Opium alkaloids, biosynthesis, pharmacology and association with cancer occurrence.

Papaver somniferum L. (Family: Papaveraceae) is a species well known for its diverse alkaloids (100 different benzylisoquinoline alkaloids (BIAs)). L-tyrosine serves as a precursor of several specific metabolites like BIAs. It has been used as an antitussive and potent analgesic to alleviate mild to extreme pain since ancient times. The extraction of pharmaceutically important alkaloids like morphine and codeine from poppy plant reflects the need for the most suitable and standard methods. Several analytical and extraction techniques have been reported in open literature for morphine, codeine and other important alkaloids which play a vital function in drug development and drug discovery. Many studies suggest that opioids are also responsible for adverse effects or secondary complications like dependence and withdrawal. In recent years, opium consumption and addiction are the most important risk factors. Many evidence-based reviews suggest that opium consumption is directly linked or acts as a risk factor for different cancers. In this review, we highlight significant efforts related to research which have been done over the past 5 decades and the complete information on Papaver somniferum including its phytochemistry, pharmacological actions, biosynthetic pathways and analytical techniques of opium alkaloid extraction and the link between opium consumption and cancer-related updates.

Pharmacokinetics and transplacental transfer of codeine and codeine metabolites from Papaver somniferum L.

ETHNOPHARMACOLOGICAL RELEVANCE: Papaveris Pericarpium, which is the dried husk of Papaver somniferum L., has been used as a phytomedicine to relieve cough, diarrhea and pain. The alkaloid codeine contained therein via biotransformation converts to morphine and potentially produces addictive and toxic effects. Due to the healthy concern for a pregnant woman, our hypothesis is that codeine and its metabolites can penetrate the placental barrier to reach the foetus and amniotic fluid, and these processes may be modulated by the transporter. AIM OF THE STUDY: Because codeine is also considered a prodrug of morphine, it has a good analgesic effect. It is often used by pregnant women but may expose the foetus to the risk of morphine harm. The aim of this study is to investigate the metabolic rate, distribution and transplacental transfer mechanism of codeine and its metabolites morphine and morphine-3-glucuronide (M3G) in pregnant rats and to assess the risk of medication for pregnant women. MATERIALS AND METHODS: Ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) combined with a microdialysis system was developed to monitor codeine, morphine and M3G in multiple sites of maternal blood, placenta, foetus and amniotic fluid after codeine administration. A compartmental model was used to calculate the pharmacokinetic parameters of codeine in blood after codeine administration (10 mg/kg, i.v.). The area under the concentration (AUC) ratio of AUCmetabolite/AUCcodeine and AUCtissue/AUCblood was used to represent the metabolic biotransformation ratio and the drug from blood-to-tissue transfer ratio, respectively. RESULTS: The pharmacokinetic results demonstrated that codeine fit well with a two-compartment model and went through rapid metabolism to morphine and M3G in pregnant rats after codeine administration (10 mg/kg, i.v.). The biotransformation ratios of AUCmorphine/AUCcodeine, AUCM3G/AUCmorphine and AUCM3G/AUCcodeine were 0.12 ± 0.03, 54.45 ± 20.61 and 6.53 ± 2.47, respectively, after codeine administration (10 mg/kg, i.v.), which suggested that codeine was easily metabolized into M3G through morphine. The tissue distribution results demonstrated that all of the analytes penetrated into the foetus through the placenta; however, the blood-to-tissue transfer ratio (AUCtissue/AUCblood) of morphine and M3G was relatively lower than that of codeine after codeine administration (10 mg/kg, i.v.), which suggested that the blood-placenta barrier blocks the penetration of morphine and M3G into the foetus. Thus, the tissue transfer of morphine in the placenta and foetus was significantly enhanced by treatment with corticosterone, an inhibitor of organic cation transporter (OCT). CONCLUSION: Based on microdialysis coupled to a validated UHPLC-MS/MS system, the pharmacokinetics and metabolic biotransformation of codeine and its metabolites were analyzed and clarified. The potential mechanism of morphine placental transfer was modulated by OCT transporters.

Confirmation of recent heroin abuse: Accepting the challenge.

Confirmation or exclusion of recent heroin consumption is still one of the major challenges for forensic and clinical toxicologists. A great variety of biomarkers is available for heroin abuse confirmation, including various opium alkaloids (eg, morphine, codeine), street heroin impurities (eg, 6-acetylcodeine [6-AC], noscapine, papaverine) as well as associated metabolites (eg, 6-monoacetylmorphine [6-MAM], morphine glucuronides). However, the presence of most of these biomarkers cannot solely be attributed to a previous heroin administration but can, among other things, also be due to consumption of poppy seed products ('poppy seed defense'), opium preparations or specific medications, respectively. A reliable allocation is of great importance in different contexts, for instance in the case of DUID (driving under the influence of drugs) investigations, in driving licence re-granting processes, in workplace drug testing (WDT), as well as in post-mortem identification of illicit opiate use. Additionally, differentiation between illicit street heroin abuse and pharmaceutical heroin administration is also important, especially within the frame of heroin-assisted treatments. Therefore, analysis of multiple biomarkers is recommended when illicit opiate consumption is assumed to obtain the most reliable results possible. Beyond that, interpretation of positive opiate test results requires a profound insight into the great variety of biomarkers available and their validity regarding the alleged consumption. This paper aims to provide an overview of the wide variety of heroin abuse biomarkers described in the literature and to review them regarding their utility and reliability in daily routine analysis.

Morphine-6-glucuronide, an active morphine metabolite for the potential treatment of post-operative pain.

Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is being developed by CeNeS Pharmaceuticals as an alternative to morphine (the most commonly used opioid) for the management of postoperative pain. M6G is currently undergoing phase III clinical trials in patients with postoperative pain.

Synthesis and biological evaluation of some 6-arylamidomorphines as analogues of morphine-6-glucuronide.

A series of 6-beta-arylamidomorphines was synthesized and biologically evaluated. Various aryl substituents were introduced into the arylamidomorphines to examine substituent structure-activity relationships. Competition binding assays showed that compounds 10a-h bound to the mu opioid receptor with high affinity (0.2-0.6 nM). Functional assays showed that compounds 10a-h acted as full mu opioid receptor agonists. The ED(50) of compound 10e.HCl as an analgesic was 12.6 mg/kg in the tail flick latency test in the rat.

New dimeric morphine from opium poppy (Papaver somuniferum) and its physiological function.

Together with bismorphine A (1), a new compound bismorphine B (2) was identified in the wounded capsules of Papaver somniferum. On the basis of analyses of the various spectral data, bismorphine B (2) was determined as a novel morphinan alkaloid, in which two morphine units are coupled through a biphenyl ether bond. When the physiological function of bismorphine B (2) in opium poppy was investigated, it was evident that this alkaloid more effectively cross-links cell wall polysaccharide pectins than bismorphine A (1) and that such cross-linking reaction leads to resistance against hydrolysis by pectinase.

Morphine-induced analgesia in rats withdrawn from concurrent nimodipine and morphine treatment.

The effect of repeated administration of dihydropyridine calcium channel antagonist, nimodipine, given concurrently with morphine on the development of tolerance to the antinociceptive actions of morphine in rats was studied. In acute experiments nimodipine (1 mg/kg i.p.) enhanced the antinociceptive effect of morphine (2.5 mg/kg s.c.) in the hot-plate and tail immersion tests. Daily administration of morphine either for 10 days (increasing the daily dose from 20 to 35 mg/kg) or for 24 days (increasing the daily dose from 20 to 70 mg/kg) induced tolerance to the antinociceptive effect of a challenge dose of morphine (10 mg/kg) administered 24 h after the withdrawal from chronic morphine. Concurrent administration of nimodipine (1 mg/kg per day) with morphine for 10 or 24 days augmented the reduction of the antinociceptive effect of morphine. Neither acute nor repeated administration of nimodipine with morphine altered the concentrations of morphine or its metabolite morphine 6-glucuronide in the brain tissue or in the plasma. The observed further reduction in the nociceptive response in morphine tolerant animals pre-treated with nimodipine is, most probably, due to the adaptive changes in the central dihydropyridine calcium channels induced by the withdrawal from repeated nimodipine treatment.

The apparent affinity of morphine-3-glucuronide at mu1-opioid receptors results from morphine contamination: demonstration using HPLC and radioligand binding.

Equilibrium binding studies in sheep thalamic homogenates indicated that morphine-3-glucuronide (M3G) had an apparent affinity for mu1-opioid binding sites (IC50 = 178 +/- 40 nM, Ki = 116 +/- 25 nM, mean +/- s.e.m., n = 4) similar to that reported by Pasternak and co-workers (1). However, when the chemical purity of M3G was investigated using high-performance-liquid-chromatography (HPLC) with electrochemical detection, it was found to be contaminated with 0.5% (molar basis) of morphine. Reduction of the morphine contamination of M3G to 0.08% resulted in a 7.2-fold decrease in apparent binding affinity (IC50 = 1279 +/- 287 nM, Ki = 766 +/- 30 nM, mean +/- s.e.m., n = 4), indicating that the small percentage of morphine present in the M3G raw material drug is the likely explanation for M3G's apparent binding to mu1-opioid receptors.

6-Acetylmorphine: a natural product present in mammalian brain.

Recently, we described three substances in bovine hypothalamus, adrenal, and rat brain recognized by antisera raised against morphine, and we identified one as morphine and another as codeine by GC/MS. We now report the identification of the third immunoreactive (ir) morphinan from bovine brain as 6-acetylmorphine by chemical conversion to morphine, GC/MS, and high-resolution mass measurement. 6-Acetylmorphine has not previously been described as a natural product in plants or animals, but it has long been known as the metabolite in part responsible for the biological properties of heroin. However, we have excluded slaughter-house or laboratory contamination by any morphinan as well as derivation from the morphine in tissues during our procedures. 6-Acetylmorphine is known to be more potent than morphine in vivo chiefly by virtue of its greater penetration into the central nervous system. Should morphinans prove to have physiological functions in animals, the properties of 6-acetylmorphine make it ideal for fulfilling the role of a peripheral-to-central hormone.

The therapeutic use of heroin: a review of the pharmacological literature.

Heroin is currently being advocated by some as a superior therapeutic agent for use in terminal illness. However, a review of the literature on heroin presently available does not support this contention. Administered orally, heroin is approximately 1.5 times more potent than morphine in controlling chronic pain in terminal cancer patients. Its effects on mood and the incidence and nature of side effects do not differ from those of morphine except in males where poorer pain control probably accounts for the worse effect on mood. Given parenterally for acute pain, heroin is 2-4 times more potent than morphine and faster in onset of action. When the potency difference is accounted for, the pharmacological effects of heroin do not differ appreciably from those of morphine. Heroin is metabolized to 6-acetylmorphine and morphine. After oral administration of heroin, morphine but not heroin or 6-acetylmorphine is detected in blood. In this case, heroin is a prodrug for the delivery of systemic morphine. Following acute i.v. administration, heroin appears transiently in blood with a half-life of about 3 min. The half-life of heroin exposed to blood or serum in vitro is 9-22 min, indicating that organ metabolism is involved in blood clearance as well. Direct renal clearance of heroin is less than 1% of the administered dose. In animal studies, heroin and 6-acetylmorphine are both more potent and faster acting than morphine as analgesics, effects attributed to their greater lipid solubility and subsequent penetration of the blood-brain barrier. Given centrally, morphine is more potent than heroin and 6-acetylmorphine in producing analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of the oral contraceptive, menstranol, on drug-metabolizing enzymes of female rats in thiamin-supplemented and deficiency states.

The administration of a diet deficient in thiamin results in elevated hepatic microsomal activity of aniline hydroxylase, ethylmorphone demethylase, NADPH cytochrome c reductase and cytochrome P-450 when compared to similar female rats fed diets supplemented with thiamin. Accompanying these differences in enzyme activity are increased concentrations of microsomal docosahexaenoic acid and arachidonic acid. Binding of aniline to microsomes from rats fed high levels of thiamin is decreased due to a decrease in cytochrome P-450. On the other hand, the binding of ethylmorphine to P-450 is decreased by feeding high levels of thiamin. The daily administration of mestranol enhanced ethylmorphine and aniline metabolism to a greater extent in rats fed thiamin-rich diet than in rats fed thiamin-deficient diet or laboratory chow. This treatment did not increase cytochrome P-450 cytochrome c reductase or microsomal protein nor does it appear to affect the binding of aniline to cytochrome P-450. Ethylmorphine binding is generally decreased by this treatment. Alterations in the Michaelis constants for these reactions were limited to an increase in the Ks for aniline in pair-fed animals and in the Ks for ethylmorphine in thiamin-deficient rats receiving 1.0 mg mestranol per day.

PIP: The effect of mestranol on drug-metabolizing enzymes was studied in female rats receiving either deficient or thiamin-supplemented diets. Rats on the deficient diet showed increased hepatic microsomal activity of aniline hydroxylase, ethylmorphine demethylase, NADPH cytochrome c reductase, and cytochrome P-450. There were also increased concentrations of microsomal docosahexaenoic acid and arachidinic acid. Rats on the thiamin-supplemented diet showed decreased binding of aniline to microsomes, which was due to decreased levels of cytochrome P-450. However, high levels of thiamin decreased the binding of ethylmorphine to P-450. Mestranol increased ethylmorphine and aniline metabolism to a greater degree in animals receiving the thiamin-supplemented diet than those receiving the deficient diet or laboratory feed. However, levels of cytochrome P-450, cytochrome c reductase, or microsomal proteins were not increased, and the binding of aniline to cytochrome P-450 was not affected. Generally, treatment with mestranol decreased the binding of ethylmorphine. It appears that mestranol alters the Type I binding site on cytochrome P-450, but has no effect on the Type II binding site.

Search for an endogenous ligand for the opiate receptor.

It was investigated whether there is an endogenous factor in the brain which binds to the opiate receptor in neural tissue. Extracts from rat brain were processed in different ways; fractions were assayed for ability to inhibit the receptor binding of dihydromorphine. There was no evidence for high-molecular weight substances or lipid soluble substances with such ability. On the other hand, processing of an acid water extract of brain except the cerebellum (which was negative) yielded an active fraction with receptor blocking activity. This fraction was heat stable, polyionic and had an apparent molecular weight of 1000-1 200 dalton. These and other characteristics indicate that it might well be a peptide. The factor inhibited binding to the opiate receptor in synaptic plasma membranes of rat brain and to the receptor of the guinea-pig ileum although it was less effective on the latter, particularly after long-term incubation. The interaction between the factor and dihydromorphine was reversible and apparently competitive.