Endogenous morphine: opening new doors for the treatment of pain and addiction

Pryor, Stephen C.; Zhu, Wei; Cadet, Patrick; Bianchi, Enrica; Guarna, Massimo; Stefano, George B.

doi:10.1517/14712598.5.7.893

Cited by 16 publications

(19 citation statements)

References 109 publications

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“…In this regard we are drawn to nitric oxide (NO) signaling because of its uniform presence in living organisms and its coupling to morphine signaling (28,(32)(33)(34). Initially, it was demonstrated that vascular dilation is mediated to a large extent by endothelium-dependent NO, produced by the enzyme nitric oxide synthase (NOS) in the presence of the cofactor tetrahydrobiopterin (BH4), found only in animals, as well as mediated via the cGMP-dependent downstream signaling cascade (35)(36)(37)(38)(39), found in both plants and animals.…”

Section: Intracellular Signalingmentioning

confidence: 99%

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

Stefano¹,

Kream²

2007

Int J Mol Med

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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.

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Section: Intracellular Signalingmentioning

confidence: 99%

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

Stefano¹,

Kream²

2007

Int J Mol Med

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“…Dopamine and NO are important neurotransmitters. Many previous studies showed that their abnormality was concerned with morphine dependence and tolerance [19][20][21][22] . As GTP is the precursor of BH4, excessive catabolism and insufficient anabolism of purine nucleotides by morphine administration may cause serious subsequent effects in vivo.…”

Section: Discussionmentioning

confidence: 99%

Morphine enhances purine nucleotide catabolism in vivo and in vitro

Liu

Kan

et al. 2007

Acta Pharmacologica Sinica

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Aim: To investigate the effect and mechanism of morphine on purine nucleotide catabolism. Methods: The rat model of morphine dependence and withdrawal and rat C6 glioma cells in culture were used. Concentrations of uric acid in the plasma were measured by the uricase-rap method, adenosine deaminase (ADA) and xanthine oxidase (XO) in the plasma and tissues were measured by the ADA and XO test kit. RT-PCR and RT-PCR-Southern blotting were used to examine the relative amount of ADA and XO gene transcripts in tissues and C6 cells. Results: (i) the concentration of plasma uric acid in the morphine-administered group was significantly higher (P<0.05) than the control group; (ii) during morphine administration and withdrawal periods, the ADA and XO concentrations in the plasma increased significantly (P<0.05); (iii) the amount of ADA and XO in the parietal lobe, liver, small intestine, and skeletal muscles of the morphine-administered groups increased, while the level of ADA and XO in those tissues of the withdrawal groups decreased; (iv) the transcripts of the ADA and XO genes in the parietal lobe, liver, small intestine, and skeletal muscles were higher in the morphineadministered group. The expression of the ADA and XO genes in those tissues returned to the control level during morphine withdrawal, with the exception of the skeletal muscles; and (v) the upregulation of the expression of the ADA and XO genes induced by morphine treatment could be reversed by naloxone. Conclusion:The effects of morphine on purine nucleotide metabolism might be an important, new biochemical pharmacological mechanism of morphine action.

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“…More specifically, cortisol and norepinephrine are primarily responsible (61)(62)(63)(64)(65). Other molecules involved, e.g., melatonin (66) and anandamide (28), and the connection of NO with the pain response (16,28,65,66), as mentioned above, have also been detected.…”

Section: Pain Perception As a Homeostatic Mechanism And The Relaxatiomentioning

confidence: 92%

“…This information can further be used to understand some of the endogenous pain relief that occurs particularly after exposure to a series of painful stimuli, a mechanism that is found to have morphine-like properties and, perhaps, is mediated via these endocannabinoid and morphine-laden amygdalar pathways (14,16). Further credence to these findings stems from lesional data.…”

Section: Specific Neural Pathways Involved In Pain Processingmentioning

confidence: 99%

“…It therefore seems that the relaxation response has a role in pain palliation and that this effect is critically mediated by catecholamines and NO (52,80). This is especially true because of the emotional qualities that a pain stimulus may depend on, which involve limbic structures (15,16,71,81,82).…”

Section: Pain Perception As a Homeostatic Mechanism And The Relaxatiomentioning

confidence: 99%

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Pain and relaxation (Review)

Salamon

Esch²,

Stefano³

2006

Int J Mol Med

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Abstract. The modern notion of pain and its clinical management, along with its physiological origins, is of exceeding interest to both clinicians and basic science researchers. While much is known about the control of pain via non-steroidal anti-inflammatory medications or comparative exogenous analgesics, little is known about the interplay between pain perception and its relationship with catecholamine molecules. We believe that the perception of pain and the body's self-attempt to alleviate it utilizing conventional homeostatic mechanisms via endogenous opiate release is mediated by key catecholamines, and that this effect is further modulated by nitric oxide. We further propose a new paradigm which links pain, endogenous opiates, and the catecholamines in a unique robust fashion demonstrating a complex symbiotic signaling system.

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Endogenous morphine: opening new doors for the treatment of pain and addiction

Cited by 16 publications

References 109 publications

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

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

Morphine enhances purine nucleotide catabolism in vivo and in vitro

Pain and relaxation (Review)

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