Endogenous morphine is produced in response to cardiopulmonary bypass in neonatal pigs

State University of New York College at Old Westbury, Old Westbury, New York, United States
Acta Anaesthesiologica Scandinavica (Impact Factor: 2.32). 12/2000; 44(10):1204-8. DOI: 10.1034/j.1399-6576.2000.441004.x
Source: PubMed


Cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response. Endogenous morphine production has previously been demonstrated in humans after cardiac surgery with CPB. It has been hypothesized that morphine plays a role as an anti-inflammatory mediator in the systemic inflammatory response. The aim of this study was to investigate if the CPB procedure in itself elicits an endogenous morphine production in neonatal pigs.
Endogenous morphine production was measured in arterial blood in piglets exposed to sternotomy alone (sham group, n=10) or sternotomy and CPB (n=10). Blood samples were obtained immediately after the induction of anaesthesia, at the end of CPB and 4 h later. Morphine in arterial blood was detected by radioimmunoassay and confirmed by gas chromatography mass spectrometry.
Animals undergoing CPB showed detectable endogenous morphine concentrations immediately after CPB, with increased concentrations postoperatively. There was no measurable morphine production in the sham operated pigs.
The CPB procedures elicits an endogenous morphine production in neonatal pigs. This morphine response is analogous to the previously demonstrated response in patients subjected to cardiac surgery and CPB.

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    • "Endogenous morphine levels have been investigated after surgical intervention and have been found to be elevated after cardiovascular bypass [25], [26]. Morphine concentrations in the blood are higher after open cholecystectomy compared with laparoscopic cholecystectomy as the less invasive surgical procedure [27]. "
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    ABSTRACT: Mammalian cells synthesize morphine and the respective biosynthetic pathway has been elucidated. Human neutrophils release this alkaloid into the media after exposure to morphine precursors. However, the exact role of endogenous morphine in inflammatory processes remains unclear. We postulate that morphine is released during infection and can be determined in the serum of patients with severe infection such as sepsis. The presence and subcellular immunolocalization of endogenous morphine was investigated by ELISA, mass spectrometry analysis and laser confocal microscopy. Neutrophils were activated with Interleukin-8 (IL-8) or lipopolysaccharide (LPS). Morphine secretion was determined by a morphine-specific ELISA. mu opioid receptor expression was assessed with flow cytometry. Serum morphine concentrations of septic patients were determined with a morphine-specific ELISA and morphine identity was confirmed in human neutrophils and serum of septic patients by mass spectrometry analysis. The effects of the concentration of morphine found in serum of septic patients on LPS-induced release of IL-8 by human neutrophils were tested. We confirmed the presence of morphine in human neutrophil extracts and showed its colocalisation with lactoferrin within the secondary granules of neutrophils. Morphine secretion was quantified in the supernatant of activated human polymorphonuclear neutrophils in the presence and absence of Ca(2+). LPS and IL-8 were able to induce a significant release of morphine only in presence of Ca(2+). LPS treatment increased mu opioid receptor expression on neutrophils. Low concentration of morphine (8 nM) significantly inhibited the release of IL-8 from neutrophils when coincubated with LPS. This effect was reversed by naloxone. Patients with sepsis, severe sepsis and septic shock had significant higher circulating morphine levels compared to patients with systemic inflammatory response syndrome and healthy controls. Mass spectrometry analysis showed that endogenous morphine from serum of patient with sepsis was identical to poppy-derived morphine. Our results indicate that morphine concentrations are increased significantly in the serum of patients with systemic infection and that morphine is, at least in part, secreted from neutrophils during sepsis. Morphine concentrations equivalent to those found in the serum of septic patients significantly inhibited LPS-induced IL-8 secretion in neutrophils.
    Full-text · Article · Jan 2010 · PLoS ONE
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    • "2) The ability of a related set of small molecules including L-aromatic amino acid L-tyrosine (L-TYR), its monoamine homologue tyramine (TA), L-3,4-dihyd- roxyphenylalanine (L-DOPA), and dopamine (DA) to significantly increase cellular morphine concentrations in these same tissue preparations, presumably via de novo biosynthetic mechanisms (Stefano et al., Vol. 56 1993, 2002, 2003, 2004a, b; Brix-Christensen et al., 2000; Goumon and Stefano, 2000; Goumon et al., 2000a-c, 2001, 2005; Guarna et al., 2002; Cadet et al., 2003a, 2004; Zhu and Stefano, 2004; Casares et al., 2005; Dusek et al., 2006; Zhu et al., 2001a-c, 2002a, b, 2003, 2004a, b, 2005a-c, 2006a-d). De novo biosynthesis and utilization of endogenous morphine by animal systems is governed by a complex set of regulatory controls that reflect both evolutionary conservation and divergent adaptation of biochemical, molecular, and cellular processes required for the emergence , elaboration, and maintenance of DA-ergic and related catecholaminergic signalling systems (Stefano and Kream, 2007). "
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    ABSTRACT: For over 30 years empirical studies have repeatedly demonstrated that the biosynthesis of morphine by diverse animal and human tissues occurs. Recently, the blue mussel's neural tissues and human white blood cells were used to demonstrate the de novo biosynthesis of morphine for small precursor molecules derived from the aromatic amino acid L-tyrosine. Because catecholamine precursors, i.e., L-3,4-dihydroxyphenylalanine (L-DOPA), were also found to be utilized as morphine precursors, a novel reciprocally interactive mechanism is apparent that links catecholamine and opioid pathways in the activation and inhibition of diverse tissue responses. Additionally, these observations provide new insights into morphinergic signalling that transcend analgesia and addiction. We have also linked the biological effects of nitric oxide into a common effect in endogenous morphine signalling. Given the singular importance of dopamine and morphine's interaction in the CNS, the presence and association of this signalling with nitric oxide all promises to provide novel answers for mental health phenomena, which have been lacking because of the inability in accepting the empirical endogenous morphine studies.
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    ABSTRACT: Morphine was first identified in opium from Papaver somniferum, and is still one of the strongest known analgesic compounds used in hospital. Since the beginning of the 80s, endogenous morphine, with an identical structure to that of morphine isolated from poppies, has been characterised in numerous mammalian cells and tissues. In mammals, the biosynthesis of endogenous morphine is associated with dopamine, as demonstrated in the SH-SY5Y human neuronal catecholamine-producing cell line. More recently, morphine and morphine-6-glucuronide has been shown to be present in the human neuroblastoma SH-SY5Y cell line and that morphine is secreted from the large dense core vesicles in response to nicotine stimulation via a Ca 2+-dependent mechanism suggesting its implication in neurotransmission. An increasing number of publications have demonstrated its presence and implication in different biological processes at the central and peripheral levels. The present review reports the major data concerning endogenous morphine presence and implication in physiological processes.
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