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morphine
Morphine (
INN) (
IPA:
[ˈmɔ(ɹ)fin]) is a highly potent
opiate
analgesic
drug and is the principal active agent in
opium and the prototypical opiate. Like other
opiates, e.g.
diacetylmorphine (
heroin), morphine acts directly on the
central nervous system (CNS) to
relieve pain, and at
Patients on morphine sometimes report insomnia, visual hallucinations and nightmares; [1] if these occur then reduction in dosage or switch to an alternative opioid analgesic should be considered. The word "morphine" is derived from Morpheus, the god of dreams in Greek mythology. He is the son of Hypnos, god of sleep. Medical usesMorphine is used legally:
Contraindications
PharmacologyMorphine is the prototype narcotic drug and is the gold standard to which all other opioids are tested against. It interacts predominantly with the µ-opioid receptor. These µ-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve. [2] Morphine is a
phenanthrene
opioid receptor
agonist – its main effect is binding to and activating the
µ-opioid receptors in the
central nervous system. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Activation of the
µ-opioid receptors is associated with
analgesia, sedation,
The effects of morphine can be countered with opioid antagonists such as naloxone, naltrexone and NMDA antagonists such as ketamine or dextromethorphan. Morphine is primarily metabolized into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) via glucuronidation by phase II metabolism enzyme [UDP-glucuronosyl transferase-2B7] UGT2B7. The phase I metabolism cytochrome P450 (CYP) family of enzymes has a role in the metabolism to a lesser extent. The metabolism occurs not only in the liver, but may also take place in the brain and the kidneys. M6G has been found to be a far more potent analgesic than morphine when dosed to rodents but crosses the blood-brain barrier with difficulty. M6G has been shown to be relatively more selective for mu-receptors than for delta- and kappa-receptors while M3G does not appear to compete for opioid receptor binding. The significance of M6G formation on the observed effect of a dose of morphine is the subject of extensive debate among pharmacologists. ConstipationLike loperamide and other opioids, morphine acts on myenteric plexus in the intestinal tract reducing gut motility, causing constipation. The gastrointestinal effects of morphine are mediated primarily by µ-opioid receptors in the bowel. By inhibiting gastric emptying and reducing propulsive peristalsis of the intestine, morphine decreases the rate of intestinal transit. Reduction in gut secretion and increases in intestinal fluid absorption also contribute to the constipating effect. Opioids also may act on the gut indirectly through tonic gut spasms after inhibition of nitric oxide generation. This effect was shown in animals when a nitric oxide precursor reversed morphine-induced changes in gut motility. Gene expressionStudies have shown that morphine can alter the expression of certain genes in human DNA. A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins. [4] Effects on the Immune SystemMorphine has long been known to act on receptors expressed on cells of the central nervous system resulting in pain relief and analgesia. In the 1970’s and 80’s evidence that opiate drug addicts showed increase risk of infection (such as increased pneumonia, tuberculosis, and HIV lead scientists to believe that morphine may also affect the immune system. This possibility increased interest in the effect of chronic morphine use on the immune system. The first step of determining that morphine may effect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that dendritic cells, part of the innate immune system, displayed opiate receptors. Dendritic cells are responsible for producing cytokines, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produced more interleukin-12 (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less interleukin-10 (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection). The pathway through which this regulation of cytokines occurs is via the p38 MAPK (mitogen activated protein kinase) dependent pathway. Usually, the p38 within the dendritic cell expresses TLR4 (toll-like receptor 4) which is activated through the ligand LPS ( lipopolysaccharide). This causes the p38 MAPK to be phosphorylated. This phosphorylation activates the p38 MAPK to begin producing IL-10 and IL-12. When the dendritic cell is chronically exposed to morphine during their differentiation process then treated with LPS the production of cytokines is different. Once treated with morphine, the p38 MAPK does not produce IL-10, instead favoring production of IL-12. The exact mechanism through which the production of one cytokine is increased in favor over another is not known. Most likely, the morphine causes increased phosphorylation of the p38 MAPK. Transcriptional level interactions between IL-10 and IL-12 may further increase the production of IL-12 once IL-10 is not being produced. Future research may target the exact mechanism that increases the production of IL-12 in morphine treated dendritic cells. This increased production of IL-12 causes and increased T-cell immune response. This response is due to the ability of IL-12 to cause T helper cells to differentiate into the Th1 cell, causing a T cell immune response. ChemistryMost of the licit morphine produced is used to make codeine by methylation. It is also a precursor for both diamorphine and hydromorphone. Replacement of the N-methyl group of morphine with an N-phenylethyl group results in a product that is 18x morphine in its opiate agonist potency. Combining this modification with the replacement of the 6 hydroxyl with a 6 methylene produces a compound some 1440x morphine in potency, stronger than the Bentley compounds such as etorphine. If this compound was cut into regular heroin it is most unlikely that it would show up on any tests. Both morphine and its hydrated form, C 17H 19NO 3H 2O, are sparingly soluble in water. In five litres of water, only one gram of the hydrate will dissolve. For this reason, pharmaceutical companies produce sulphate and hydrochloride salts of the drug, both of which are over 300 times more water-soluble than its parent molecule. Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; consequently, the morphine salts are mixed with small amounts of NaOH to make them suitable for injection. [5] Interestingly, morphine has recently been found to be endogenously produced by humans, made by cells in the heart, pancreas and brain. [6] It has also been isolated from a range of other mammals, as well as toads and some invertebrates. What the normal endogenous role of morphine might be is unclear. Legal classification
History and abuse
 Morphine was first isolated in 1804 [8] by the German pharmacist Friedrich Wilhelm Adam Sertürner (or Barnard Courtois), who named it "morphium" after Morpheus, the Greek god of dreams. But it was not until the development of the hypodermic needle in 1853 that its use spread. [9] It was used for pain relief, and as a "cure" for opium and alcohol addiction. Later it was found out that morphine was even more addictive then either alcohol or opium, and its extensive use during the American Civil War allegedly resulted in over 400,000 [10] sufferers from the "soldier's disease" of morphine addiction [11] [12]. This statement has been subjected to controversy as there have been suggestions that such a disease was in fact a hoax and soldiers disease never occurred after the civil war [13] [14]. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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