Engagement of μ-opioid receptors (sum activity) emanates from both exogenous (pharmacological), as well as endogenous sources (endogenous opioid peptides), the latter being shaped by a plethora of factors as exemplified above. Overall, biological responses prompted by μ-receptor activation occur at the expense of energetically costly (anabolic) programs such as reproduction, the immune response or bone formation. While such changes may be temporally beneficial in the face of challenging environments, their persistence (e.g. due to long-term opioid treatment) culminates in disease.