The latex obtained by the incision of unripe seed capsules of Papaver somniferum and which is known as opium is the source of several pharmacologically important alkaloids. Dioskorides, in about AD 77, referred to both the latex (opos) and the total plant extract (mekonion) and to the use of oral and inhaled (pipe smoked) opium to induce a state of euphoria and sedation. Since before the Christian era the therapeutic properties of opium were evident, with the first written reference to poppy juice by Theophrastus in the third century BC. Powdered opium contains more than 40 alkaloids which constitute about 25% by weight of the opium and are responsible for its pharmacological activity.
In 1803 the German pharmacist Sertiirner achieved the isolation of morphine as one of the active ingredients of opium. Morphine, codeine, thebaine, papaverine, narcotine and narceine are the most important bases, with many of the remaining (minor) alkaloids occurring only in traces.
Morphine has long occupied an eminent position on the list of useful drugs. As a pure alkaloid, it has been employed for over a century and a half and, as the most important constituent of opium, it has contributed to the comfort of the human race since very early times. Morphine has greatly facilitated the practice of medicine by furnishing the physician with a potent, reliable and relatively inexpensive analgesic agent, (-)-morphine, the naturally occurring enantiomer combines selectively at many recognition sites through the body to produce pharmacological effects.
Extensive structure-activity studies involving hundreds of compounds have established firm stereochemical structural requirements for morphine-like activity ().
Studies of the binding of various ligands over the past 50 years in brain and other tissues suggested the existence of multiple and distinct receptor types that can interact with opioid drugs. There is reasonably strong evidence for three main categories of opioid receptors in the brain, designated µ, κ and δ (). The affinity of morphine for µ-receptors is about ten times that for δ and κ-receptors. A fourth receptor, the s-receptor is more controversial but may be related to the dysphoric, hallucinogenic and cardiac stimulant effects of certain opioids.
Although biochemical and pharmacological evidence indicates that the µ-, δ- and κ-receptors are distinct molecular entities, all three classes of opioid receptors share a number of characteristics. They are usually found on presynaptic nerve terminals, where their action results in decreased release of excitatory transmitters. They all appear to be coupled to guanine nucleotide binding regulatory proteins (G-proteins), and elicit their actions via the cAMP system (). Collier and Roy also reported the inhibition of the accumulation of cyclic AMP in rat brain homogenates. In the neuroblastoma x glioma hybrid cell line, NG108-15 was observed to be rich in opiate receptors that are coupled as inhibitory modulators to adenyl cyclase ().
Morphine exerts its effects either by hyperpolarizing or inhibiting postsynaptic neurones, probably by increasing K+ efflux, or by reducing Ca2+ influx into presynaptic nerve endings and thereby reducing transmitter release, including acetylcholine, norepinephrine, dopamine, serotonin and substance P ().
(-)-Morphine produces its main action, analgesia, primarily through interaction with µ-receptors. The antipode, (+)-morphine is devoid of anti-nociceptive activity, although it showed some central action when administered intracerebrally ().
Other consequences of µ-receptor activation include euphoria, respiratory depression, miosis, constipation and dependence. Two apparently distinct types of µ-receptors have been detected, based on their relative affinities for agonists: µ-1, having a higher affinity to agonists, postulated to mediate supraspinal analgesic action, and µ-2, having a lower affinity, postulated to mediate spinal analgesia, dopamine turnover, growth hormone release, respiratory depression, gastrointestinal actions, inhibition of guinea pig ileum contractions, bradycardia and reversal of endotoxic shock ().
K-receptors might contribute to morphine analgesia at the spinal level and mediate sedative actions as well ().
The three main receptor types have been isolated and cloned (). It was demonstrated that the contraction of the coaxially stimulated longitudinal muscle strip of guinea pig ileum (GPI) was inhibited by morphine (). In this preparation the ID50 value means the concentration of drug required to inhibit the twitch (induced by the release of acetylcholine) height by 50% and is a measure of agonist potency. Bioassays measuring in vivo morphine analgesia or inhibition of electrically induced contraction of guinea pig ileum induced by morphine clearly showed good correlation and similar dose-dependent effects with a well defined maximal response ().
It was found that a mouse vas deferens (MVD) preparation behaved similarly to the GPI and can also be used for detection of agonist activity of morphine-like substances (). Morphine inhibits transmission in postganglionic adrenergic fibres in small doses ().
Morphine produces an increase in muscle tone (Straub’s phenomenon) and a marked increase in spontaneous motility in the mouse. In laboratory animals morphine induces catalepsy accompanied by marked rigidity, which is antagonized by morphine antagonists ().
Pharmacologically, morphine is active in all the standard bioassays for analgesia both in animal or humans (). It is able to change both pain perception and the reaction to pain. It is prescribed for the symptomatic relief of severe pain in humans.
µ-opiate receptor agonists, like morphine, are approximately equipotent in heat (hot plate, tail flick) and non-heat (acetic acid writhing and pression) induced nociception. The anti-nociceptive potency ratios of morphine in animal heat tests were found to be similar to those for analgesia in man ().
Morphine-induced analgesia is due to actions at several sites within the central nervous system (CNS): both spinal and multiple supraspinal sites have been identified. The sites of morphine analgesic action are the periaqueductal grey matter (PAG), the dorsal horn of the spinal cord and probably the limbic system. Morphine selectively inhibits various nociceptive reflexes and induces analgesia when administered intrathecally or instilled locally into the dorsal horn of the spinal cord, into the third ventricle or in the midbrain and medulla, most remarkably in the PAG and the nucleus raphe magnus ().
Brain loci involved in the transmission of pain and in the alteration of reactivity to nociceptive stimuli appear to be primary, but are not the only sites at which morphine acts. Recently, evidence has begun to accumulate regarding the possibility on peripheral opioid anti-nociception ().
Morphine is readily absorbed when taken orally, injected subcutaneously (s.c.) or intramuscularly (i.m.). It is also easily absorbed from the mucosal surfaces of the nose or mouth. Morphine gains access to the brain with difficulty, being an amphoteric agent ().
Its effects are seen in about half an hour and begin to pass away after 3-5 hours but may last for at least 12 hours. The bioavailability of morphine taken orally may be considerably reduced because of significant first-pass metabolism by glucuronidation in the liver (). Morphine is also N-demethylated in the liver. A certain amount is excreted into the stomach and probably into other parts of the alimentary canal (). Recent findings indicate that morphine-6-glucuronide possesses greater analgesic properties than morphine ().
Morphine exerts its most important actions on the CNS, where it causes depression and excitation of certain centres. The parasympathetic portion of the oculomotor nucleus is stimulated and the pupils became contracted — in cases of morphine poisoning they may be of pinpoint size. Miosis is also a pharmacological action to which little or no tolerance develops. This action can be blocked by atropine and by opioid antagonists (). Morphine depresses acetylcholine turnover in parietal and occipital cortices, hippocampus and nucleus accumbens (). Other effects mediated via the CNS include a feeling of heaviness in the limbs, a dry mouth, itching and the reduction of hunger sensations.
Morphine disrupts normal REM and NREM sleep patterns. It exercises a biphasic action on cerebral electrical activity at low doses in humans, which correspond to analgesic doses in the rat. Electrical tracings tend toward synchronization with an increase of slow waves and spindles. In the cat, desynchronization can be seen. High doses of morphine induce EEG convulsive manifestations ().
The average convulsive and fatal dose of morphine for nearly all animal species depends on several factors, such as age, diet, and degree of hydration ().
Drowsiness and mental clouding usually occurs after morphine administration. It has been proposed that morphine simultaneously activates two different processes resulting in opposite changes in spontaneous motility: hyperactivity or hypoactivity (). In contrast to humans, a number of species (cats, horses, cows, pigs) may manifest excitation rather than sedation when given morphine.
Morphine depresses the cerebral cortex and reduces the powers of concentration and fear. Morphine causes a sense of satisfaction and well being (euphoria) and freedom from anxiety and distress. In addition, pain, particularly prolonged as opposed to acute pain, is reduced and these actions produce a feeling of contentment. Its intravenous (i.v.) administration has been reported to result in a sudden ‘rush’ similarly to ‘abdominal orgasm’. Euphoria appears to be mediated by µ-receptors ().
Microinjection of morphine into the ventral tegmentum activates dopamine neurones to project to the nucleus accumbens. This pathway might be a critical element in the reinforcing effects of morphine and morphine-induced euphoria.
Various centres in the medulla are affected by morphine. Morphine activates the brain stem chemoreceptor trigger zone to produce nausea and vomiting. Also, morphine has an action of vestibular apparatus. The vomiting centre and associated centres for salivation, sweat and bronchial secretion are stimulated first, though they became depressed by large and subsequent doses. Sweating is associated with vasodilatation of the skin vessels, so that administration of morphine also increases heat loss ().
Respiratory depression is another undesirable effect of morphine. In man, respiration is depressed by doses which are below the narcotic threshold. Large doses are fatal by stopping respiration altogether (6). Morphine therapy must therefore be used with particular care in obstetrics where foetal respiration may be affected and in respiratory ailments such as bronchial asthma. Morphine interacts with respiratory modulator processes principally by decreasing the responsivity of the respiratory centre to CO2 and may have some selectivity in depressing neuronal modulation of the respiratory centre. Opioid-induced respiratory depression is mediated by µ-2 receptors.
Among the peripheral actions of morphine, constipation is one of the most important. The constipation produced is unaffected by denervation of the intestine or by atropine and is largely due to an increase of the tone of the gut and sphincters and an inhibitory action on the Auerbach plexus. Other factors that probably increase this action of morphine are inhibition of the secretion of the intestinal glands and depression of the reflexes responsible for defecation ().
Morphine has anti-diuretic action (i.e. it inhibits urinary output) because it may increase the tone and amplitude of contractions of the ureter, inhibiting the urinary voiding reflex. Urine retention is observed even with therapeutic doses. Morphine stimulates the release of anti-diuretic hormones such as prolactin and somatotropin but inhibits the release of luteinizing hormone (). Morphine also causes retention of bile by closing the sphincters. It raises the pressure in the common bile duct and may cause biliary colic ().
Morphine might produce hypotensive action in subjects whose cardiovascular system is stressed. This hypotensive effect is probably due to peripheral and arterial dilatation, which has been attributed to various factors, e.g. release of histamine and central depression of vasomotor stabilizing mechanisms.
Morphine affects cerebral circulation minimally, except when PCO2 is increased. This increased PCO2 leads to cerebral vascular dilatation, a concomitant decrease of cerebral vascular resistance, an increase of cerebral blood flow and an increase in cerebrospinal fluid pressure ().
Morphine inhibits the formation of rosettes by human lymphocytes. The administration of morphine to animals causes suppression of the cytotoxic activity of natural killer cells and enhances the growth of implanted tumours (Goodmann Gilman’s 1990 The Pharmacological Basis of Therapeutics).
Tolerance to morphine occurs, usually takes 2-3 weeks to acquire on normal therapeutic doses and it applies mostly to the depressant action of the drug. The effects on the pupils and on the intestine remained unchanged during chronic administration.
Humans or animals receiving morphine regularly are liable to become physically dependent on morphine. When this does occur, withdrawal of the drug produces symptoms within 15-20 hours. In addicts, morphine antagonists (e.g. naloxone) can produce withdrawal signs within 30 minutes. The withdrawal symptoms commence with yawning, sweating, and running of the eyes and nose, restlessness, mydriasis, the appearance of ‘goose bumps’, cramps, nausea, insomnia, vomiting and diarrhoea. Tolerance to morphine is rapidly lost during this period and the withdrawal symptoms can be terminated with a suitable dose of morphine (). Thyreotrop-releasing hormone inhibits the tolerance to and dependence on morphine ().
Codeine is the 3-O-methyl ether of morphine. In in vivo animal tests it is less potent than morphine and in vitro it is less potent still. The ID50 of codeine in guinea pig assay was found to be 10 300nM. A discrepancy between its depressant effect in the guinea pig ileum and its analgesic actions in the whole animal or in man has been noted — in the former assay it has only 0.7% of the effect of morphine whereas its analgesic effect in man is about 10% of that of morphine (). In the mouse hot plate test, or in the rat bradykinin induced flexor reflex (), codeine has about one seventh the activity of morphine as an anti-nociceptive agent, and this is reflected in the human parenteral dose, where 60-120mg of codeine is equivalent to 10mg of morphine (). It has been suggested that the virtual inactivity of codeine in vitro is because it is not converted to morphine under these conditions ().
It has been demonstrated that codeine-induced analgesia is mediated via morphine, and depends, at least in part, on centrally formed morphine (). Codeine is used orally for the relief of mild to moderate pain and as an anti-tussive (). Codeine has been used to depress pathological coughs and in patients in whom it is necessary to maintain ventilation via an endotracheal tube. Tolerance to the cough depressant actions of codeine can occur ().
It is frequently combined with mild analgesics. Since its action is much weaker than that of morphine it appears less likely to elicit nausea, vomiting, constipation or respiratory depression. It also has a lower potential for the development of tolerance and physical dependence than morphine (). Similarly to morphine, the toxicity of codeine in different animal species displays great variation, depending on the strain of the animals used and on dietary conditions. It is noteworthy that in animals particularly susceptible to the convulsant effects of codeine, this substance is more toxic than morphine.
A significant difference between the activities of morphine and codeine is that the latter retains much of its activity after oral administration relative to its parenteral effect. The olive oil/water partition coefficient of codeine is 0.25 and when the brain uptake of this compound was measured during a single rat brain passage 25% of the codeine was cleared ().
Codeine, unlike morphine, is not destroyed in the body, but is mostly excreted in the urine ().
Narcotine (noscapine) belongs to the phthalideisoquinoline alkaloid group of opium, fails to produce anti-nociceptive activity, although it has central anti-tussive action (better than that of codeine) by inhibiting the cough reflex (). Narcotine as an anti-tussive agent lacks anti-convulsant activity and fails to reduce responses to N-methylaspartate on rat spinal neurones in vivo following microelectrophoretic administration (). On the other hand, narcotine appears to be less toxic than codeine ().
It resembles papaverine in its pharmacological actions more closely than any of the other opium alkaloids. Like papaverine and many other isoquinoline alkaloids, narcotine exhibits mild local anaesthetic properties. It has no significant actions on the CNS in doses within the therapeutic range.
Narcotine has a relaxant effect on smooth muscle, similar to, but about ten times less than, that of papaverine. Contrary to codeine it does not cause constipation. A weak convulsant action of narcotine has been observed in dogs ().
It was found that narcotine did not increase the analgesic action of morphine (). In mice the analgesic effect of narcotine was very weak compared to morphine, but its toxicity was greater (). It also has a sedative action. Aldehyde reductase I enzyme has been found to be inhibited by narcotine ().
The metabolism of narcotine has been studied in detail).
Papaverine is an important member of the benzylisoquinoline group of opium alkaloids. Unlike the alkaloids of the phenanthrene skeleton, the effects of this alkaloid on the CNS are not prominent, at least with ordinary doses. Papaverine is only slightly narcotic and large doses tend to increase reflex excitability; it displays weak analgesic properties by parenteral or oral administration.
In 1914, Pal demonstrated on animals in vivo, that papaverine decreases the tone of the smooth muscle and is a very effective agent against pathological spasms of the smooth muscle. Papaverine was found to inhibit the tonic phase of contractions of guinea pig ileum and rabbit duodenum induced by acetyl choline, nicotine, heart glycosides, histamine, urea, barium chloride and copper ion. In patients with gastric and duodenal ulcers papaverine decreases the bioelectrical potential of the stomach.
On the human pregnant and non-pregnant uterus, papaverine has a strong spasmolytic effect. It has a vasodepressive effect on the vessels of perfused human placenta.
The effects of papaverine on respiration, blood pressure in dogs and cats, on isolated vessels, on the intestine in situ and in vitro as well as its toxicity in rats are not affected by nalorphine (). Papaverine was found to potentiate the analgesic action of morphine ().
Papaverine has a stimulant action on dopamine receptors in the central nervous system (). It has been shown in cats that papaverine readily penetrates the hematoencephalic barrier. Papaverine inhibits vomiting induced by apomorphine and produces vasodilatation of cerebral vessels.
Papaverine has a statistically significant palliative effect on experimentally induced pruritus.
Subcutaneous administration of papaverine to guinea pigs prevented bronchospasm induced by inhalation of an aerosol of acetylcholine or histamine. The bronchodilatory effect of papaverine was increased by alkalosis and decreased by acidosis.
Papaverine increases blood flow in the coronary arteries and causes their dilation, followed by an increase in the formation of creatine phosphate. Besides its strong coronary vasodilating effect, papaverine diminishes the tendency of the development of ventricular fibrillation.
Papaverine has a marked vasodilating effect upon the vessels: the dilatation is more significant in atherosclerotic than in intact vessels, or when the tension of the vessel walls is increased by epinephrine.
In isolated porcine coronary strips, K+-induced contractions were approximately 10000 times more sensitive to the relaxing effects of nisoldipine, nitrendipine, the Ca2+ antagonist, than to those of papaverine ().
Papaverine failed to reduce responses to N-methylaspartate on rat spinal neurones in vivo following microelectrophoretic administration ().
Intracavity injection of papaverine to impotent man induces penile swelling, attributable the smooth muscle relaxant action of this drug ().
Papaverine has also been found to inhibit cyclic GMP-stimulated nucleotide phosphodiesterase ().
The mechanism of relaxant action of papaverine differs from that of amytal. Papaverine was found to relax the taenia coli even in a sodium-free solution, although its relaxant activity was markedly reduced, while amytal failed to reveal relaxant action in the same condition. Amytal was found to be more sensitive against the re-introduction of small amounts of sodium ions to the sodium-free solution than papaverine. Papaverine induced muscle relaxation with synchronous acceleration of 45Ca, while amytal did not. The cellular uptake of 45Ca was inhibited by papaverine, but not by amytal ().
Caffeine-induced contractions of guinea pig taenia coli are attributed to mobilization of calcium ions from intracellular store sites. Papaverine decreased these contractions at 32°C, while lower temperatures were noted to inhibit papaverine’s action ().
Using several in vitro biochemical assays — related to smooth muscle excitation — contraction coupling, binding to βl, β2, and α-adrenergicreceptors, antagonismofcalcium accumulation — papaverine was observed to be inactive, except as a phosphodiesterase inhibitor ().
The mechanism of action of papaverine was studied by investigating the correlation between inhibition of cyclic AMP phosphodiesterase, antagonism of endogenous adenosine and relaxation of guinea pig tracheal smooth muscle (). Papaverine’s action seems to involve a combination of phosphodiesterase inhibition (as with methylxanthines) and block of Ca channels ().
The systemic haemodynamic and myocardial effects of papaverine administered directly into the left coronary artery were determined in anaesthetized dogs. Papaverine caused profound increases in left ventricular diastolic pressure /dt and arterial hypotension/ in the non ischemic state. In the presence of segmental ischemia papaverine proved to be significantly less potent in this respect ().
The actions of papaverine on the CNS were studied by influencing sleep ().
Papaverine was found to be an effective histamine liberator (). Papaverine, similarly to methylxanthines, relaxes smooth muscle presumably by inhibiting phosphorylation of myosin and by preventing breakdown of cAMP so, that myosin light chain kinase is converted to its less active form (). Papaverine potentiates the relaxing response to adenosine in isolated canine cerebral arteries ().
Selections from the book: “Poppy. The Genus Papaver”. Edited by Jeno Bernáth. Series: “Medicinal and Aromatic Plants — Industrial Profiles”. 1998.