Dopamine is necessary to endogenous morphine formation in mammalian brain in vivo

Abstract

Morphine, the most used compound among narcotic analgesics, has been shown to be endogenously present in different mammalian/invertebrate normal tissues. In this study, we used mice that cannot make dopamine due to a genetic deletion of tyrosine hydroxylase specifically in dopaminergic neurons, to test the hypothesis that endogenous dopamine is necessary to endogenous morphine formation in vivo in mammalian brain. When dopamine was lacking in brain neurons, endogenous morphine was missing in brain mouse whereas it could be detected in brain from wild type rodent at a picogram range. Our data prove for the first time that endogenous dopamine is necessary to endogenous morphine formation in normal mammalian brain. Morphine synthesis appears to be originated from dopamine through L-tyrosine in normal brain tissue. Morphine synthesis is not considered to occur inside the same neuron in normal tissue; released dopamine might be transported into morphinergic neuron and further transformed into morphine. A physiological role for endogenous morphine is suggested considering that dopamine could modulate thermal threshold through endogenous morphine formation in vivo. Thus, dopamine and endogenous opiates/opioid peptides may be interconnected in the physiological processes; yet, endogenous morphine may represent a basic link of this chain.

Mapping of endogenous morphine‐like compounds in the adult mouse brain: Evidence of their localization in astrocytes and GABAergic cells

“…Endogenous morphine is thought to derive from dopamine biosynthesis, and its synthesis pathway was characterized in SH-SY5Y, a tumor-derived catecholaminergic cell line (Poeaknapo et al, 2004;Boettcher et al, 2005;Goumon et al, 2009). Moreover, a recent publication showed an absence of endogenous morphine in mice lacking tyrosine hydroxylase, suggesting that dopamine is necessary for endogenous morphine biosynthesis in vivo (Neri et al, 2008). However, several reports suggest that morphinelike compounds can also be synthesized by non-dopaminergic or non-catecholaminergic cells such as pancreatic cells, hepatocytes, and placenta-derived cells (Weitz et al, 1987;Molina et al, 1995;Poeaknapo et al, 2004).…”

“…In mammals, the endogenous morphine biosynthesis pathway has been studied in the SH-SY5Y human neuronal catecholaminergic cell line and has been shown to derive from the dopamine biosynthesis pathway, leading to codeine and finally to morphine (Poeaknapo et al, 2004;Boettcher et al, 2005;Muller et al, 2008;Stefano et al, 2008). In addition, blockade of the dopamine biosynthesis using a tyrosine hydroxylase (TH) conditional knockdown mouse model is associated with a deficit in endogenous morphine synthesis (Neri et al, 2008), suggesting that dopamine is a precursor of endogenous morphine in mammalian cells. However, because the non-dopaminergic cell line DAN-G produces morphine (Poeaknapo et al, 2004), it is possible that non-dopaminergic cells can internalize dopamine or intermediate metabolites of the morphine biosynthesis pathway, such as tetrahydropapaveroline (THP; also called norlaudanosoline), but also synthesize intermediate metabolites for morphine biosynthesis, to complete the production of endogenous morphine (Boettcher et al, 2005;Goumon et al, 2009;Grobe et al, 2010).…”

Localization of endogenous morphine‐like compounds in the mouse spinal cord

“…Moreover, a recent publication showed the absence of endogenous morphine in mice lacking TH, suggesting that dopamine is necessary for endogenous morphine biosynthesis in vivo (Neri et al, 2008). However, two recent articles revealed that, in the mouse and rat brains, endogenous alkaloids are absent from dopaminergic neurons of the substantia nigra and their processes in the striatum (Charron et al, 2011;Laux et al, 2011).…”

“…Endogenous morphine biosynthesis pathways have been demonstrated in the SH-SY5Y human cell line and shown to be derived from dopamine (Boettcher et al, 2005;Muller et al, 2008;Neri et al, 2008;Poeaknapo, 2005;Poeaknapo et al, 2004). However, several reports have noted that endogenous alkaloids can be synthesized by nondopaminergic or noncatecholaminergic cells (i.e., pancreatic cells, hepatocytes, and placenta-derived cells; Molina et al, 1995;Poeaknapo et al, 2004;Weitz et al, 1987), suggesting that nondopaminergic cells may internalize dopamine or intermediate metabolites to finalize morphine biosynthesis (Charron et al, 2011;Goumon et al, 2009;Laux et al, 2011).…”

Sample preparation and separation techniques for bioanalysis of morphine and related substances

“…This field of research is not thoroughly investigated and the significance of these finding is not known at present but it is stated that morphine represents a new endogenous neurotransmitter in brain physiology [75]. The endogenous concentration of morphine in human plasma is up to 0.1 ng/mL [76]. Thus a very sensitive and selective method of analysis is required to measure such levels in biosamples [77,78] (Table 3).…”