Opioids history,

1
Opioids history, receptors, addiction.
Regina Komsa
2
Opioids history

• Opium has been used for hundreds years to
  relieve pain. Word opium is derived from "opos -
  juice in Greek
• Opium is the dried milky juice of the unripe
  seed capsule of the poppy, the Papaver
  somniferum,.
• Opium is a complex chemical cocktail of morphine
  (10-15), codeine (1-3), noscapine (4-8),
  papaverine (1-3), and thebaine (1-2
• The opioid analgesics are of inestimable value
  because they reduce or abolish pain without
  causing a loss of consciousness. They also
  relieve coughs, spasms, fevers and diarrhea

3

• Archaeological evidence and fossilised poppy
  seeds suggest that Neanderthal man may have used
  the opium poppy 30,000 BC.
• The first known written reference to the poppy
  hul gil - plant of joy appears in a Sumerian
  text dated around 4,000 BC..
• The art of poppy-culling continued from Sumerians
  to Assyrians, Babylonians who in turn would pass
  their knowledge to the Egyptians.
• Throughout the Egyptian civilisation,
  priest-physicians promoted the household use of
  opium preparations. In the capital city of
  Thebes, Egyptians begun the cultivation of opium
  thebaicum.

4

• c. 460 B.C. Hippocrates, "the father of
  medicine", dismissed the magical attributes of
  opium but acknowledged its usefulness as a
  narcotic and styptic in treating internal
  diseases, diseases of women and epidemics.
• 330 B.C. Alexander the Great introduced opium to
  the people of Persia and India.
• Arabic physicians used opium quite often and
  Arabic traders brought opium from the eight
  century on, first to the East, to India and
  China, and later to Europe.

5
Marcus Aurelius(AD 121 - 180)

• Stoic philosopher and illustrious opium-eater
  Emperor Marcus Aurelius (reigned AD 161 - 180),
  Emperor ruled during "...the period in the
  history of the world, during which the condition
  of the human race was most happy and
  prosperous..." (Gibbon).
• Marcus Aurelius wrote Meditations (AD 167).
  Meditations explains how the moral life leads to
  tranquillity. Marcus stresses the virtues of
  wisdom, justice, fortitude, and moderation. He
  recommended opium-eating for headache, dizziness,
  epilepsy, asthma, fever, leprosy and other ills
  of the flesh.

6
Greek physician Galen lists medical indications
of opium... ".. resists poison and venomous
bites, cures chronic headache, deafness,
epilepsy, apoplexy, dimness of sight, loss of
voice, asthma, coughs of all kinds, spitting of
blood, tightness of breath, colic, the lilac
poison, jaundice, hardness of the spleen stone,
urinary complaints, fever, dropsies, leprosies,
the trouble to which women are subject,
melancholy and all pestilences."

Galen(AD 131-200 )
7
Philippus Aureolus TheophrastusBombastus von
Hohenheim"Paracelsus"(1490-1541
Medicinal use of opium was stimulated by the
famous physician Paracelsus at the end of the
middle ages by the introduction of tincture of
opium or laudanum. Paracelsus claimed ".. .I
possess a secret remedy which I call laudanum and
which is superior to all other heroic remedies."
8

• The Mohammedan prohibition of wine favored the
  spread of opium

9

• The banning of wine and tobacco smoking in China
  may have favored the spread of opium.
• An attempt to forbid the import of opium into
  China by the authorities, led to the so-called
  "Opium War" between England and China, launched
  by the biggest, and richest perhaps drug cartel
  the world has ever known, the British Empire.
• The Chinese were defeated. They were forced to
  sign the Treaty of Nanjing in 1842.
• The British required that the opium trade be
  allowed to continue that the Chinese pay a large
  settlement and open five new ports to foreign
  trade and that China cede Hong Kong to Britain.
• Peace didn't last. The Second Opium War began and
  ended in 1856 over western demands that opium
  markets be expanded.

10

• In 1805 Morphine was first isolated from opium
  by a German pharmacist, Wilhelm Sertürner
  (1783-1841). Sertürner named it morphium - after
  Morpheus, the Greek god of dreams.
• From the mid-nineteenth century on, morphine was
  parenterally administered as premedication for
  surgical procedures and for postoperative and
  chronic pain.
• The fact that Morphine appeared to be as
  addictive as opium stimulated research to develop
  nonaddictive opiates.

11

• In 1874, English pharmacist Alder Wright had
  boiled morphine and acetic acid to produce
  diacetylmorphine - heroin, a white, odourless,
  bitter, crystalline powder.
• Heinrich Dreser - a head of Bayer's
  pharmacological laboratory from 1897 to 1914
  was the first to see its commercial potential.
  Under his instructions it was synthesized by
  Hoffmann in Bayer laboratory.
• In 1898, heroin was introduced as the ideal
  nonaddictive substitute for morphine.

Professor Heinrich Dreser(1860 - 1924)
12

• In November 1898, Dreser presented the drug to
  the Congress of German Naturalists and
  Physicians, claiming it was 10 times more
  effective as a cough medicine than codeine, but
  had only a tenth of its toxic effects. It was
  also more effective than morphine as a painkiller

• it was launched and registered as a trademark in
  various countries in November 1898
• The initial response to its launch was
  overwhelmingly positive.
• Dreser had already written about the drug in
  medical journals, and studies had endorsed his
  view that heroin could be effective in treating
  asthma, bronchitis, phthisis and tuberculosis

13
Advertisement
Heroin as a cough medicine
14

• By 1899, Bayer was producing about a ton of
  heroin a year, and exporting the drug to 23
  countries.
• There were heroin pastilles, heroin cough
  lozenges, heroin tablets, water-soluble heroin
  salts and a heroin elixir in a glycerine
  solution.
• In 1906, the American Medical Association
  approved heroin for medical use, though with
  strong reservations about a "habit" that was
  "readily formed".
• As early as 1899, researchers began to report
  patients developing "tolerance" to the drug,
  while a German researcher denounced it as "an
  extremely dangerous poison".

15

• By 1902 - when heroin sales were accounting for
  roughly five percent of Bayer's net profits
• French and American researchers were reporting
  cases of "heroinism" and addiction.
• In 1913, Bayer decided to stop making heroin.
• 1924 - Heroin Act - made manufacture and
  possession of heroin illegal.1930 - Federal
  Bureau of Narcotics was created.1970 -
  Controlled Substances Act was passed - divided
  drugs into categories, set regulations and
  penalties for narcotics

16

• The exact brain mechanisms that cause tolerance
  and addiction are not completely understood.
• Opiates stimulate a "pleasure system" in the
  brain. This system involves neurons in the
  midbrain that use the neurotransmitter called
  "dopamine." These midbrain dopamine neurons
  project to another structure called the nucleus
  accumbens which then projects to the cerebral
  cortex. This system is responsible for the
  pleasurable effects of heroin and for the
  addictive power of the drug.
• Other neurotransmitter systems, such as those
  related to endorphins, are also likely to be
  involved with withdrawal from and tolerance to
  heroin
• .

17

• We are all naturally dependent on opioids for our
  emotional health
• The term opioid is used for all substances with
  an opiate-agonistic action.
• Endogenous and exogenous opioids can be
  distinguished, depending on whether the
  substances are normally present in the body or
  not.
• Exogenous opioids natural -morhine, codeine,
  thebaine,
• semi synthetic, heroin,
• synthetic fentanyl, methadone, nalloxone
• During the 20th century a number of drugs were
  synthesized with a morphine-like action, but with
  a structure somewhat different from that of
  morphine

18

codeine
morphine
heroin
19
naloxone
methadone
fentanyl
20

• First discovered endogenous opioids - enkephalins
  (from the Greek "in the head"), (Hughes et al.
  1975).
• There appeared to be two pentapeptides,
• Met-enkephalin
• Leu-enkephalin
• Nowadays endogenous opioids are schematically
  divided into three main classes enkephalins,
  dynorphins, endorphins.
• These peptides are synthesized via the
  proteolytic processing of larger inactive
  precursor molecules i.e. proenkephalin,
  prodynorphin and proopiomelanocortin.

21

• The opioids produce their effects by interacting
  with a specific receptor.
• The structural similarities between all
  substances with an opiate-like action and the
  discovery of opiate agonists and antagonists,
  generated the concept of opiate receptors.
• Goldstein et al. (1971) used radiolabeled
  levorphanol to discover opiate-binding sites in
  subcellular fractions of mouse brain.

22

• Based on their behavioral and neurophysiological
  findings three types receptors were distinguished
• µ-type for morphine, which induces analgesia,
  hypothermia, meiosis, addiction. µ- receptors are
  found mainly in the brainstem and the medial
  thalamus.
• There are two primary sub-types µ-1 and µ-2.
• Stimulation of the µ-1 receptors is primarily
  responsible for the beautiful sense of euphoria,
  serenity and analgesia
• ? -type (antinociception) As compared with µ-type
  - greater relief of neuropathic pain , reduced
  respiratory depression, and constipation as well
  as a minimal potential for the development of
  physical dependence was identified
• ? -type (induces depression of flexor reflexes,
  sedation, mediates dysphoria, ),

23

• More recently, cDNA encoding an "orphan" receptor
  was identified with high degree of homology to
  the "classical" opioid receptors.
• It has been named ORL1 (opioid receptor-like).
• This receptor is widely distributed in the brain
  and is responsive to the novel peptide orphanin
  FQ also known as nociceptin.
• In contrast to the effects of classic opioid
  receptors, the ORL1 receptor appears to mediate
  hyperalgesia.
• ORL1 receptor can also mediate analgesia
• Studies conducted on the cloned opioid receptors
  demonstrate that the amino acid sequence of the
  ?-, ?-, µ-opioid and ORL1 receptors are 65
  homologous

24

• Some kind of preference for the different
  endogenous opioid ligands for the certain
  receptors was found
• ?-endorphin and Endomorphins 1 and 2 for µ,
• enkephalins for ?
• and dynorphins for ? ,
• nociceptin -orphanin FQ for ORL1.

25
(No Transcript)
26

• Studies conducted on the cloned opioid receptors
  demonstrate that the MOR-1 gene, encoding for one
  form of the m-receptor, shows approximately
  50-70 homology to the genes encoding for the ?
  -(DOR-1), ?-(KOR-1) and orphan (ORL1) receptors
• All classes of opioid receptor share key
  similarities. Their activation produces a wide
  array of cellular responses as analgesia,
  suppression of protein synthesis, schizophrenia,
  and immune response regulation.
• Based on results of pharmacological
  investigations, ? -, ? -, and µ-opioid receptors
  have been further subdivided into receptor
  subtypes ( µ1, µ2 ? 1, ? 2 ? 1, 2, 3).
• There is pharmacological evidence for subtypes of
  each receptor and other types of novel, less
  well-characterised opioid receptors, e, l, i, z,
  have also been postulated.

27

• Opioid receptor types belong to the Gi/Go-coupled
  superfamily of receptors,
• includes numerous neurotransmitter and hormonal
  receptors
• possesses a common three-dimensional structure
  that spans the cell membrane seven times, forming
  three extracellular loops and three intracellular
  loops.
• extracellular amino terminus
• intracellular carboxyl terminus
• the transmembrane regions and the intracellular
  loops possess the greatest similarity
• the most divergent regions are the extracellular
  loops and the amino- and carboxyl-terminals .
• 370-400 amino acids
• 2-5 glycosylation sites
• negatively coupled through Gi protein to
  adenylate cyclase.

28
DELTA
KAPPA
MU
ORPHAN
29
(No Transcript)
30

• When they are activated, they activate other
  downstream effectors to mediate a biological
  response in the cell
• There are four general families of ? subunits
  Gs, Gi, Gq, and G12.

31

• The Gs ? subunit primarily activates an enzyme
  called adenylyl cyclase that catalyzes the
  formation of cAMP from ATP.
• The Gi ? subunit inhibits adenylyl cyclase.
• The Gq ? subunit activates an enzyme called
  phospholipase C Beta (PLC) that cleaves
  phosphotidylinositol-4, 5-bisphosphate (PIP2) in
  the cell membrane to release two second
  messengers diacylglycerol (DAG) and inositol-(1,
  4, 5)-trisphosphate (IP3).
• The G12 ? -subunit has been shown to stimulate
  c-Jun N-terminal kinase (JNK) activity through
  the low molecular weight GTP-binding proteins
  Ras, Rac, and Cdc42.
• G ? 12Q229L stimulated Src family kinase activity
  and v-Src induced JNK activation. Heterotrimeric
  G protein G12 stimulates diverse physiological
  responses including the activities of Na/H
  exchangers and Jun kinases.

32

• The G12 ?-subunit
• has been shown to induce cellular transformation
  when overexpressed or oncogenically activated in
  rodent fibroblasts, interacting between with the
  Ras-Raf-MAPK pathway
• cooperative effect on focus-forming ability when
  G ? 12 and c-raf-1 cDNAs were co-transfected into
  NIH3T3 cells. NIH3T3 cells coexpressing both G ?
  12 and c-raf-1 resulted in the constitutive
  activation of the mitogenic-activated protein
  kinase (MAPK

33
(No Transcript)
34
(No Transcript)
35
Opioids addiction.

• Opiate addiction is a chronically relapsing
  disorder that is characterized by compulsive drug
  taking, an inability to limit intake, and bouts
  of intense drug craving that can be precipitated
  by the mere presence of people, places, or
  objects previously associated with drug use.
• Opiate drugs exert their effects by binding to
  three opioid receptor types (µ, ? , and ) and
  mimicking the actions of endogenous opioid
  peptides, the endorphins, endomorphins,
  enkephalins, and dynorphins.
• The µ-opioid receptor (MOR) subtype is critical
  for the rewarding effects of heroin and morphine.
  Blockade of MORs but not other opioid receptors
  attenuates opiate self-administration, and
  constitutive deletion of MORs attenuates the
  conditioned preferences that animals exhibit for
  contextual cues previously associated with opiate
  administration

36

• As a result of tolerance formation multiple
  cellular adaptations are elicited by chronic
  exposure to opioids. These include
• diminution of spare opioid receptors,
• decreased opioid receptor density and G protein
  content and coupling thereof.
• All imply that opioid tolerance is a
  manifestation of a loss of opioid function, i.e.,
  desensitization

37

• These molecular changes include the up-regulation
  of adenylyl cyclase (AC) isoforms of the type two
  family as well as a substantial increase in their
  phosphorylation state.
• There are as many as nine isoforms of AC many of
  which are differentially regulated.
• It was found that chronic morphine induces
  phosphorylation of AC isoforms II and/or VII and
  also increases the synthesis of AC IV and VII.
• These changes should result in a shift in opioid
  receptor signaling from predominantly Gia
  inhibitory to Gbg stimulatory.
• Indeed, we have demonstrated that Gsa/Gbg
  stimulation of AC is significantly augmented
  following chronic morphine.
• Thus, one consequence of chronic morphine would
  be the up-regulation of divergent
  receptor-coupled stimulatory AC signaling

38

• The schematic diagram shows new signaling
  strategies after chronic morphine treatment.
  Chronic morphine augments production of new
  adenylyl cyclase isoforms of the type II family
  as well as their phosphorylation. As a result,
  opioid signaling shifts from predominantly Gsa
  inhibitory to Gsa/Gbg stimulatory.