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Two young dogs which played in a domestic garden in which the opium poppy (Papaver somniferum) grew as wild flowers, developed euphoric as well as other nervous signs, reminiscent of opium poisoning. No medicinal treatment was given. The one dog recovered in one day while the other one took one to two weeks to recover.
Two early and potential rate-limiting steps in the biosynthesis of isoquinoline alkaloids, such as morphine and codeine, in opium poppy (Papaver somniferum) involve decarboxylation of L-tyrosine and L-dihydroxyphenylalanine (L-dopa) to yield tyramine and dopamine, respectively. A DNA fragment was amplified by polymerase chain reaction (PCR) using degenerate primers designed to two highly conserved domains found in other aromatic amino acid decarboxylases. A poppy seedling cDNA library was screened with this PCR product and a cDNA (cTYDC1) for tyrosine/dopa decarboxylase (TYDC/DODC) was isolated. Two other independent cDNAs (cTYDC2 and cTYDC3) encoding TYDC/DODC were isolated by heterologous screening with a plant tryptophan decarboxylase (TDC) cDNA as probe. A poppy genomic library was screened with cTYDC1 and two intronless genomic clones (gTYDC1 and gTYDC4) were isolated. The deduced amino acid sequences of all poppy clones share extensive identity with other reported pyridoxal phosphate-dependent decarboxylases from both plants and animals. Based on sequence homology, members of the gene family were divided into two subsets (cTYDC1 and gTYDC4; cTYDC2 and cTYDC3) of proteins with predicted M(r) = 56,983 and 59,323, respectively. Within each subset the clones exhibit greater than 90% identity, whereas clones between subsets share less than 75% identity. Expression of gTYDC1 and cTYDC2 as beta-galactosidase fusion proteins in Escherichia coli resulted in catalytically active enzymes immunodetectable with TDC-specific polyclonal antibodies. Each enzyme showed marginally higher substrate specificity for L-dopa over L-tyrosine, but did not accept L-tryptophan and L-phenylalanine as substrates. Genomic DNA blot-hybridization analysis revealed 6 to 8 genes homologous to cTYDC1 and 4 to 6 genes homologous to cTYDC2 in the tetraploid poppy genome. A premature translation stop codon was found in the gTYDC4 clone suggesting that it may not encode a functional protein. RNA blot-hybridization with probes specific to the gTYDC1- or cTYDC2-like subsets showed that members of the TYDC gene family are differentially expressed in various plant tissues.
Incubated tissue slices from different regions of the rat brain contained cyclic guanosine 3',5'-monophosphate (cyclic GMP) in the following descending order of content: cerebellum greater than hypothalamus greater than striatum greater than thalamusmidbrain greater than brain stem greater that hippocampus greater than cerebral cortex. Cholinomimetic agents at 10(-5) M (carbamylcholine, pilocarpine, acetylcholine and eserine) and papavering at 14(-4) M significantly elevated cyclic GMP accumulation in the cerebral cortex. Three min incubation with carbamylcholine (10(-5) M) did not increase cyclic nucleotide accumulation in the remaining brain regions.
Morphine is the most widely used compound among narcotic analgesics and remains the gold standard when the effects of other analgetic drugs are compared. Apart from its presence in the poppy plant Papaver somniferum, morphine has been shown to be present in milk, cerebrospinal fluid and also in nervous tissue extracts. Recent evidence suggests that biosynthetic pathways for morphine exist in animal and even human tissues such as liver, blood and brain. The most characteristic effect of morphine is the modulation of pain perception resulting in an increase in the threshold of noxious stimuli. Antinociception induced by morphine is mediated via opioid receptors and therefore can be inhibited by opioid antagonists, e.g., naloxone. Nevertheless, consideration of morphine as endogenous ligand for opioid receptors seems to be speculative. Recently, the primary receptor for morphine-type drugs called the mu-opioid receptor has been cloned from rat brain. There is accumulating evidence that morphine actions are, at least partly, due to one of its major metabolite morphine-6-glucuronide in man. It is concluded that further investigations are necessary to elucidate the mechanisms, whereby multiple actions of morphine are expressed in the nervous system.
The anticarcinogenic properties of some commonly consumed spices and leafy vegetables were investigated. The effects of feeding the plant products on the induction of squamous cell carcinomas in the stomachs of Swiss mice by feeding benzo[a]pyrene(B[a]P) and on the induction of hepatomas in Wistar rats by feeding 3'-methyl-4-dimethylaminoazobenzene (3'MeDAB) were investigated. Among the nine plant products tested, cumin seeds (Cuminum cyminum Linn) and basil leaves (Ocimum sanctum Linn) significantly decreased the incidence of both B[a]P-induced neoplasia and 3'MeDAB-induced hepatomas. Poppy seeds (Papaver somniferum Linn) significantly inhibited B[a]P-induced neoplasia alone, while the other plant products, asafoetida, kandathipili, turmeric, drumstick leaves, solanum leaves and alternanthera leaves were ineffective. These results suggest that cumin seeds, basil leaves and to a lesser extent poppy seeds, which are all widely used in Indian cooking, may prove to be valuable anticarcinogenic agents.
Cunninghamella echinulata was used to assess the cytotoxicity of papaverine (papaver), at concentrations ranging from 1 x 10(-5) to 1 x 10(-3) M for 1-6 days. Leakage of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT), and changes in alkaline phosphatase (AP) activity and lactate/pyruvate (L/P) ratios were used as indices of cytotoxicity. Leakage of LDH occurred at the 6th day with 1 x 10(-3) M; AP activity and L/P ratios decreased after 6 days treatment with 1 x 10(-4) M, after 1 day with 1 x 10(-3) M, and after 3 days with 1 x 10(-4) M, respectively. This study provides support for the use of fungal cell systems to evaluate the toxicity of drugs and chemicals.
Examination by microscopy, thin-layer chromatography, gas-liquid chromatography alone and combined with mass spectrometry, and radioimmunoassay methods of materials from the tomb of the ancient Egyptian chief royal architect Kha, who is believed to have died about 1405 BC, has shown that there is no morphine--and hence no opium--present. This finding casts doubt on the results of an earlier analysis. Tropane alkaloids are likewise absent. The significance of the present findings for the history of the opium poppy, Papaver somniferum L., in the eastern Mediterranean region is discussed. Evidence (chemical, botanical, artefactual, and linguistic) for the supposed presence of the opium poppy and opium in Egypt in the Late Bronze Age is briefly reviewed. These considerations and the negative outcome of the present analyses mean that the earlier reported finding can no longer be accepted as evidence.
Vinorine synthase (EC 2.3.1.160) catalyses the acetyl-CoA- or CoA-dependent reversible formation of the alkaloids vinorine (or 11-methoxy-vinorine) and 16-epi-vellosimine (or gardneral). The forward reaction leads to vinorine, which is a direct biosynthetic precursor along the complex pathway to the monoterpenoid indole alkaloid ajmaline, an antiarrhythmic drug from the Indian medicinal plant Rauvolfia serpentina. Based on partial peptide sequences a cDNA clone was isolated and functionally expressed in Escherichia coli. The Km values of the native enzyme for gardneral and acetyl-CoA were determined to be 7.5 and 57 microM. The amino acid sequence of vinorine synthase has highest level of identity (28-31%) to that of Papaver salutaridinol acetyltransferase, Fragaria alcohol acyltransferase, and Catharanthus deacetylvindoline acetyltransferase involved in morphine, flavor, and vindoline biosynthesis, respectively. Vinorine synthase is a novel member of the BAHD superfamily of acyltransferases. Site-directed mutagenesis of 13 amino acid residues provided clear evidence that both, His160 and Asp164 of the consensus sequence HxxxD belong to the catalytic center. The mutations also showed that an amino acid triad is not characteristic of vinorine synthase. The experiments demonstrated the importance of the conserved motif SxL/I/VD near the N-terminus and the consensus sequence DFGWG near the C-terminal.
BACKGROUND: Chelidonii herba is classified as Papaver somniferum L. Aqueous extract from C. herba is traditionally used for disorders with symptoms like pain, bloating, abdominal cramp after meals. METHODS: Modulation of C. herba on glycine-activated and glutamate-activated ion currents in the acutely dissociated periaqueductal gray (PAG) neurons was investigated by the nystatin-perforated patch-clamp technique. RESULTS: C. herba inhibited glycine-activated ion current and increased glutamate-activated ion current. C. herba-induced inhibition on glycine-activated ion current is implicated in opioid receptors and GTP-binding proteins (G-proteins). Increased glutamate-activated ion current induced by C. herba is linked neither by opioid receptors nor GTP-binding proteins. CONCLUSIONS: Suppressed glycine-induced response and elevated glutamate-induced response by C. herba may increase neuronal excitability in PAG, results in activation of descending pain control system, and this mechanism can be suggested as one of the analgesic actions of C. herba.
From the first recorded accounts, over 7000 years ago, various forms of natural products have been utilized to treat pain disorders. Prototypical examples of such natural products are the opium poppy (Papaver soniferum) and the bark of the willow tree (Salix spp.). It was not until the 19th century when individual compounds were isolated from these substances and were determined to posses the desired effects. The known sources of these substances have been thoroughly investigated. Over the last several decades, more analgesic substances have been purified from natural products resulting in novel structural classes and mechanisms of actions. Plants and other natural products described in historical ethnobotanical and ethnopharmacological literature have become of more recent interest in drug discovery efforts. These manuscripts and reports are being utilized to aid in the identification of natural products that have been historically employed in the alleviation of pain. A large factor that has highlighted the importance of discovering novel compounds to treat pain has been in the fundamental understanding of the complex mechanisms of pain transmission in the nervous system. Nociceptive processing involves many receptor classes, enzymes and signaling pathways. The identification of novel classes of compounds from natural sources may lead to advancing the understanding of these underlying pharmacological mechanisms. With the potential of uncovering new compounds with idealistic pharmacological profiles (i.e., no side effects, no addictive potential), natural products still hold great promise for the future of drug discovery especially in the treatment of pain disorders and potentially drug addictions.
All major fragment ions of codeine and morphine were elucidated using LC-electrospray MS/MS and high resolution FT-ICR-MS combined with an IRMPD system. Nanogram quantities of labeled codeine were isolated and purified from Papaver somniferum seedlings, which were grown for up to 9 days in the presence of [ring-13C6]-l-tyrosine, [ring-13C6]-tyramine and [1,2-13C2], [6-O-methyl 13C]-(R,S)-coclaurine. The labeling degree of codeine up to 57% into morphinans was observed.
Benzylisoquinoline alkaloids (BIAs) consist of more than 2500 diverse structures largely restricted to the order Ranunculales and the eumagnoliids. However, BIAs also occur in the Rutaceae, Lauraceae, Cornaceae and Nelumbonaceae, and sporadically throughout the order Piperales. Several of these alkaloids function in the defense of plants against herbivores and pathogens - thus, the capacity for BIA biosynthesis is expected to play an important role in the reproductive fitness of certain plants. Biochemical and molecular phylogenetic approaches were used to investigate the evolution of BIA biosynthesis in basal angiosperms. The occurrence of (S)-norcoclaurine synthase (NCS; EC 4.2.1.78) activity in 90 diverse plant species was compared to the distribution of BIAs superimposed onto a molecular phylogeny. These results support the monophyletic origin of BIA biosynthesis prior to the emergence of the eudicots. Phylogenetic analyses of NCS, berberine bridge enzyme and several O-methyltransferases suggest a latent molecular fingerprint for BIA biosynthesis in angiosperms not known to accumulate such alkaloids. The limited occurrence of BIAs outside the Ranunculales and eumagnoliids suggests the requirement for a highly specialized, yet evolutionarily unstable cellular platform to accommodate or reactivate the pathway in divergent taxa. The molecular cloning and functional characterization of NCS from opium poppy (Papaver somniferum L.) is also reported. Pathogenesis-related (PR)10 and Bet v 1 major allergen proteins share homology with NCS, but recombinant polypeptides were devoid of NCS activity.
In vivo and in vitro binding studies with natural thebaine and its enantiomer, (+)-thebaine were conducted to elucidate further their interactions with the opioid system. (-)-Thebaine a key intermediate in the biosynthesis of morphine in the poppy plant (Papaver somniferum) and in mammalian tissue, was poorly effective antinociceptively in mice at doses to 30 mg/kg. Its principal behavioral manifestation was lethal convulsions. Naltrindole, at doses of 1 and 10 mg/kg did not block either the convulsions or lethal effects, suggesting that the delta-opioid receptor system was not involved in this action. Surprisingly, the dextrorotatory isomer exhibited significant antinociceptive activity in the tail-flick [ED50 = 8.9 (3.4-22.1) mg/kg], hot-plate [ED50 = 22.9 (10.9-48.1) mg/kg] and phenylquinone [ED50) = 1.9 (1.6-9.5) mg/kg] assays. Studies with opioid receptor-subtype antagonists, beta-funaltrexamine, nor-binaltorphimine and naltrindole, indicated that antinociception was associated with mu- and delta-opioid receptors. Results of displacement experiments supported the in vivo data. Significant competition for [3H]diprenorphine binding with both isomers for cloned mu- and delta-opioid receptors was observed. However, (-)-thebaine was more effective at the delta-opioid receptor (Ki = 1.02+/-0.01 microM) whereas (+)-thebaine was more effective at the mu-opioid receptor ( Ki = 2.75+/-0.01 microM). Opioid-induced antinociception associated with unnatural thebaine raises the possibility of additional mu- and delta-opioid receptor sites.
One idea to explain the high incidence of specialisation in phytophagous insects is that their nervous systems are simple and unable to efficiently recognise multiple host plants. Here this 'neural limitations' hypothesis is tested using a generalist (the summer winged virginopara) and specialist (the autumn gynopara) morph of a single clone of the black bean aphid, Aphis fabae, that are almost identical morphologically and have the same genotype. Electrical monitoring of stylet behaviour and non-invasive behavioural observations are used to compare initial plant recognition, first reproduction, 'first registered phloem contact' and 'phloem acceptance' of the generalist and specialist on their specific host plants (generalist--herbaceous hosts, Beta vulgaris, Papaver dubium, Rumex obtusifolius, Vicia faba; specialist--woody host, Euonymus europaeus) and on the same host (E. europaeus). Additional analyses of behaviour over the first few minutes of plant contact are carried out for three mutual non-host plants: Euonymus alatus, Prunus padus and Brassica pekinensis. Few examples are found where the host-selection behaviour of the specialist on its host plant is more efficient than the generalist across its hosts and there is little difference in the behaviour of the different forms on the same host. Indeed there are several instances where the generalist is behaviourally more efficient than the specialist. These include absolute time to first reproduction by the generalist on various herbaceous hosts and the same host, E. europaeus, absolute time to first registered phloem contact by the generalist on P. dubium, and incidence of phloem acceptance by the generalist on several of its herbaceous hosts. Rejection of non-hosts is carried out more efficiently by the specialist gynopara on P. padus and B. pekinensis but not on E. alatus. For generalist and specialist morphs of the same A. fabae genotype, therefore, broad host range does not appear to be associated with a reduced ability to make plant-use decisions.
Papaver orientale, Dicentra spectabilis and Chelidonium majus, three Papaveraceae collected from Hokkaido area, were studied for their fungitoxic alkaloids. Ten alkaloids were isolated, identified and tested for their fungitoxic activity. Two of these isolates were found to be new compounds.
An elicitation protocol, resulting in the accumulation of sanguinarine in suspension cultures of Papaver bracteatum, was assessed for induction of the same alkaloid in Sanguinaria canadensis. Although only a trace constituent of P. bracteatum plants, sanguinarine is a major alkaloid (1-3% dry wt) of S. canadensis rhizomes. By combining hormonal deprivation for various intervals and a 3-day fungal (Verticillium dahliae) elicitation, benzophenanthridine alkaloid accumulation was induced in S. canadensis cell suspensions. Chelirubine content increased (0.1-1.3% dry wt) consistently in elicited cell cultures while chelerythrine (0.01-0.10% dry wt) and sanguinarine (0-0.02% dry wt) levels were considerably less. Alkaloid accumulation always occurred upon removal of hormone but only at certain time intervals in the log phase upon fungal elicitation. Levels of dopamine, a precursor of the alkaloids, fluctuated over the incubation period, but displayed a 2- to 6-fold increase in cell suspensions grown without hormone. In some experiments dopamine accumulated to levels > 20% dry wt, and these increases were enhanced by the addition of fungal elicitor. Although the same fungal elicitor induces benzophenanthridines in taxonomically related S. canadensis and P. bracteatum, it did not elicit the accumulation of the same alkaloid in the two different plant cultures.
Since many centuries mankind has been aware of the poppy (papaver somniferum) and has known its product opium as an analgesic drug. Until the beginning of the 19 (th) century its compounds were not known, making it almost impossible to apply the substance in exact doses. 1803/04, Friedrich Wilhelm Sertürner (1783 - 1841) succeeded in isolating a crystalline substance from opium in the test tube, which he called morphium. In animals and in man he was able to prove that this new compound he had discovered was the principium somniferum of opium. He isolated morphine, the first pure opioid available for calculated pain therapy with one defined compound. Moreover, he laid the foundations of a new class of pharmaceutical drugs, the alcaloids.
16 patients (12 men, 4 women; mean age 62.8 +/- 9.8 years) with inoperable advanced hepatocellular carcinoma were treated palliatively by chemoembolization. 50 mg/m2 epirubicin, 30 mg/m2 cisplatin, 8 ml fatty acid ethyl ester of iodinated papaver oil and 10 ml nonionic contrast medium were injected under fluoroscopy into the proper hepatic artery. Partial remission was achieved in 10 patients after a median of 4 months. In 4 patients there was no change in the morphological and biochemical findings, in two others the tumour progressed, i.e. an overall response rate of 62.5%. The median survival time was 9 months. There were no serious complications ascribable to the treatment. Chemoembolization is a palliative treatment with few side effects which can also be effective in prolonging survival time in advanced hepatocellular carcinoma.