PS 3010 Behavioural Pharmacology lecture 4a, semester 2: 20042005

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PS 3010 Behavioural Pharmacology lecture 4a,
semester 2 2004-2005

• Opiates analgesia and abuse.
• Prof. Michael H. Joseph
• School of Psychology

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Introduction

• Opium is the dried sap of the opium poppy
• About 10 of opium by weight is morphine. The
  other main opiate present is codeine, 0.5.
• Opiates are properly referred to as narcotic
  analgesics (cf aspirin), but in the US narcotic
  refers to any addictive drug.
• Hence we use the term opiates
• Heroin is a derivative of morphine which reaches
  the brain more easily.

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Agonists Antagonists   Morphine Naloxone
Codeine Naltrexone Heroin Pethidine (short
acting) Partial agonists Pentazocine. Methadone
(long acting) Nalorphine LAAM (v. long
acting) Cyclazocine
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History and use

• Possibly the oldest psychoactive drug (pace
  Carlsberg)
• Early use against diarrhoea
• Treated as recreational drug like tobacco
• 19th C England, laudanum used in this way, also
  to quieten babies.
• Morphine available through doctors, leading to
  medicalisation of abuse, as addiction.

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Absorption and distribution

• Morphine and Heroin are poorly absorbed orally,
  and suffer first pass metabolism. Hence, to
  produce central effects, they are injected.
  Heroin can also be taken nasally.
• Half-life of morphine is about 2 hours. Methadone
  has a much longer half-life, and is used for
  maintenance therapy

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Neuropharmacology

• The idea of specific opiate receptors came from
  SARs (structure activity relationships),
  and stereospecific binding.
• Pert, Snowman and Snyder (1974), and other labs,
  identified specific opiate receptors in rat
  brain.
• This was on the basis of stereospecificity
  saturability, reversibility and high-affinity.
  These criteria had been developed from
  experience with other types of CNS receptors

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Enkephalins and Endorphins

• Why are there brain receptors for plant derived
  drugs ?
• Anticipating their discovery, putative ligands
  for these receptors in the brain were named
  ENDogenous mORPHINe-like compoundS
• Identification of brain peptides binding to
  opiate receptors very small by Hughes and
  Kosterlitz (Aberdeen) met- and leu-enkephalin.

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Enkephalins and Endorphins

• Enkephalins only 5 amino acids long.
• Two versions, differing in one AA
• Structure verified when sequence found within
  peptides being studied independently by Howard
  Morris at Imperial college.
• Cleavage of precursors c.260 AAs long to
  enkephalins (5) and endorphins (16-30 AA)

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Large Precursor Proteins

• Pro-opiomelanocortin (POMC)
• a, ß, ? -MSH ACTH met-Enk ß-endorphin
• Pro-enkephalin
• met- and leu-Enkephalin (61)
• Pro-dynorphin
• leu-Enkephalin leading each of a family of
  dynorphins
• After cleavage stored in vesicles in respective
  neurones.

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Opiate receptors functions and locations

• Name Avid binding
• mu (?) receptor morphine
• delta (?) receptor enkephalin analogues
• kappa (?) receptor cyclazocine
• sigma (?) receptor SKF 10,047 (opiate
  analogue)

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Physical effects of opiates

• Analgesia (pain relief), reward - mu (?)
• Spinal cord, limbic system, striatum, neocortex
• Respiratory depression - mu (?)
• Constipation - kappa (?)
• Temperature control - kappa (?)

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Behavioural effects of opiates(humans and
animals)

• Sleep cause sleepiness, but do not increase
  sleep times, unless through pain relief.
• Performance humans low/moderate doses,
  little effect high doses reduced motivation,
  lethargy
• Performance rats and mice increases in
  unconditioned behaviours, LMA.
• Higher doses stereotyped responses, but wider
  range (e.g. social) than amphetamine.

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Behavioural effects of opiates (animals)

• Positively motivated behaviours increased on FI
  schedule, but not on FR, at moderate doses. (i.e.
  not simply activation)
• Higher doses slow both
• Aversively motivated behaviours increased at
  moderate doses. Higher doses impair avoidance,
  but not escape (i.e. not simply analgesic).
• No evidence for anxiolytic effect

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Subjective effects of opiates (humans)

• Increased sensitivity in hearing and vision.
  Trance like state with vivid dreams, can be
  auditory as well. Artists feel increased
  creativity.
• Intravenous injection causes the rush. Intense
  momentary feeling of pleasure.
• Mood euphoric mood as initial response over
  time this becomes unpleasant mood, relieved only
  briefly by the injections (Meyer and Mirin, 1979
  hospital setting).
• Performance little effect at low or moderate
  dose. Famous US surgeon was an addict recent
  reports.

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Subjective effects of opiates (animals)

• Performance Food seeking and shock avoidance not
  disrupted in monkeys, unless in withdrawal
• Drug discrimination Animals trained to press one
  key for reward after a drug and another after
  saline.
• Morphine readily discriminable from saline.
• Morphine cue generalises to all the other
  opiates, but only partly to cyclazocine.
• Self-administration in non-humans Morphine was
  the first drug for which this was demonstrated
  (i.v.). Initially in dependent animals, later in
  non-dependant animals.

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Tolerance

• Marked and rapid tolerance occurs to opiates.
• Can be up to 10-fold or more over a few months.
• Tolerance to analgesia and positive reinforcing
  effects may be accompanied by little tolerance to
  pupil constriction, and none to constipation.
• Cross tolerance shown to other opiates, but not
  to depressants, stimulants or hallucinogens.
• There is however some degree of cross tolerance
  with alcohol.

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Withdrawal

• Unpleasant combination of  restlessness,
  agitation, yawning, chills and hot flushes.
  Gooseflesh on the skin.
• Drowsy/ deep sleep, cramps, vomiting, diarrhoea,
  twitching and kicking of the legs, profuse
  sweating opposite of effects of the drug.
• Not however life threatening, as withdrawal from
  alcohol or barbiturates can be.
• Can be stopped by the drug, or to some extent by
  alcohol. Is precipitated by an opiate
  antagonist.

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Patterns of use

• Clear that not all users become addicts - stable
  pattern of occasional use possible.
• An addict is typically scoring at least once a
  day, and more and more of their resources become
  taken up with acquiring the drug.
• There appears to be pattern of maturing out of
  the drug in 30s/40s, after some 5-10 yrs of
  heroin use.
• Pattern (human or primate) is of regular use with
  increasing doses to a plateau.
• No intake-abstinence cycles as for
  psycho-stimulants - appears to be a careful
  titration of blood levels to avoid withdrawal
  symptoms.

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Treatment I

• Therapeutic communities simply keep the addict
  away from previous environments. Work at the
  time, but relapse rate on leaving is high - 90  
• Methadone maintenance can be taken orally, and
  prevents withdrawal symptoms for 24 hrs. Blocks
  subjective effects of heroin used in conjunction
  with psychological or social treatments - a
  holding operation. However the relapse
  rate after that is high again.
• LAAM (L-acetyl-methadol) is an alternative drug
  to methadone with a longer half life.  

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Treatment II

• Buprenorphine is another alternative. Binds to
  mu receptors as a partial antagonist. Hence
  blocks opiate effects with only mild agonist
  effects itself.
• It should be easier to come off, and reduce
  withdrawal effects when later switching to
  antagonist therapy.

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Treatment III

• Antagonist therapy patients withdrawn from
  heroin 7 to 10 days. Clonidine may help to
  manage the withdrawal (reverses the rebound
  activation of the LC noradrenaline neurones)
• As early as possible addicts are given daily
  doses of an antagonist. naloxone, naltrexone or
  cyclazocine. Blocks rewarding effects of heroin
  subsequently
• Better success rates. 70 were still in the day
  program at the end of one year fewer than half
  of these were still taking the antagonist.

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Treatment IV

• Another more controversial approach is rapidly
  precipitated withdrawal using antagonists, under
  anaesthesia so that patients do not experience
  the withdrawal symptoms.
• This approach pioneered in Spain by Juan Legarda,
  but worries about medical complications while
  under anaesthetic.
• Studies are continuing to assess ethics and
  applicability.

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Conclusions I

• Opiates are some of the oldest known, and most
  effective, drugs for pain control, and the
  control of diarrhoea.
• Unfortunately, they have a poor therapeutic
  index, and a high abuse potential.
• Abuse of opiates is a widespread social problem.
• We have achieved limited understanding of the
  biological basis of addiction.
• This has not so far illuminated treatment.

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Conclusions II

• Neuroscience research has uncovered hitherto
  unknown opiate receptors, and opiate peptide
  transmitter systems in brain.
• This has revolutionised our understanding of
  brain chemistry, pharmacology and
  neurotransmission.
• However, so far, there has not been much clinical
  benefit in the treatment of pain, or of opiate
  abuse