Co-Morbidity and Self Medication in Schizophrenia: Involvement of Endogenous Morphine Signaling Mechanisms

Richard      M. Kream; Hana      Kuzelova; Milena      Kralickova; Radek      Ptacek; George      B. Stefano

Abstract

For over 30 years, empirical studies have demonstrated expression of chemically authentic morphine by diverse animal tissues and organs systems. De novo biosynthesis of endogenous morphine by animal cells displays striking similarities to the multi-enzyme mediated biosynthetic pathway previously characterized in great biochemical and molecular detail in opium poppy (Papaver somniferum). The committed enzyme step within this pathway involves an asymmetric Pictet-Spengler condensation of dopamine (DA) and 3,4 dihydroxyphenylacetaldehyde (DOPAL), the oxidation product of L- 3,4-dihydroxyphenylalanine (L-DOPA), to form the essential intermediate precursor tetrahydropapaveroline (THP). We have hypothesized that endogenous morphine is synthesized within peripheral sites via conversion of THP in a regulated biosynthetic pathway, or conversely, THP may be directly transported into the CNS and converted to endogenous morphine within a similar biosynthetic pathway. The fundamental chemical relationship of the prototype catecholamine DA and its immediate precursor L-DOPA to endogenous morphine expression indicates a novel reciprocally interactive mechanism that links catecholamine and “morphinergic” pathways in the activation and inhibition of key physiological responses, including higher order neural integration. Dysregulation of interactive DAergic and “morphinergic” signaling pathways within CNS foci may contribute to the etiological factors driving co-morbid behavioral syndromes in major psychiatric disorders. Our short review is designed to provide insights on comorbidity and self-medication in schizophrenia from a novel perspective involving endogenous morphine signaling mechanisms.

Keywords: Schizophrenia, comorbidity, self-medication, endogenous morphine, dopamine, catecholamines, L-DOPA, tetrahydropapaveroline (THP), CNS, De novo biosynthesis.