There are several key intracellular signalling pathways implicated in MDD that may be directly or indirectly modulated by opioid receptors including extracellular signal-related kinase/mitogen-activated protein kinase (ERK/MAPK), cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) and activator protein-1 (AP-1) (Puryear et al., 2020). This evidence concerns the gene CREB1 and major depressive disorder.