Endogenous morphine synthetic pathway preceded and gave rise to catecholamine synthesis in evolution (Review)

Abstract

Abstract. The biological presence and regulatory function of the plant alkaloid morphine in relatively simple and complex integrated animal systems has previously been shown. The pivotal role of dopamine as a chemical intermediate in the morphine biosynthetic pathway in plants establishes a functional basis for its expansion into an essential role as the progenitor catecholamine signaling molecule. In invertebrate neural systems, dopamine serves as the preeminent catecholamine signaling molecule, with the emergence and limited utilization of norepinephrine and its biosynthetic enzyme dopamine ß-hydroxylase in newly defined adaptational chemical circuits required by a rapidly expanding set of physiological demands. In vertebrates, epinephrine emerges as the major end of the catecholamine synthetic pathway consistent with a newly incorporated regulatory modification, i.e. N-methylation of norepinephrine. Given the striking similarities between the enzymatic steps in the morphine biosynthetic pathway and those driving the evolutionary adaptation of catecholamine chemical species to accommodate an expansion of interactive but distinct signaling systems, we surmise that the evolutionary emergence of catecholamine systems required conservation and selective 'retrofit' of specific enzyme activities, i.e. catechol O-methyl transferase and phenylethanol-amine N-methyl transferase, drawn from cellular morphine expression. This hypothesis is further supported by the critical recruitment of enzymatically synthesized tetrahydrobiopterin (BH4) both as an essential cofactor for tyrosine hydroxylase-mediated dopamine production and as a secondary electron donor for nitric oxide synthase-mediated nitric oxide (NO) production. The establishment of a reciprocal regulatory linkage between NO and catecholaminergic processes, as mediated by BH4, subserves a pivotal capacity to promote autocrine and paracrine regulation of signaling molecules. In summary, ongoing development and adaptation of catecholamine signaling pathways in animals appear to be related to their mobile lifestyle associated with complex feeding, sexual and protective processes, which also generate free radicals, thus requiring morphinergic signaling coupling to NO release.

Endogenous morphine/nitric oxide-coupled regulation of cellular physiology and gene expression: Implications for cancer biology

“…Importantly, candidate genes involved in endogenous morphine biosynthesis including catechol-O-methyl transferase (COMT), CYP2D6, and phenylethanolamine N-methyltransferase (PNMT) are expressed in both undifferentiated and differentiated MLPC, suggesting that MLPC have the potential for morphine expression. This data also suggests that morphinergic signaling preceded that of catecholamines [148]. Taken together, for the first time, we show elements of an endogenous morphine signaling in progenitor stem cells, suggesting the presence and physiological significance of a μ 3 -receptor during early development.…”

“…Furthermore, in medullary histolytic reticulosis, which is exemplified by cells having hyperactivity, an absence of μ 3 receptors, suggests a perturbation of morphine-regulated cellular events [155]. Thus, it would appear that morphinergic signaling has inserted itself in many processes taking a long time to evolve during evolution [148], including those regulating the proliferation of cells across diverse phyla.…”

Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy

“…Dopamine neurons, particularly those located in the VTA, have been strongly implicated in reinforcement in general and addiction in particular. Hypocretin and dopamine are evolutionarily linked from both a neurochemical and an anatomical perspective (23). The VTA receives a major hypocretin projection and projects to the nucleus accumbens.…”

The neurobiological link between compassion and love

“…Obviously, endogenous morphinergic signaling plays a significant role here [11,14]. This is especially true since endogenous morphine biosynthesis, found in humans, vertebrates, mammals, and invertebrates [14,42,43,81], involves elements of dopamine synthesis and its metabolism [11,14,82–85], thereby linking two critical signaling systems [86,87]. Specifically, endogenous morphine production has been demonstrated in limbic tissues, e.g., hippocampus and amygdala [42,43,88,89].…”

“…Specifically, endogenous morphine production has been demonstrated in limbic tissues, e.g., hippocampus and amygdala [42,43,88,89]. It is made by human and invertebrate cells [90,91] and dopamine serves as a major precursor, linking many of these phenomena (love, addiction, eating) into a “common” signaling family [87,92]. It’s presence in human stem cells underscores its importance in evolution as well as its persistence [92,93].…”