Morphine stimulates nitric oxide release in human mitochondria

Abstract

The expression of morphine by plants, invertebrate, and vertebrate cells and organ systems, strongly indicates a high level of evolutionary conservation of morphine and related morphinan alkaloids as required for life. The prototype catecholamine, dopamine, serves as an essential chemical intermediate in morphine biosynthesis, both in plants and animals. We surmise that, before the emergence of specialized plant and animal cells/organ systems, primordial multi-potential cell types required selective mechanisms to limit their responsiveness to environmental cues. Accordingly, cellular systems that emerged with the potential for recruitment of the free radical gas nitric oxide (NO) as a multi-faceted autocrine/paracrine signaling molecule, were provided with extremely positive evolutionary advantages. Endogenous morphinergic signaling, in concert with NO-coupled signaling systems, has evolved as an autocrine/paracrine regulator of metabolic homeostasis, energy metabolism, mitochondrial respiration and energy production. Basic physiological processes involving morphinergic/NO-coupled regulation of mitochondrial function, with special emphasis on the cardiovascular system, are critical to all organismic survival. Key to this concept may be the phenomenon of mitochondrial enslavement in eukaryotic evolution via endogenous morphine.

Reciprocal Evolution of Opiate Science from Medical and Cultural Perspectives

“…Significantly, however, empirical research examining the developmental and regulatory roles of endogenously expressed, and chemical authentic, morphine in the course of biological evolution of lower and higher animal phyla is still in its infancy. Recent work from our laboratory has helped to establish a working hypothesis with respect to morphine and its cognate μ3 receptor playing a key regulatory role in intermediate metabolic processes via their ability to modulate mitochondrial respiratory complexes through nitric oxide recruitment [81,83]. …”

Dysregulated mitochondrial and chloroplast bioenergetics from a translational medical perspective (Review)

“…In light of the above, we previously hypothesized that the multi-enzyme biosynthetic pathway responsible for endogenous morphine in animal cells may be similarly compromised in neuropsychiatric disorders due to their dependence on dopamine as a major synthetic precursor ( 137 , 138 ). Morphine administration engenders inhibitory effects on neuronal excitation and associated integrated behaviors that are consistent with coordinate regulatory activities on mitochondrial respiration, O 2 consumption, and aerobic ATP synthesis ( 139 ). Furthermore, the metabolic effects of endogenous morphine on CNS mitochondrial functions are selectively mediated by a novel 6-transmembrane domain GPCR, the mu-3 opiate receptor subtype, that is functionally coupled to constitutive NO production and release ( 139 – 145 ).…”

“…Morphine administration engenders inhibitory effects on neuronal excitation and associated integrated behaviors that are consistent with coordinate regulatory activities on mitochondrial respiration, O 2 consumption, and aerobic ATP synthesis ( 139 ). Furthermore, the metabolic effects of endogenous morphine on CNS mitochondrial functions are selectively mediated by a novel 6-transmembrane domain GPCR, the mu-3 opiate receptor subtype, that is functionally coupled to constitutive NO production and release ( 139 – 145 ). The multi-faceted regulatory role of mitochondrial NO on O 2 consumption, oxidative phosphorylation, and ATP production reinforce the biological importance of morphine-coupled regulatory responses in integrated CNS behavioral pathways and their dysregulation in oxidative stress-associated neuropsychiatric disorders ( 95 ).…”

Microbiome: A Potential Component in the Origin of Mental Disorders

“…Morphine exerts cell membrane and mitochondrial membrane actions, which appear to be evolutionarily conserved, probably due to the mitochondrion’s bacterial origin [29]. Thus, morphine-nitric oxide synthase (morphine-NOS) coupling to produce NO, is a mitochondrial regulating chemical messenger [22,29–34].…”

“…Thus, morphine-nitric oxide synthase (morphine-NOS) coupling to produce NO, is a mitochondrial regulating chemical messenger [22,29–34]. This newer coupling phenomena in eukaryotic cells probably supplemented the already present nitrite reductase driven NO generating system found in prokaryotic and eukaryotic cells, thus producing more NO for mitochondrial modulation in an aerobic environment [35–38].…”