We surmise that opioid peptides, i.e., methionine enkephalin, first arose during evolution as modulators of cellular immune function given their immune actions and the presence of enkelytin, a potent antibacterial peptide, and its precursor proenkephalin in animals 500 million years divergent in evolution. Pain probably emerged from this perspective because of its association with proinflammatory events. Endogenous morphine appears to exert positive effects on homeostasis by limiting the degree of excitation. Supporting this view is the fact that the mu3 opiate receptor subtype, which is opioid peptide insensitive and morphine selective, is coupled to constitutive nitric oxide release, which also has this down regulating action in neural, immune, vascular and gastrointestinal tissues. Thus, morphine down regulates immune processes in addiction, an action/function that it appears to normally perform when the situation calls for this action and by so doing in this natural setting, sustains life.

Keywords: Drug Tolerance - physiology, Enkephalins - genetics, Enkephalins - physiology, Pain - immunology, Protein Precursors - physiology, Amino Acid Sequence, Drug Tolerance - physiology, Enkephalins - physiology, Evolution, Molecular, Molecular Sequence Data, Morphine - metabolism, Narcotics - pharmacology, Opioid Peptides - physiology, Pain - physiopathology, Protein Precursors - physiology, Sequence Homology, Amino Acid, Substance-Related Disorders - physiopathology