Morphine synthesis in animals.
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Alkaloids↗
Biomedical subjects
Richard M Kream
Publications and source records attributed to Richard M Kream.
De novo biosynthesis of morphine in animal cells: an evidence-based model.
Recent empirical findings have contributed valuable mechanistic information in support of a regulated de novo biosynthetic pathway for chemically authentic morphine in animal cells, with many similarities to the extensively characterized multi-enzyme plant pathway in opium poppy (Papaver somniferum). The present review elaborates an evidence-based model of cellular morphine expression that reflects a coalescence of these recent biochemical data with historical data gleaned from over thirty years of neurochemical/neuropharmacological investigation into the etiology and biological significance of dopamine (DA)-related heterocyclic conjugate molecules, termed tetrahydroisoquinoline (TIQ) or benzylisoquinoline (BIQ) alkaloids, and with outstanding work completed over the last decade that has elucidated biochemical and molecular bases of morphine and related isoquinoline alkaloid expression in plant systems. In essence, we are now afforded a rare window of opportunity to firmly establish essential biochemical linkages between plant and animal biosynthetic pathways that have been conserved throughout evolution.
Alkaloids↗
Alcohol-, nicotine-, and cocaine-evoked release of morphine from invertebrate ganglia: model system for screening drugs of abuse.
BACKGROUND: Invertebrates express regulatory receptors, transporters, and channels responsive to established drugs of abuse, many of which mediate their effects through catecholamine pathways. We hypothesized that invertebrate neural systems may serve as models by which to evaluate the interactive pharmacological effects of these agents. MATERIAL AND METHODS: Ex vivo pharmacological trials determined the effects of saturating levels of ethanol on morphine levels in pooled Mytilus edulis ganglia via HPLC coupled to electrochemical detection and/or HPLC/RIA analyses. Additional trials evaluated the ability of ethanol, nicotine, and cocaine, to promote evoked release of 125I-labeled morphine from neural tissues, because intrinsically low levels of morphine did not allow direct quantification of its release. RESULTS: Incubation of pooled M. edulis pedal ganglia with 200 mM ethanol (approximately 1% ethanol v/v) resulted in a two-fold increase in morphine concentration at 15 min, return to baseline at 30 min, and a 50% decrease in morphine concentration at 60 min. Separate incubations of pooled M. edulis pedal ganglia and H. americanus nerve cord with ethanol, cocaine, and nicotine resulted in a statistically significant enhancement of 125I-trace labeled morphine release. CONCLUSIONS: The stimulatory effects of ethanol, nicotine, and cocaine on cellular expression and release of endogenous morphine suggest convergent mechanisms underlying the reinforcing and addictive properties for a variety of drugs of abuse. The evolutionary conservation of L-tyrosine as a common precursor to catecholamine and opiate/opioid signaling systems may define a functional triad involving endogenous morphine, dopamine, and other classes of addictive drugs.
Animals↗
Cholinergic regulation of endogenous morphine release from lobster nerve cord.
BACKGROUND: Invertebrate nervous systems are regulated by G-coupled protein receptors, chemical transporters, and ion channels responsive to established drugs of abuse including opiates, alcohol, psychostinulants, and nicotine. Thus, invertebrate nervous tissue preparations can be used as predictive model systems by which to evaluate underlying pharmacological mechanisms of addictive processes. MATERIAL/METHODS: Ex vivo pharmacological trials were used to determine the comparative effects of the nicotinic agonists and antagonists on the evoked release of labeled morphine from H. americanus nerve cord. The intrinsically low basal levels of endogenous morphine required that we utilize an ex vivo model system involving pre-labeling of intracellutlar opiate alkaloid pools with high specific activity 125I labeled morphine. RESULTS: Both nicotine and epibatidine promoted evoked release of 125I labeled morphine that is selectively linked to activation of invertebrate nicotinic receptors based on pharmacological inhibition by alpha bungarotoxin (alpha-BuTx). Epibatidine promoted release at concentrations 2-3 orders of magnitude higher than nicotine. Co-administration of nicotine (60 nM) and the pre-junctional ganglionic nicotinic antagonist hexamethonium (1 microM) produced a marked potentiation of 125I labeled morphine release; a pharmacological effect also observed for epibatidine (35 microM) co-administered with the competitive nicotinic antagonist chlorisondaminie at 1 microM. The stimulatory effects of ethanol to promote enhanced release of endogenous morphine were not affected by co-admninistration of alpha-BuTx at 1 microM. CONCLUSIONS: The stirmulatory effects of nicotine on cellular expression and release of endogenous morphine occurs via specific alpha-BuTx sensitive receptors, suggesting a novel mechanism underling the reinforcing and addictive properties of nicotine via endogenous morphine.
Animals↗
Alcohol-, nicotine-, and cocaine-evoked release of morphine from human white blood cells: substances of abuse actions converge on endogenous morphine release.
BACKGROUND: Normal human white blood cells (WBC) have the ability to synthesize morphine as do invertebrate ganglia. Furthermore, invertebrate neural tissues incubated with ethanol, cocaine, or nicotine results in a statistically significant enhancement of labeled morphine release. We now demonstrate that this also occurs with human WBC. MATERIAL/METHODS: Human blood was obtained from the Long Island Blood Services (Melville, NY). Polymorphonuclear cells (PMN) or mononuclear cells (MN) (10 million/ml) were bathed in phosphate buffered saline (PBS) medium containing purified RIA grade 125I-labeled morphine for trace labeling and quantification of media concentrations of morphine were via RIA. Cells were then incubated with cocaine, alcohol or nicotine and morphine release was determined. Residual levels of radioactivity in control tissues were always greater than 65% of total cpm, whereas in treated tissue differences depended on the amount of drug added. RESULTS: Incorporation rates of 125I-labeled morphine into PMN and MN were 7.85+/-0.36% and 1.42+/-0.19%, respectively. Separate incubations of PMN with ethanol, cocaine, or nicotine resulted in a statistically significant enhancement of 125I-labeled morphine released into the extracellular medium in a concentration dependent manner. CONCLUSIONS: These substances of abuse have been linked into a common pathway because of the common dopamine connection. Now, they are additionally linked because of their common effect on endogenous morphinergic processes. It is highly significant that these substances of abuse converge on a similar process, providing a mechanism to initiate their pleasure and addicting actions with continued frequent use.
Alcohols↗
Altered tachykinin expression by dorsal root ganglion neurons in a rat model of neuropathic pain.
The experiments described in the present study approached nerve injury from both a biochemical and anatomical perspective by monitoring changes in expression of preprotachykinin (PPT) mRNA encoding the prototypic tachykinin substance P and related peptide species in neurons of the rat dorsal root ganglia (DRG) following unilateral chronic constriction injury of the sciatic nerve. In situ hybridization histochemistry (ISHH) analyses in conjunction with computer-assisted image processing were employed to quantify levels of PPT mRNA distributed in DRG neurons. Injury-induced changes in PPT mRNA expression by affected DRG neurons included: (1) at early postoperative times, generally increased levels of PPT mRNA associated with small and intermediate-size B cells exhibiting normal morphology, (2) at late postoperative times, markedly decreased levels of PPT mRNA associated with degenerating B cells, and (3) induction of PPT gene expression by large A cells which is highly correlated with degenerative morphological changes. The significant aspects of these changes are discussed with special emphasis on the contribution of altered transmitter expression by DRG neurons to the pathophysiology of causalgia. In particular, the induction of PPT gene expression by many of the large neurons undergoing degenerative changes may represent an important biochemical parameter which is associated with the development and persistence of experimental allodynia.
Animals↗