Orexin-A and -B neuropeptides are exclusively synthesized in hypothalamic neurons. These have been implicated to play critical roles in the expression of various behavioral manifestations such as feeding, arousal, wakefulness, drug dependence and tolerance. Orexin ligands activate orexin type-1 and orexin type-2 receptors each displaying a distinct selectivity and distribution profile. Orexinergic neurons innervate various brain structures among which the locus coeruleus (LC) and the lateral paragigantocellularis (LPGi) nuclei are well established as the two key mediators of opiate dependence and tolerance. Both nuclei express OX1Rs and the LC receives excitatory and inhibitory inputs from LPGi. Interestingly, the expression of opiate withdrawal signs is temporally associated with the enhanced activity of LC neurons. Numerous studies support the involvement of the orexin system in mediating opiate effects via affecting OX1Rs within the LC and LPGi. Extensive research has long been focused on the role of the ventral tegmental area (VTA) as a critical center in mediating orexin effects as well as reward processing and addiction. However, a growing amount of evidence supports the involvement of some other brain nuclei (such as LC and LPGi) in these phenomena. The mutual contribution of these structures has not been previously addressed in the literature. The present review aims to discuss and piece together the recent findings on the role of OX1Rs in modulating opiate withdrawal and tolerance with an emphasis on the involvement of the putative paragiganto-coerulear pathway. We conclude with a discussion about possible mechanisms of orexin actions within this pathway and its interaction with other neurotransmitter/modulator systems.