Likely reaction to 1st doses of opiates
Nausea and emesis
Effects of opiates. “Side-effects”?
Rush in 1st few minutes, euphoria for an hour or 2, sedation and analgesia for 2-4 hours. Side-effects include respiratory depression, loss of consciousness, endocrine/immune disturbances and constipation. Note that these are decent anesthetics because they don’t depress the heart.
Neural pathway that mediates reward and behavior reinforcement
VTA -> NAc by DA release
Neural pathway that mediates the cognitive aspects of reward and learning
VTA -> PFC by DA release
Neural pathway that mediates habit learning and compulsive behaviors
SN -> Caudate/Putamen by DA release
Neural pathway that mediates arousal, alertness and focus of attention
LC -> forebrain/cerebellum by NE release
Neural pathway that mediates mood and visual function?
RN -> forebrain/cerebellum by 5HT
DA pathways in the brain
DA fibers project from the VTA (1) to the NAc (2), PFC (3) and extended amygdala (4).
How do the VTA and NAc work together? What is the implication of this interaction for drug abuse?
VTA has dopaminergic neurons with GABA a and b receptors and GABA neurons with D2 and morphine receptors. There are regulatory enkephalin neurons that bind to the morphine receptors on the GABA neurons, inhibiting the release of GABA and increasing release of DA from the dopaminergic neurons in the VTA onto the NAc. Basically, morphine turns off GABA feedback inhibition on DA neurons.
Why do people on opiates have difficulty focusing attention?
They suppress release of NE from locus ceruleus pathways to the forebrain and spinal cord.
Physiology of opioid withdraw
DA pathways are less active when opiates are not suppressing the GABA inhibitory neurons -> less neural stimulation/reward. Locus ceruleus is more active than when on opiates and NE release increases -> anxiety. Some of the symptoms can be relieved by reducing NE release and potentiating DA release.
Features of dependence to opiates
Cross-tolerance to other centrally acting opiates, physical dependence and withdraw syndrome after discontinuation of drug or administration of naloxone (opiate antagonist). This sometime presents as “goosebumps” after naloxone injection.
Why do morphine and heroin have similar withdraw symptoms?
Heroin is diacetyl morphine, it is converted to 6 mono acetyl morphine and morphine in the liver.
What opiate has a more rapid withdraw period? What has a slower and less intense withdraw period?
Rapid = meperidine. Slow and less intense = methadone.
Psychological symptoms of opioid withdraw
Severe craving w/ repeated attempts to get more drugs for months to years, exaggerated claims to withdraw discomfort/dangers
A child is born with irritability, excessive high pitched crying, tremors, violent sucking on fists, hyperactive reflexes, increased bowel activity, vomiting and fever. What drug was the child’s mom likely addicted to? How do you treat the baby?
This is opiate withdraw of the newborn. The baby can be treated with small amounts of opiate.
Conditioned withdraw syndrome
Induced by return to an environment in which drugs have previously been used…same features of opiate withdraw
How does opiate tolerance develop?
1) u opioid receptors are desensitized (accumulate in phosphorylated state and do not return to membrane as quickly) 2) Receptors are down regulated 3) Opiate-regulated neurons become less sensitive to the drugs as they compensate to chronic abuse (this is why the pathway is hyperactive in withdraw)
How does opiate dependence develop?
Compensatory changes are unmasked when the opiate is removed, withdraw symptoms are opposite the acute effects of the drug and withdraw is precipitated by administration of naloxone or naltrexone.
What parts of the brain are involved in opiate addiction?
1) Reinforcement from the high = VTA -> NAc. 2) Drug seeking behavior = PFC. 3) Withdraw autonomic symptoms and pain = peri-aqueductal gray, locus ceruleus. 4) Anxiety, fear, dysphoria = VTA -> NAc and amygdala.
A 35 year old woman returns for a follow-up appointment. She has had several oxycodone refills over the past six months. She claims to feel pain all over when the oxycodone wears off and that it gives her energy. She claims to have stolen morphine from her mother. What does she have?
Most common cause of deaths from drug use
1) Cocaine 2) Opioids 3) Methadone 4) Synthetic narcotics 5) Heroin
Common cause of death in patients who abuse methadone
Arrhythmias from long QT
Acute physiologic changes with ethanol toxicity
Inhibition of NMDA cation currents prevents glutamate release and decreases neuronal excitability. Potentiation of GABAa receptors activated Cl currents and facilitates hyperpolarization and reduces excitability. It may also increase adenosine levels in the NAc, causing ataxia.
Why is decision making impaired in the drug addicted brain?
There is increased stimulation coming to and from the NAc and VTA, releasing inhibitions.