Lecture 16: Opioids (Part 2) Flashcards
What are the characteristics of opioid receptors in the brain?
opioids bind to receptors expressed in many parts of the brain, including the cerebellum, nucleus accumbens, and hypothalamus
many of these regions are involved in pain perception, emotion, reward, and addiction
What are the characteristics of opioid receptors in the brainstem?
opioid activity in the brainstem can affect breathing by quieting neurons that control respiration
respiratory depression is a dangerous side effect of opioid drugs, and is commonly cited as the cause of death in cases of opioid overdose
What are the characteristics of opioid receptors in the spinal cord?
the transmission of pain signals in the spinal cord, especially in a region called the dorsal horn, is dampened by opioids binding to receptors on these cells
this is one intended target of opioid treatments and a mechanism of the drugs’ unrivaled analgesic properties
What are the characteristics of opioid receptors in the peripheral neurons?
pain-sensing neurons send nociceptive messages from the periphery to the spinal cord
binding opioid receptors in these neurons is another way that opioid drugs curb pain sensations
What are the characteristics of opioid receptors in the intestines?
opioid receptors are expressed in neurons regulating peristalsis
inhibition of these cells upon opioid binding leads to another side effect of opioid medications, constipation
What is the effect of opioids on pain?
Mu and kappa opioid receptors are localized on primary and secondary afferents in the skin and spinal cord
agonist binding to opioid receptors inhibits pain transmission from skin to brain
opioid receptors are also localized in the brainstem (rostroventral medulla) where they increase diffuse noxious inhibitory control
the diffuse noxious inhibitory circuit is comprised of descending excitatory and inhibitory neurons in the medulla that inhibit neurons in the medulla that inhibit or activate pain synapses in the spinal cord
allows our brain to gate the amount of nociceptive information that reaches the brain
mu and delta opioid receptors are located on the ON cells in the medulla
activation of opioid receptors leads to inhibition of medulla ON cells
this produces a net reduction in nociceptive signals reaching the brain
What is the relationship between opioids and reward?
dopamine is involves in motivated behavior
dopamine neurons are located primarily in the ventral tegmental area (VTA)
mu opioid receptors in the VTA are located on inhibitory GABAergic interneurons
so, opioids inhibit inhibition (called disinhibition) leading to dopamine release
What is nociception?
relay of pain signal from periphery to the brain
What is pain?
integration of that pain signal with cognitive and emotional context
(requires the brain, always subjective experience)
How do opioid receptors inhibit pain?
decreasing nociception at the level of the nociceptor, in the spinal cord, and in the brain stem
decreasing the emotional and cognitive aspects of pain (make the pain bother you less)
drugs that target the sensory, as well as cognitive and emotional circuits, will always be better analgesics
What are the characteristics of opioid agonists used for pain?
most opioid agonists used for pain are mu agonists
include drugs such as morphine, fentanyl, codeine, oxycodone
differences efficacy (full/partial agonist) and potency drive differences
What are the characteristics of delta agonists?
delta agonists are being developed for chronic migraine
the development of delta agonists were initially limited because of severe side effects (seizures)
enthusiasm renewed with the discovery you can isolate the analgesic effects from seizures through biased agonism
TRV250 is a delta opioid receptor biased agonist, currently under development by Trevena
What are the characteristics of kappa agonists?
kappa agonists that penetrate the brain have not been developed for pain because of dysphoria/hallucinogenic effects (i.e. Salvia)
peripherally restricted kappa agonists do not cross the blood brain barrier
these drugs bind kappa receptors in the skin and inhibit pain transmission, while avoiding central nervous adverse events
CR845, potent analgesic, anti-inflammatory, and anti-itch properties with little CNS effects, currently under development
What is tolerance?
decreased response to the effects of the drug, necessitating ever larger doses to achieve the same effect
What is opioid tolerance?
opioid tolerance develops to the analgesic, euphorigenic, sedative, and respiratory effects the drugs
an opioid tolerant individual can take enormous doses
What is the mechanism of desensitization in opioid tolerance?
following agonist binding and G-protein signaling, beta-arrestin is recruited to shut-off signaling (desensitization)
receptor + agonist is pulled off the membrane and recycled in an endosome; is either degraded or recycled back to the membrane
repeated opioid use leads to less receptors on the membrane –> reduced agonist effect (tolerance)
What is opioid physical dependence?
physical dependence develops following chronic opioid use and is revealed following abrupt discontinuance of drug as withdrawal
acute opioid withdrawal includes; rhinorrhea (runny nose), lacrimation (tearing eyes), chills, muscle aches, diarrhea, yawning, anxiety
withdrawal is high aversive and some symptoms can persist for months; may motivate the drug user to make robust efforts to avoid withdrawal
this can drive the transition to addiction, but dependence does not equal addiction
What is addiction?
is a brain disease driven by dysfunction in reward, motivation, memory circuitry
What is addiction characterized by?
inability to abstain consistently
impairment of behavioral control
drug craving
diminished recognition of significant problems with ones behaviors and interpersonal relationships
dysfunctional emotional response
What are preventative treatments for opioid use disorder?
usually people will abuse prescription opioids by grinding oral tablets and snorting or injecting (faster onset, bigger high)
most preventative measures are about making this difficult
What are physical barriers used as treatment for opioid use disorder?
prevent chewing/crushing of oral tablets for intravenous/intranasal drug use
What are chemical barriers used as treatment for opioid use disorder?
can be added to resist extraction of the opioid by common solvents like water/alcohol
How are agonist/antagonist combinations used as treatment for opioid use disorder?
an antagonist can be added to an agonist to interfere with euphoria associated with abuse
the antagonist is only released when oral tablet is tampered with (crushed, injected, etc.)
How is agonist replacement therapy used as a treatment for opioid use disorder?
agonist replacement therapy is a comprehensive treatment approach including maintenance on an opioid agonist and cognitive behavioral therapy
agonist therapy blunts the symptoms of opioid withdrawal
replacement agonists have longer half-lives, so avoid the repeated high/crash cycle
What are the advantages of agonist replacement therapy?
reduced drug cravings
better participation in addiction treatment (behavioral therapy) since withdrawal symptoms aren’t a distraction
improved social functioning
reduction in infectious disease/death associated with illicit drug use (particularly injection drug abuse)
What is methadone?
methadone is a long-acting full agonist at the mu opioid receptor
it was the first replacement therapy approved for opioid use disorder
disadvantage is that it is full agonist, so overdose still possible
What is buprenorphine?
buprenorphine is a partial agonist at the mu opioid receptor, an a antagonist at the kappa and delta opioid receptor
safer agonist profile
antagonist activity at kappa may improve mood
marketed as suboxone (buprenorphine + naloxone)
What are supervised consumption sites?
provide a safe place to take drugs to reduce harm or poisonings (overdose)
clients bring own drug
are provided clean needles and medical supervision in case of overdose
any one can access (do not need referral) and can remain anonymous
What is injectable opioid therapy (aka iOAT)?
clients must be referred to program by health care practitioner and must have failed all other addiction treatment
clients are prescribed specific doses of injectable opioids (usually hydromorphone) and are expected to self-specific doses at the iOAT clinic
clients are closely monitored for adverse reactions
What are the advantages to opioid harm reduction?
reduce morbidity and mortality associated with opioid use
provide access to information and resources for additional treatment
What are the disadvantages to opioid harm reduction?
moral argument for providing drugs to people with addiction
NIMBY related to location of SCS/iOAT clinics
What is acute opioid intoxication treatment?
naloxone (Narcan)
non-selective competitive opioid receptor antagonist
available to the public (without a prescription) as intramuscular or nasal spray
works within minutes
lasts about 1/2 hour (multiple doses may be necessary)
