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The cross-talk between the apelin\/APJ system and hypothalamic mu opioid signaling, as well as its heterodimerization with kappa opioid receptors (KORs), supports the potential relevance of this system to addiction. Moreover, several protective effects of apelin against various addictive substances, including methamphetamine, morphine, and alcohol, underscore the need for further investigation into its role in substance use disorder. Understanding the contribution of the apelin\/APJ system in addiction may offer valuable insights into the underlying neurobiology and pave the way for novel therapeutic interventions in substance use disorders. 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