L8 - Opioids and Pain Part Two Flashcards
What is the difference between dependence and addiction?
Dependence refers to the physical adaptation to a substance, where the body requires it to function normally, and withdrawal symptoms occur if the substance is reduced or stopped.
Addiction involves psychological and behavioral compulsions to use a substance, characterized by loss of control, persistent use despite negative consequences, and cravings.
What are the key features of dependence?
Tolerance: The need for increased doses of a substance to achieve the same effect.
Withdrawal: Physical symptoms that occur when substance use is reduced or stopped.
What are the key features of addiction?
Compulsive use: Persistent and uncontrollable urge to use the substance.
Cravings: Strong desire to use the substance.
Loss of control: Inability to reduce or stop use despite negative consequences.
Behavioral changes: Prioritizing substance use over other important aspects of life.
What is the pharmacological definition of tolerance?
Tolerance is the increase in concentration of an agonist required to produce half-maximal stimulation.
What is the explanation of tolerance?
Tolerance occurs when the effect of a drug gradually diminishes over time when it is administered continuously or repeatedly.
It can develop within a few hours to weeks of repeated administration.
What is the mechanism behind opioid tolerance?
Opioid tolerance is mainly due to receptor desensitization and down-regulation of opioid receptors.
What are the pros of tolerance/desensitization?
Prevention of overstimulation: Tolerance/desensitization helps cells reduce their sensitivity to a stimulus, preventing saturation or over-stimulation of the system.
What are the cons of tolerance?
Reduced therapeutic usefulness: The effectiveness of a drug diminishes with continuous or repeated use, limiting its long-term therapeutic potential.
How soon does tolerance to drug action (analgesia) occur after treatment?
Tolerance can occur within 12-24 hours of continuous opioid treatment.
How much can the ED50 increase in high-dose treatment?
With high-dose treatment, the ED50 can increase up to 5-fold over a period of 3-4 days.
Which effects of opioids develop tolerance, and which do not?
Tolerance develops to euphoria, analgesia, and respiratory depression.
No tolerance develops to constipation and pupil constriction.
What can chronic opioid users tolerate without respiratory depression?
Chronic opioid users can take doses 50-100 times higher than the therapeutic dose without experiencing significant respiratory depression.
What is the first step in the process of opioid receptor desensitization?
The mu-receptor is phosphorylated by G-protein receptor kinase (GRK), initiating desensitization.
What is the role of arrestins in opioid tolerance?
Arrestins bind to the phosphorylated mu-receptor, preventing further G-protein signaling and contributing to receptor desensitization.
What are the two main types of covalent modification that contribute to opioid receptor desensitization?
Phosphorylation (reversible)
Down-regulation (irreversible)
How long does phosphorylation take in the process of opioid tolerance?
Phosphorylation occurs within seconds to minutes and is reversible. It can lead to internalisation or sequestration of the receptor.
What is the time scale for internalisation of opioid receptors?
Internalisation occurs within minutes to hours and is part of the reversible tolerance process.
What is down-regulation of opioid receptors and how long does it take?
Down-regulation refers to the irreversible reduction in receptor availability. This process occurs over hours.
How do proteins contribute to opioid tolerance?
Proteins involved in opioid tolerance inactivate receptors, promote or inhibit ion channel gating, and modify enzyme activity, which leads to altered physiological responses.
How does over-exposure to an agonist cause tolerance?
Over-exposure to an agonist (like opioids) leads to receptor desensitization, either through phosphorylation, internalisation, or down-regulation of the receptor. This reduces the receptor’s sensitivity to the agonist.
What role do phosphatases and protein kinases play in opioid tolerance?
Phosphatases and protein kinases regulate the function of opioid receptors by phosphorylating intracellular loops of the receptor, such as serine/threonine residues, which alters receptor activity.
How do protein kinase A and protein kinase C influence opioid tolerance?
Protein kinase A (PKA) and protein kinase C (PKC) play key roles in modifying the activity of the opioid receptor and contribute to receptor desensitization and tolerance.
How do G-protein receptor kinases (GRK) mediate tolerance?
G-protein receptor kinases (GRK) phosphorylate intracellular loops of opioid receptors, particularly serine/threonine residues, which inactivate the receptors and reduce their responsiveness to opioids.
What is the overall effect of these mechanisms on opioid receptors?
The combined effect of these processes is to decrease receptor sensitivity, leading to tolerance and altered physiological responses to opioids.
How do proteins contribute to opioid tolerance?
Proteins involved in opioid tolerance inactivate receptors, promote or inhibit ion channel gating, and modify enzyme activity, which leads to altered physiological responses.
What role do phosphatases and protein kinases play in opioid tolerance?
Phosphatases and protein kinases regulate the function of opioid receptors by phosphorylating intracellular loops of the receptor, such as serine/threonine residues, which alters receptor activity.
How do protein kinase A and protein kinase C influence opioid tolerance?
Protein kinase A (PKA) and protein kinase C (PKC) play key roles in modifying the activity of the opioid receptor and contribute to receptor desensitization and tolerance.
How do G-protein receptor kinases (GRK) mediate tolerance?
G-protein receptor kinases (GRK) phosphorylate intracellular loops of opioid receptors, particularly serine/threonine residues, which inactivate the receptors and reduce their responsiveness to opioids
What occurs during early endosomal phase of opioid receptor down-regulation?
During the early phase (4h), opioid receptors are internalized and either recycled back to the plasma membrane or directed towards late endosomes for further processing. This phase also involves down-regulation of receptor activity.
What happens during the late endosomal phase of opioid receptor down-regulation?
In the late phase (14h), opioid receptors in the late endosomes are either dephosphorylated, degraded in the lysosome, or recycled. This contributes to the down-regulation and desensitization of opioid receptors.
What is resensitization in the context of opioid receptors?
Resensitization refers to the replenishment of opioid receptors on the cell membrane through recycling of internalized receptors or new protein synthesis that restores receptor function after down-regulation.
How does down-regulation of opioid receptors affect gene expression?
Down-regulation involves suppressed gene expression, including decreased mRNA stability, which limits the production of new receptors and contributes to long-term tolerance
What role does lysosomal degradation play in opioid receptor regulation?
Lysosomal degradation of internalized opioid receptors contributes to down-regulation, reducing the overall number of receptors available for activation.
What does tolerance to opioid drugs mean?
Tolerance occurs when a higher dose of opioid is required to achieve the same level of analgesic effect, leading to dose escalation.
When does tolerance to opioids typically develop?
Tolerance develops in individuals taking long-term opioids, particularly for the treatment of chronic pain.
What are the strategies to improve analgesia after opioid tolerance occurs?
Increase the dose of the opioid, but this increases the potential for side effects.
Opioid rotation—switching from one opioid to another. This may help because cross-tolerance is incomplete between different opioids.
What is the concept of opioid rotation and how does it affect analgesia?
Opioid rotation involves switching from one opioid to another. The equipotent analgesia dose for the new opioid may be reduced by up to 40%, suggesting that full cross-tolerance does not occur between opioids.
How does dose escalation relate to the development of tolerance in opioid users?
As tolerance develops over time, dose escalation is required to maintain the same level of analgesic effect, but this increases the risk of adverse effects and potential overdose.
What is the relationship between euphoria and opioid use?
Euphoria occurs when the drug activates the mesolimbic reward pathway, stimulating areas of the brain and creating conditional associations. This leads to memories of pleasurable feelings, resulting in cravings for the drug.
What does tolerance to opioids mean?
Tolerance means that higher doses of the drug are required to achieve the same effect, such as causing enough dopamine release to feel euphoric. Over time, the body becomes less responsive to the drug’s effects.
What is dependence in the context of opioid use?
Dependence is a biological consequence of taking the drug. A person develops a need to take the drug regularly to avoid withdrawal symptoms.
How does addiction or substance use disorder manifest in opioid users?
Addiction or substance use disorder is characterized by intense cravings for the drug, compulsive use, and impairment or distress in the individual’s life due to drug use.
What is the mechanism underlying opioid-induced euphoria?
The mechanism is complex and not fully understood, but it involves the mesolimbic pathway (a reward system) and the mu-opioid receptor.
Opioids act on both the ventral tegmental area (VTA) and the nucleus accumbens (NAc), leading to an increase in dopamine release in the nucleus accumbens.
This increased dopamine results in a feeling of euphoria.
What areas of the brain are involved in opioid-induced euphoria?
The ventral tegmental area (VTA) and the nucleus accumbens (NAc) are key brain regions involved in the release of dopamine, contributing to the euphoria experienced with opioid use.
What is the normal state of the mesolimbic pathway?
In the normal state, the ventral tegmental area (VTA) and nucleus accumbens (NAc) are involved in the mesolimbic pathway.
GABA interneurons inhibit dopamine (DA) neurons, reducing dopamine release into the nucleus accumbens.
How does opioid exposure affect the mesolimbic pathway?
After acute opioid exposure, opioids bind to mu-opioid receptors in the VTA, leading to disinhibition of GABA interneurons.
This disinhibition allows dopamine neurons to become more active, resulting in increased dopamine release into the nucleus accumbens, which leads to euphoria.
How do opioids cause euphoria at the neuronal level?
Opioids inhibit GABAergic activity, reducing the inhibitory tone on dopamine neurons in the VTA.
This causes increased dopamine release in the nucleus accumbens, producing a feeling of euphoria.
What is euphoria in the context of opioid use?
Euphoria occurs when opioids activate the mesolimbic reward pathway.
Other brain areas are activated, leading to conditional associations (memories of good feelings), which can result in cravings for the drug.
What is tolerance in the context of opioids?
Tolerance is when a higher dose of the drug is needed to achieve the same effect, such as causing enough dopamine release to feel euphoric.
What is dependence (or withdrawal) related to opioid use?
Dependence is a biological consequence of using the drug.
The person needs to take the drug regularly to avoid withdrawal symptoms.
What defines addiction or substance use disorder?
Addiction or substance use disorder is characterized by intense drug cravings and compulsive use of the drug, leading to impairment or distress in daily life.
How do opioids initially cause euphoria?
Opioids reduce the release of GABA from interneurons, leading to a large release of dopamine.
This results in a feeling of euphoria.
What brain regions are involved in opioid-induced euphoria?
The mesolimbic pathway is involved, particularly the ventral tegmental area (VTA) and the nucleus accumbens (NAc).
Dopamine release in the nucleus accumbens causes euphoria.
How does tolerance develop to the euphoric effects of opioids?
With repeated opioid use, the brain becomes less responsive, requiring higher doses of opioids to achieve the same level of dopamine release and euphoria.
What happens to GABA release with chronic opioid use?
The body increases the amount of GABA released by interneurons in response to chronic opioid use.
How does increased GABA release affect dopamine levels?
Increased GABA release leads to a decrease in dopamine (DA) release, reducing the euphoric effect even when opioids are used.
How do opioids initially affect GABA and dopamine release?
Opioids initially reduce GABA release from interneurons, leading to a large release of dopamine (DA), causing euphoria.
How does the body respond to chronic opioid use in terms of GABA release?
The body increases the amount of GABA released by interneurons in response to chronic opioid use.
What effect does increased GABA release have on dopamine?
Increased GABA release results in a decrease in dopamine (DA) release, reducing the euphoric effect even with continued opioid use.
What happens when tolerance develops due to chronic opioid use?
Users must take higher doses of opioids to achieve the same euphoric effect due to tolerance.
How does chronic opioid use lead to tolerance through receptor changes?
Tolerance can occur through opioid receptor desensitisation, internalisation, and down-regulation due to chronic opioid use, resulting in decreased receptor signaling.
How does the body adapt to chronic opioid use in terms of GABA release?
The body increases GABA release above basal levels to control excessive dopamine release during chronic opioid use.
What happens when a patient suddenly stops taking opioids?
When opioids are suddenly stopped, GABA release increases even more, leading to greater inhibition of dopamine release.
: What effect does the increased GABA release have on dopamine and how does it contribute to withdrawal symptoms?
Increased GABA release causes dopamine deprivation in the nucleus accumbens, leading to dysphoria-like symptoms such as pain, agitation, and malaise.
What is a potential outcome of the dysphoria caused by opioid withdrawal?
The dysphoria can lead to relapse, where the individual starts taking opioids again to alleviate the withdrawal symptoms and prevent the dysphoria.
What is the physiological role of basal adenylate cyclase activity?
Basal adenylate cyclase (AC) activity synthesizes cAMP from ATP, leading to the activation of PKA (Protein Kinase A).
What does the activation of PKA trigger in the locus coeruleus?
PKA activation triggers the release of noradrenaline (NA) from the locus coeruleus.
What physiological functions are mediated by noradrenaline release from the locus coeruleus?
A:
Noradrenaline release mediates:
Wakefulness
Muscle tone
Respiration
How do opioids affect adenylate cyclase activity?
Opioids inhibit adenylate cyclase via the Gi alpha subunit, reducing its efficiency and lowering adenylate cyclase activity.
What is the consequence of reduced adenylate cyclase activity on noradrenaline release?
Reduced adenylate cyclase activity leads to less activation of PKA and consequently, decreased release of noradrenaline from the locus coeruleus.
What are the acute effects of reduced noradrenaline release due to opioid use?
The reduced release of noradrenaline results in the following acute effects:
Sedation
Shallow breathing
How does the body adapt to chronic opioid use in relation to adenylate cyclase (AC)?
The body attempts to overcome AC inhibition by increasing the amount of substrate (ATP) and enzyme (adenylate cyclase) to restore normal levels of noradrenaline release.
What is the result of this adaptation in chronic opioid use?
This adaptation helps restore noradrenaline release to near-normal levels, reducing the symptoms associated with acute opioid use despite the ongoing presence of the opioid inhibiting AC efficiency.
How does chronic opioid use affect the symptoms of opioid use?
The adaptation to chronic opioid use reduces the symptoms (e.g., sedation, shallow breathing) typically experienced during acute opioid administration.
What happens to adenylate cyclase (AC) when an opioid is discontinued?
The inhibitory effect on AC is lost, and AC returns to normal efficiency.
How does the body respond to chronic opioid use when an opioid is discontinued?
Due to chronic opioid use, the body has an increased supply of ATP (substrate) and adenylate cyclase (AC), which results in abnormally high levels of cAMP and PKA production.
What is the consequence of this increase in cAMP and PKA during opioid withdrawal?
The increase in cAMP and PKA leads to excessive noradrenaline release, causing withdrawal symptoms such as:
Jitters
Anxiety
Muscle cramps
Diarrhoea
Tachycardia
What is the DSM-5 definition of substance use disorder?
Substance use disorder is defined as:
“A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by 2 or more of the following occurring within a 12-month period.”
What is the cause of death in opioid overdose?
Death in opioid overdose is primarily due to inhibition of respiratory centers in the brainstem and carotid bodies, leading to respiratory depression.
What are the common signs and symptoms of opioid overdose?
Signs and symptoms of opioid overdose include:
Pinpoint pupils
Unconsciousness
Vomiting
Difficulty breathing
How many deaths are estimated to occur due to opioid overdose annually?
According to the WHO, approximately 125,000 people died of opioid overdose in 2019.
What factors contribute to the increasing number of opioid overdose deaths?
The increase in opioid overdose deaths can be attributed to:
Increased availability of opioids for chronic pain management.
The rise of illicit opioids in the market, such as heroin and fentanyl (which is 10-100 times more potent than morphine).
What is naloxone and what is its mechanism of action?
Naloxone is a competitive antagonist at the μ, δ, and κ opioid receptors, used to reverse opioid overdose.
How is naloxone administered and what is its onset?
Naloxone has a rapid onset after parenteral administration (e.g., injection) and is also available as a nasal spray.
What is the limitation of naloxone in treating opioid overdose?
Limitations of naloxone include:
Inducing abrupt opioid withdrawal in opioid-dependent patients if given at a too high dose.
Its short duration of action may lead to recurrence of respiratory depression with long-acting opioids, though this is not a problem with heroin (short-acting).
What happens if naloxone is given at too high a dose to opioid-dependent patients?
Too high a dose of naloxone can induce an abrupt opioid withdrawal in opioid-dependent patients.
How does the duration of naloxone affect its use in overdose treatment?
Naloxone’s short duration of action can lead to recurrence of respiratory depression in cases involving long-acting opioids.
This issue is not a problem with heroin, as it is short-acting.
What is the comparison between i.v. morphine and naloxone in overdose treatment?
i.v. morphine can be compared with naloxone or placebo in terms of its effectiveness in reversing opioid overdose, where naloxone acts to reverse the effects of opioid toxicity.
What is naloxone?
Naloxone is a competitive antagonist that acts on the μ, δ, and κ opioid receptors.
It is used to reverse opioid overdose by blocking opioid receptor activity.
Naloxone has a rapid onset of action when administered parenterally (e.g., via injection) and is available in a nasal spray form.
What is the first-line treatment for opioid dependence?
Opioid Agonist Substitution Treatment (OST) is the first-line treatment for opioid dependence.
It includes methadone (a slow-acting full agonist) and buprenorphine (a partial agonist).
These treatments prevent cravings and withdrawal symptoms, but they do not cause euphoria, reducing the risk of relapse.
