unraveled that Orx1 blockade is involved in the development of morphine dependency through diminution of a variety of intracellular events including the cAMP, CREB and PLCβ3 levels in morphine-dependent rats. Furthermore, the Orx1 blockade could decrease the percentage of tyrosine hydroxylase (TH)+/CREB+ and TH+/PLCβ3+ neurons in LC of morphine-treated rats. It is concluded that the activation of Orx1 in LC nucleus might be involved in some intracellular changes in morphine dependent rats.