1
Q
What is the simple definition for opioids?
A
any ligand for opiod receptors
2
Q
Give some general knowledge about Opioids?
A
- Opioid drugs are narcotic analgesics: they reduce pain but do not produce unconsciousness
- They are the most effective painkillers known
- They also create a feeling of relaxation, euphoria, and sleep
- At high doses they can induce coma and death
3
Q
What are the origins of Opium?
A
- Opium is an extract of the poppy plant (Papver somniferum)
- Most of these plants are grown in Southeast Asia, India, China, Iran, Turkey, and southeastern Europe
- They have a very long history of use, with both recreational and medical use dating back thousands of years
4
Q
What are some historic uses of opium?
A
- Descriptions date back to the early 3rd century B.C.
- Galen (130 - 200 AD) recommended it for medicinal purposes (loss of voice, asthma, deafness)
- Arabs also used it for various medicinal purposes (including diarrhea)
- Spread to India and China
- 11th and 12th centuries crusaders brough it back to Western Europe
5
Q
What is Laudanum?
A
- Laudanum is an opium-based medicinal drink which was introduced in England in 1680
- Drinking laudanum-laced wine was the accepted form of opium use in Victorian England and Ameica
- Especially women
- Up to the twentieth century, laudanum was common in popular remedies
6
Q
What is opium’s history in the United States?
A
- Opium was cultivated in Vermont, New Hampshire, Florida, Louisiana, California and Arizona
- It was grown legally until 1942
- Women drunk it more than men
- Smoking was not socially accepted
- In 1875 San Francisco outlawed opium smoking
- Largely due to anti-Chinese attitude
7
Q
How did morphine originate?
A
- Morphine was isolated in 1803
- 10X more potent than raw opium
- 1856, the hypodermic syringe was invented
- During the American Civil War (1861-1865) many soldiers became dependent (“the soldier’s disease”)
8
Q
How did Heroin originate?
A
- Bayer introduced heroin in market in 1898
- Heroin is 3X stronger than morphine
- In 1910 they realized that it was addictive
9
Q
How is morphine made?
A
- Morphine is one of the typical opiates and is a natural product
- Extracted from poppy plant by cutting surface of seed pod and harvesting the “milk” that comes out
- Morphine is part of this “milk” and can be purified from ti
10
Q
How is Heroin made?
A
- Heroin was made by adding two acetyl groups to morphine, making it more lipid soluble
- This reaches the brain faster, so it is much more potent than morphine, when injected
11
Q
What are semi-synthetic drivatives? entirely synthetic?
A
- Some opium derivatives are “semi-synthetic” chemically modiced versions of opium igredients
- Other narcotics are entirely sysnthetic and may have very different chemical structures.
12
Q
What are partial agonists?
A
**Partial agonists **are the product of modification to opium, they bind to receptrs but have less biological effect.
13
Q
What are pure antagonists?
A
**Pure antagonists, **such as naloxone and nalorphine, are structurlaly similar but have no efficary. They can prevent or reverse the effect of opioids.
14
Q
What are some Opiate Effects?
A
- Pain reduction
- Produce euphoria
- Also cause tolerance and addiction
- Promote relaxation
- Slow breathing
- At high dose can result in death
- Actws on bainstem’s respiratory center
- Cause constipation
- A reason for its use in treating diarrhea
- Constrict pupils
- Induce nausea and vomiting
- Thus, classic signs in emergency room is contricted pupils and depressed breathing
15
Q
Why does morphine cause vomiting?
A
Morphine affects the area postrema and thus elicits vomitings.
Recal we discussed the area postrema/chemical trigger zone when discussing the blood brani barrier.
16
Q
How does morphine relate Diarrhea?
A
- Morphine also affectsz the GI tract
- Opium and morphine have been used to treat diarrhea and can be life-saving to stop fluid loss in severe bacterial and parasitic diseases
- Unfortunately, when opioids are used for pain management, constipation is a common side effect.
17
Q
How do opiates relate to withdrawal?
A
- After developing physical addiction and tolerance, removal of the drug will result in:
- Dysphoria
- Craving for drug
- Diarrhea and vomiting
- Pain
- Sweating and tremors
- Mental confusion and memory deficits
18
Q
How can we treat opiate dependence?
A
- When addicted, two different drugs can be sued to reduce withdrawal
- Methadone is an opiate as well and can be administered to reduce drug craving
- In effect, it satisfies some of the drug cravins and thus reduces withdrawal effects
- Naltrexone is an opiate blocker/antagonist
- Will compete wit opioids for receptors and if given enough, opioids will have no effect
19
Q
What are some interesting facts?
A
- The potency of heroin and morphine is equivalent when take orally
- Heroin molecule is a slight modification of morphine (Diacetylmorphine)
- Heroin in the brain is metabolized into morphine
- Endogenous opioids (endorphin, enkephalin) are more potent than heroin
20
Q
How does opioid binding work?
A
- Bind to specific receptors for naturally occurrring opioid-like neurotransmitters
- Thus, basis of action is on a system that is already found in the brain
21
Q
Identifying the Recpetors (opioid)
A
- Opioid receptors were identified by radioligand binding methods.
- As the amount of radioactive opioid (e.g., the antagonist naloxone) is increased, binding increases and then tapers off until the receptors are fully occupied.
- Thus, there was no binding to other receptors, and binding was shown to be reversible.
22
Q
What are the receptor subtypes?
A
- Selective radioligands were used to identify receptor subtypes: mu, delta, kappa, and the nociceptin/orphanin FW receptor (NOP-R)
- The receptor subtypes have distinct distributions in the brain and spinal cord, suggesting that they mediate a wide variety of effects
23
Q
What do opioids bind to?
A
Opioids bind to opioid receptors in the brain -> endorphins
24
Q
What are 3 types of receptors?
A
- 3 types of receptors -> metabotropic
- mu
- delta
- kappa
25
Opiates bind to receptors?
* Opiates bind to the receptors
* Analgesia-\> medial thalamus, median raphe
* Reward (pleasure) -\> limbic system
26
How do receptors mediate the rewarding effects?
* Increase in dopamine release -\> limbic system
* Euphoria
* Relaxed state
* Opiates can act
27
How can opiates act to mediate the rewarding effects?
* Spinal cord
* inhibit the release of substance P between afferent neurons
* Brain: brain stem, thalamus, limbic system
* Involved in interpretation of pain and pain responses
* Opiates in the brain don't block the pain messages
* They change the subjective experience of pain
28
Describe the mu receptors?
* The mu receptor has a high affinity for morphine
* They are widely distributed in both the brain and spinal cord
* Location of mu-receptors reflect the effects of morphine
29
What are some locations of the mu-receptors?
* Analgesia- [medial thalamus, periaqueductal gray, median raphe, spinal cord].
* Feeding and positive reinforcement- [nucleus accumbens].
* Cardiovascular and respiratory depression, cough control, nausea and vomiting- brainstem
* Sensorimotor integration- [thalamus, striatum].
30
Describe delta-receptors:
* Delta-receptors are predominantly found in forebrain structures (fewer than mu).
* Many of these sites are consistent with a possible role for delta-receptors in modulating olfaction, motor integration, reinforcement, and cognitive function.
* Areas of overlap with mu-receptors suggest modulation of both spinal and supraspinal analgesia
31
Describe Kappa-receptors:
* Kappa-receptors have distinct distribution
* Initially identified by binding to ketocyclazocine, and opioid analog that produces hallucinations and dysphoria
* Found in the striatum and amygdala, specific for hypothalamus and pituitary; may participate in regulation of pain perception, gut motility, and dysphoria (remember how hormones differ from neurotransmitters)
32
What do we know about natural binding concerning opioids?
* The presence of receptors for opium derivaties suggested there might be endogenous opioid neurochemicals
* In the 1970s, **endorphins**- peptides that could bind to receptors- were identified
* Four large propeptides (precursor peptides) are processed into smaller active opioids
* Widespread location of the peptides implicate them in many functions, including pain suppression, reward, motor coordination, endcrine function, fedding, body temperatur and water regulation and response to stress
* The peptides are not selective for a receptor type but show only a relative preference.
33
How is studying pain special?
* Pain varies in intensity and quality, and one's perception of pain can be highly subjective
* Difficult to study (finding pariticpants)
* Pain is also modified by factos such as strong emotion, stress, hypnosis, acupuncture, and opiod drugs
34
What are the 2 components of pain?
* First or early pain- immediate, sensory component. Signals are carried by myelinated Adelta neurons, which conduct action potentials rapidly
* Second or late pain- emotional component. Signal carried by thin and unmyelinated C fibers; transmission is slower.
35
How do opioids work with pain?
* Opioid drug bind to opioid receptors and mimic the inhiboty action of the endogenous opioids at many stages of pain transmission
* Opioids regulate pain in important ways:
* Within the spinal cord by small inhibitory interneurons
* By pathway from the brain to the spinal cord that influence in PNS
* At many higher brain sites, which explains opioid effects on emotional and hormonal aspects of the pain response
36
What role do **spinal interneurons** play in opioids and pain?
* Small inhibitory **spinal interneurons** relase endorphins that inhibit the spinal projection neurons
* Morphine can act directly on those same opioid receptors to inhibt transmission of pain signals to higher brain centers
* An example of drugs having effects outside of CNS/brain that leads to sensation difference
37
Regulating from the brain:
* Opioid activity occurs in other **supraspinal **(above the spinal cord) locations, including sensory areas, limbic structures, and the hypothalamus
* These areas may be responsible for the emotional component of pain and for autonomic and neuroendocrine responses.
38
What about acupunture and pain?
* Research with opioids and pain perception led to studies of acupuncture
* Why think it is related to opioids?
* naloxone reduces acupuncture-induced analgesia
* How can insertion of needles reduce pain?
* Acupuncture relases endogenous opioids
39
How can opiates be taken?
* Orally
* Injection
* Rectally
* Smoked
* Snorted
40
How is heroin metabolized?
* Heroin in the brain: morphine + monoacetyle morphine
* Morphine
* breaks down in the liver
* metabolite-\> morphine-6-glucuronide (10-20X more analgesic than morphine)
* Eliminated 90% urine ( 10% unchanged)
* Elimination half-life 2-3 hours
* Can be detected for 24h in urine
* If morphine + codine found in urine
* patient is suspected of heroin use (due to metabolism)
41
What is the history of heroin abuse?
* After 1924 illegal heroin emerge
* recall that at this time it was not allowed for "non medical" use
* priced 50X more than before
* In the 60s
* Crackdown in heroin smuggling
* resulted in increase in prices, adulterated heroin up, criminality up
* Vietnam war-\> 250mg/ $10 Vietnam ($500 in USA)
* 11% Army returnees in 1971 regular users of heroin
* In 1974-\> 1-2% were regular users
* In the 80s and 90s
* Synthetic opiated -\> dervied from fentanyl -\> China White (α-methylfentanyl)
* South American heroin -\> 60% pure and cheaper
42
What are some medical uses of opiates?
* Relief of pain
* Treatment of acute diarrhea
* Suppression of coughing
* Today we use DM (dextromethorphan) medicines
43
How do we treat opiate addiction?
* Removal of drug from system
* Methadone maintenance program
* Substitution for heroin relieves cravings (withdrawal)
* With methadone no euphoria with oral, but could with IV, so close supervision needed
* Cross-tolerance will reduce euphoric effects of heroin, reduce chance of relapse
44
What do we use now a days to treat opiate addiction?
* Today Buprenorphine (Buprenex) may be preferred to methadone
* An opioid partial agonist, weaker effect than methadone and longer duration
* Dose 1 to 3 per week (reduce cost, less to monitor)
* Variant Suboxone is bupreorphine plus naloxone
* Taken orally the naloxone is not absorbed, but injected (crushed pill) it will be and block effects
* bu can still be abused if crushed and snorted
45
Is Buprenorphine abused?
* Yes! Even with drugs designed for addiction treatment, abuse is still possible
* Other treatment programs use antagonists like naloxone
* Effective for highly motivated individuals (does not reduce drug craving)
* Multidimensional approach
46
What are **Psycomotor stimulatns? **who belongs in this group?
* Cocaine and amphetamine belong to a class of drugs called **psychomotor stimulants**
* They cause sensorimotor activation and are characterized by their ability to increase alertness, heighten arousal, and cause behavioral excitement
47
What is coca's origins?
* Cocaine is an alkaloid found in the leaves of the shrub *erythroxylon coca*
* It is native to South America and is cultivated in northern and central Andes Mountains
* The practive of chewing coca leaves began as early as 5000 years ago
48
Historically what was coca's use? spaniards?
* Coca chewing was an important part of ceremonial or religious occasions in the Incan civilization
* After the Spanish conquest, coca chewing was discouraged by the Catholic church
* Allowed when they realized Incan workers lacked the endurance needed to work long hours in mines and fields at high altitudes and with little food... unless they chewed coca leaves
49
What is cocaine's history?
* By the 1850s, German chemists had isolated and charaterized cocaine
* Cocaine use became popular as many doctors and scientists lauded its properties.
* The most famous user was Sigmud Freud: claimed it was nonaddictive
50
Cocaine Libations:
* French chemist Angelo Mariani created Vin Mariani
* 6mg cocaine/ounce
* John Pemberton in the US created French Wine Coca mimicking Vin Mariani
* Under influence from temperance movement, removed the alcohol and replaced with soda
* Coca and syrup of the African kola nut
* Coca-cola was born
* 1902 the amount of cocaine in Coca-Cola was measured at 0.2mg/ounce syrup
51
History of Cocaine in the U.S.?
* Cocaine also became popular in the U.S. and was used in many medications
* In 1886, Coca Cola was introduced, containing coaine and caffeine. It was marketed as an alternative to alcohol as the temperance movement gained strength.
52
History of cocaine in the U.S. and shifting attitudes
* Cocaine abuse became widespread. President taft declared it to be "public enemy number one" in 1910
* The 1914 Harrison Narcotic Act prohibited inclusion of cocaine (and opium) in over-the-counter medicines and specified other restrictions on import and sale.
* Ocerall public use declined, but in the 1970s, cocaine use by snorting or IV injection increased
* Later, smoking "crack" cocaine has driven the latest epidemic of caine use
53
Is there any synthetic cocaine like structures?
* Two synthetic cocaine-like drugs have been synthesized
* WIN 35, 428 (also known as CFT) and RTI-55 (also called B-CIT)
* They are more potent than cocaine, but are used only experimentally
54
What different forms of cocaine are there?
* The cocaine alkaloid is extracted from coca leaves and then converted to a hydrochloride (HCl) salt and crystallized.
* Cocaine HCl is water-soluble and thus can be taken orally, intranasally (snorting), or by IV injection
* It is not heat-stable, and cannot be smoked.
55
How can you smoke cocaine?
hint: heat stable
* Cocaine HCl can be transformed back into cocaine freebase by two different methods:
* Dissolve in water, add alkaline solution such as ammonia, then extract the cocaine base with an organic solvent, typically ether
* The term **freebasing** refers to smoking cocaine that was obtained in this manner
* Mix dissolved cocaine HCl with baking soda, heat the mixture, the dry it
* Chunck of the dried mixture are known as crack (because of the sound they make when heated)
56
How can cocaine be administered?
* Eaten
* Chewing the leaves
* result: mild stimulant
* Snorted or sniffed
* absorption is around 80%
* Rhnitis and necrosis of nasal membrane (vasoconstrictor)
* Injected
* alone or mixed with heroin
* speedball
* Smoked
* mixed with marijuana (primo or hype) or tobacco
57
How do the different routes of administration of cocaine affect absoprtion?
* Extremely rapid absorption occurs with IV injection and smoking
* Absorption is slower with snorting and oral use
58
What is the pharmacology of cocaine?
hint: this is specificly about lipid solubility
* Cocaine is sufficiently lipophilic (fat-soluble) that it passes readily through the blood-brain barrier
* Smoking results in a large surge of cocaine in the brain that is not reflected in peripheral blood concentrations
* Crack cocaine's strong addictive properties are thought to be due to rapid entry into the brain
59
How is cocaine broken down? what is the result?
hint: in terms of the "high"
* Cocaine is broken down by enzymes in the blood and liver and is rapidly eliminated, wtih a half-life ranging from 0.5 to 1.5 hrs.
* The "high" lasts only about 3 minutes
* Breakdown product such as **benzoylecgonine **persist and can be detected in the urine for several days
* Benzoylecgonine itself is active and is a part of prescriptions used to relieve topical pain
* Alcohol or other depressants are sometimes taken along with cocaine to "take the edge off" the extreme arousal produced by cocaine
* Cocaine plus alcohol produce a unique metabolite called **cocaethylene, **which has activity similar to cocaine, but a longer half-life
60
What are most of cocaine's action due to?
* Most of cocaine's actions are due to blocking reuptake of three transmitters: dopamine (DA), norepinephrine (NE), and serotonin (5-HT)
* These transmitters are cleared from the synaptic cleft by membrane transporters. Cocaine binds to the transporters and inhibits their function.
61
Cocaine has affinity for which transporters?
* Cocaine binds with greatest affinity to the 5-HT transporter, followed by the DA transporter, and then the NE transporter
62
Is blocking DA reuptake an important function of cocaine?
* YES! Blocking DA reuptake appears to be most important for cocaine's stimulating, reinforcing, and addictive properties.
* Contrast with many antidepressants, which blcok 5-HT but not DA and do not have rewarding properties
63
What do transporter studies say (cocaine)?
* Neurochemical mechanisms studied using genetic knockout mice
* DA transporter (DAT) knockout mice show no hyperactivity after given psychostimulant
* Thomsen (2009) et al. created mutant DAT that could take up DA, but was impervious to cocaine (so only natural function)
* These mice did not self-administer
64
How had DA been implicated with the reward system?
* DA in the nucleus accumbens has also been implicated in cocaine reward using pardigms that test for **drug-seeking behaviorb **as a model of relapse
* Reinstatement of cocaine-seeking behavioral in previously extinguished rats can be stimulated by microinjection of DA receptor agonists directly into the nucleus accumbens
* Baseline level of DA activity in the mesolimbic pathway also matters
65
What can affect cocaine besides transporter action?
* At high concentrations, cocaine also inhibits voltage-gated Na+ channels in axons, blocking nerve conduction
* Blocking sodium channel blocks action potential, blocks nerve conduction, result in anestheisa
* When applied locally, it acts as a local anesthetic by preventing transmission of signals along sensory nerves
* Procaine (Novocain) and lidocaine (Xylocaine) were developed from cocaine
66
What effects does cocaine have on the nervous system?
* Recall the autonomic nervous system has both the sympathetic and parasympathetic branches
* Cocaine is a sympathomimetic drug
* Mimic sympathetic nervous system activation
* Increased heart rate
* Vasoconstriction
* Hypertension
* Hyperthermia
* Dilate pupils
* Decreased appetite
* At high doses these effects can be toxic/fatal
* Cardiac arrhythmia- chance of heart attack up 24% during hour after taking cocaine
67
What are the behavioral results of cocaine?
* Typical aspects of cocaine "high": feelings of exhiliration and euphoria, sense of wellbeing, enhanced alertness, heightened energy, and great self-confidence
* Cocaine's supposed ability to enhance sexual proweress is exaggerated
* One is more energetic, and if one feels euphoric, they may feel that everything they do is done well
* Increased aggressive behavior may contribute to the street violence associated with cocaine use
68
Moderate vs Severe cocaine effects:
* Mild to moderate effects generally produced by single, low to moderate doses
* Usually in naive subjects or users who have not yet progressed to heavy use
* Severe effects most likely with high dosages, particularly in chronic users.
* What are the differences in these effects...
69
What are some moderate effects of cocaine?
* Mood amplification; both euphoria and dysphoria
* Heightened energy
* Sleep disturbance, insomnia
* Motor excitement, restlessness
* Talkativeness, pressure of speech
* Hyperactive ideation
* Increased sexual interest
* Anger, verbal aggression
* Mild to moderate anorexia
* Inflated self-esteem
70
What are some severe effects of cocaine?
* Irritability, hostility, anxiety, fear, withdrawal
* Extreme energy or exhaustion
* Total insomnia
* Compulsive motor stereotypies
* Rambling, incoherent speech
* Disjointed flight of ideas
* Decreased sexual interest
* Possible extreme violence
* Total anorexia
* Delusions of grandiosity
71
What is really happening when people take cocaine (in terms of mood)?
* people feel good
* improved mood
* sense of well being and exhilaration
* high spirits
* "bubbling inside"
* friendliness
72
What are some chronic effects of cocaine?
* Undesirable mood changes
* Leads to irribility
* Depression
* Paranoia
* Hallucination-\> formication
* sensation like insects are crawling over skin
* Hallucinations + Anxiety + paranoia
* Nasal blood vessels relax
* runny noses and bleeding
* Tolerance
* Reduction in euphoric
* Sensitization
* To motor behavior and brain excitation
* Seizures
73
How powerful is cocaine? breakpoint?
•In studies in which cocaine is available during limited periods, other reinforcers such as food or even a sweetened water solution are sometimes chosen by animals over IV cocaine.
•On right is example with sweetened water
•BUT the cocaine has a higher break point (showing that looking at break point by itself doesn’t reveal entire story)
•
74
What do studies on cocaine say about reinforcers?
* In humans, preference depends on the type of user, dose, and value of the alternative reinforcer
* Occasional cocaine users would typically choose $2 reward over snorting as much as 100mg of cocaine HCl
* Relatively low value of the cocaine
* Recall teh Hart research: regular crack cocaine mokers were given a choice between a $5 reward and bing allowed to smoke a given amount of cocaine, there was a clear realtionship between the dose and the cocaine choice
75
What influences addiciton?
hint: reward circuit
* Level of access matters
* Data shows that longer periods of access to cocaine can lead to an escalation of intake that, in turn, downregulates the reward circuit
* This presumably makes the cocaine less rewarding and encourages further increases in consumption
76
How are receptor subtypes important for treatment?
* There are five DA receptor subtypes. Genetic knockout mice have been used to study which receptors are influenced by cocaine.
* D1 receptors are required for the locomotor-stimulating effects of cocaine
* D1 receptor knockout mice do not self-administer cocaine, which suggests a critical role in reinforcement.
* D2 knockout mice do self-afdminister cocaine
77
What do blocked receptors mean for the reward effect of cocaine?
hint: D3
* Pharmacological studies of D3 receptors in the mesolimbic DA areas show that the D3 antagonist SB-277011-A completely blocked the reward effect of cocaine.
* D3 receptors have an important role in cocaine's rewarding and reinforcing effects.
78
What are some of the advancement in treatment of cocaine addiction?
* Many compounds have been tested as potential medications to help cocaine users stop and remain abstinent
* Many have shown effectiveness in animal models, none are currently licensed fo rmedical use
* due to unacceptrable side effects and/or lack of therapeutic efficacy
* no equivalent of methadone or naloxone
* Several compound that compete with cocaine for access to the DA transporter show promise
* Other drugs being studied target other neurotransmitters, including 5-HT, glutamate, and GABA
79
What about vaccines to treat cocaine?
* Cocaine vaccines= pharmacotherapy
* Antibody binds to the cocaine
* Can't pass the blood-brain barrier
* But it doesn't take care of craving
* Similar to opioid treatment by Naloxone
80
What about behavioral and psychosocial therapies to treat cocaine addiction?
* Behavioral and psychosocial therapies
* Cognitive behavior therapies
* Teach the users to avoid situations
* If the situations occur--\> coping mechanisms
* 12 step programs
* Vouchers
Drugs and Behavior
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