1. Opioid Receptors and Dependency
Faculdade de Medicina da Universidade de Coimbra
2009/2010
Mestrado Integrado em Medicina – BCM I
Opioid Receptors and Dependency
Turma 5 e 6:
Diana Silva
Daniela Silva
Filipa Nunes
Filipe Mira
24 de Novembro de 2009

2. Objectives
Characterize each type of opioid receptors by explaining the preferential endogenous ligand;
Explain how the reaction processes using a specific example;
Talk about dependency and its relation with the opioid receptors.

3. Opioid Receptors
Belong to the superfamily of seven transmembrane- spanning G protein-coupled receptors.
Are key elements in a regulatory system.
Allow opioids outside the cell to modify intracellular events and alter cell function.
Are divided into three types: mu, kappa and delta.

4. μ δ κ Receptor Where is produced Where is expressed Effect Agonist
Thalamus
Pain, breathing, nausea and vomiting areas in the brain
Lungs
Intestines
Adrenals
Kidneys
Spleen
Supraspinal analgesia
Bradycardia
Ventilatory depression
Hypothermia
Euforia
Dependence miosis
ß endorphin
Dynorphin A1-13
Morphine and derivates δ
Stomach
Splean
Sexual organs
Heart
Cerebral cortex
Hippocampus
Olfatory tubercle
μ modulation
Analgesia
Leu-enkephalin
Dynorphin A1-8 κ
Spinal
Hypothalamus
Brain
Spinal analgesia
Sedation
Miosis
Dynorphin
Morphine
Nalbuphine

5. same biochemical brain processes
Drug Liking
Basic life functions
(e.g.: eating)
Opioid molecules
same biochemical brain processes
The linkage of these chemicals with the receptors triggers the same biochemical brain processes that reward people with feelings of pleasure when they engage in activities that promote basic life functions.
Opioids are prescribed therapeutically to relieve pain, but when opioids activate these reward processes in the absence of significant pain, they can motivate repeated use of the drug simply for pleasure.
Feelings of pleasure

6. The Opioid Receptors In a normal state
Normally, natural opiatelike chemicals produced by the body link to mu opioid receptors on the surface of neurons.
This activates an enzyme that converts ATP into cAMP (cyclic adenosine monophosphate)  production of NA (noradrenaline)
Normal levels of alertness and respiration
noradrenaline (NA), a brain chemical that stimulates wakefulness, muscle tone, and respiration, among other functions.
A. Normally, natural opiatelike chemicals produced by the body link to mu opioid receptors on the surface of neurons. This linkage activates an enzyme that converts a chemical called adenosine triphosphate (ATP) into another chemical, called cyclic adenosine monophosphate (cAMP), which in turn triggers the release of NA. Prior to initiation of opioid drug abuse, the neuron produces enough NA to maintain normal levels of alertness, muscle tone, respiration, etc.
Normal production of NA, no external opioids

7. The Opioid Receptors
After linkage of an opioid drug to the Mu receptor:
The enzyme that converts ATP into cAMP is inhibited.
cAMP is less produced.
Less NA is released.
Effects of sedation appear (alertness and breathing frequency drop)
B. When heroin or another opioid drug links to the mu opioid receptors, it inhibits the enzyme that converts ATP to cAMP. As a result, less cAMP is produced, less NA is released. Alertness, muscle tone, and respiration drop, and the acute opioid effects of sedation, shallow breathing, etc., appear.
After linkage of na opioid to the Mu receptor

8. The Opioid Receptors After repeated opioid exposure:
The neuron increases its supply of enzymes and ATP molecules.
It produces enough cAMP to offset the inhibitory effect of the drug.
Releases almost the same amounts of NA even though the drug is present.
The individual doesn’t experience the same intensity as in early stages.
C. With repeated heroin exposure, the neuron increases its supply of enzyme and ATP molecules. Using these extra raw materials, the neuron can produce enough cAMP to offset the inhibitory effect of the drug and release roughly normal amounts of NA despite the presence of the drug. At this stage, the individual no longer experiences the same intensity of acute opioid effects as in earlier stages of abuse.
Repeated exposure to opiods

9. The Opioid Receptors When the drug is discontinued:
The inhibitory impact is lost.
The neuron operates at normal efficiency but with more enzymes and more cAMP production out of ATP.
More cAMP leads to the release of more NA.
Over release of NA  symptoms of withdrawal (jitters, anxyety, cramps, etc)
D. When heroin is discontinued after chronic abuse, the drug’s inhibitory impact is lost. Operating at normal efficiency but with enhanced supplies of converting enzyme and ATP, the neuron produces abnormally high levels of cAMP, leading to excessive release of NA. The patient experiences the clinical symptoms of withdrawal—jitters, anxiety, muscle cramps, etc., that can lead individual to relapse to drug use. If no further drugs are taken, the neuron will largely revert to its predrug condition (panel A) within days or weeks.
After discontinuing the drug

11. Opioid Tolerance
The need to take higher and higher dosages of drugs to achieve the same opioid effect.
Brain neurons are naturally “set” to release enough DA in the NAc
Dopamine (DA): A neurotransmitter present in brain regions that regulate movement, emotion, motivation, and the feeling of pleasure.
VTA – ventral tegmental area
NAc – nucleus accumbens
Normal level of pleasure

12. Opioid Tolerance Pleasure signals are continued given
Heroin links to mu receptors
Dopamine transporter is blocked
Dopamine accumulates in the synaptic cleft
Pleasure signals are continued given
Activation of opioid receptors by heroin or other opiate drugs cause an increase of DA in synaptic cleft, because opiaite drugs link to dopamine transporters so that they are blocked and DA can’t back to transmitting neuron, giving continued signals of pleasure to receiving neuron.
With repeated heroin use,
the brain responds to these successive large DA releases by increasing the number and strength of the brakes on the VTA DA neurons, inhibiting the neurons’ resting DA release.

13. Dependent addict wants more heroin
Opioid Tolerance
Neurons’ resting DA release are inhibited
Dependent addict wants more heroin
Reduction of normal DA release
On the other hand, when he stops to consume , a state of DA deprivation will result, manifesting in dysphoria and other withdrawal symptoms.
When neurons’ resting DA release are inhibited, the dependent addict will take even more heroin to offset the reduction of normal resting DA release.
On the other hand, when he or she stops to consume, a state of DA deprivation will result, manifesting in dysphoria (pain, agitation, malaise) and other withdrawal symptoms, which can lead to a cycle of relapse to drug use.

14. Opioid Dependency Because of… Withdrawal symptoms;
The need of having pleasure;
Environmental issues.
- withdrawal symptoms – to avoid this symptoms caused by the abstinence of the substance;
- the need of having pleasure – because repeated exposure to escalating dosages of opioids alters the brain so that it functions more or less normally when the drugs are present and abnormally when they are not;
- environmental issues – because the local where individual use to consume, can remember drug that lead to desire or craving that.

15. Bibliography
“Revista Portuguesa de Cardiologia”, Artigo de Revisão, SARAIVA Joana, et al, publicação de Julho 2004, pp – accao.htm