Opiods

endogenous proteins are generated from protein precursors called propeptides (larger peptides that break down into smaller active opiods

• These propeptides are processed by specific enzymes, resulting in the formation of active peptides that can bind to opioid receptors in the brain, thereby modulating pain and emotional responses.

• the class of peptides that activate opiod receptors are called endorphins

• propeptides are manufactured in the soma, cleaved by enzymes, packaged in vesicles, and are further processed as they are transported down the axon to be released at the synapse where they can exert their effects on pain perception and mood regulation.

  *axon terminals contain different types of synaptic vesicles : small clear vesicles and large dense core vesicles

  *opiods can be co-released with small molecule neurotransmitters such as dopamine and serotonin, which can enhance the overall modulatory effects on neuronal communication and contribute to the complex interactions involved in pain relief and emotional responses.

3 Major classes of opiod receptors (THEY ARE NOT LIGAND GATED ION CHANNELS)

• Mu (μ) receptors: Primarily responsible for analgesic (pain relieving) effects and are associated with the euphoric effects of opioids.

• Delta (δ) receptors: Involved in modulating mood and emotional responses, as well as contributing to analgesia.

• Kappa (κ) receptors: Play a role in pain relief and can produce dysphoria; they have a different effect profile compared to mu and delta receptors.

Shared traits:

• all inhibitory

• activated subunits - interact with proteins, enzymes, and ion channels

  Modulate neurotransmitter release, reducing the perception of pain and altering emotional responses.

Pain

what is pain?

• unpleasant sensory or emotional experiences in response to tissue damage

• acute or chronic

• neuropathic: damage to nervous system

• nociceptive: response to stimulus

  • most common

The ascending pain pathway: sends pain signals from body to brain

1. primary sensory neurons (cell bodies in the dorsal root ganglia) convert pain stimuli into action potentials

2. the action potentials cause neurotransmitter release in the spinal cord

3. information is then sent from the sponal cord to the thalamus, and eventually the primary somatosensory cortex for pain perception

The descending pain pathway: modulates or reduces pain by sending signals from brain to body

1. opiod producing neurons in the brainstem send projections to serotonergic and noradrenic neurons

2. the neurons then descend into the spinal cord to inhibit the incoming pain stimulus.

Dopamine:

dopamine vs serotonin synthesis:

• similarities:

  • both neurotransmitters are synthesized from precursor amino acids and follow similar enzymatic changes

• differences:

  • dopamine is synthesized from tyrosine hydroxylase , while serotonin is derived from tryptophan through the action of tryptophan hydroxylase.

Enzyme expression of dopamine producing neurons vs norepinephrine producing neurons:

• dopamine: neurons that use dopamine as their transmitter contain only tyrosine hydroxalase and AADC (aromatic amino acid decarboxylase) so the biochemical pathway stops at dopamine.

• norepinephrine: neurons that need to synthesize norepinephrine possess a third enzyme called DBH

How dopamine gets around: NOT LIGAND GATED ION CHANNELS

1. tyrosine is imported into the nerve terminal where it gets turned into dopamine

2. dopamine is then packaged into vesicles

3. when an action potential reaches the terminal, dopamine is released where it can then bind to pre- and post-synaptic receptors

Dopamine is removed from the synaptic cleft in 2 ways:

1. Degradation: monoamine oxidase (MAO) and catechol O-methyltransfesase (COMT) both degrade dopamine intracellularly, but COMT additionally degrades extracellularly.

   1. the degraded product is homovanillic acid

2. Reuptake

Dopamine Receptors:

dopamine receptors are neuromodulatory, meaning they dont directly open ion channels, but activate second messenger cascades

There are 5 main types of dopamine receptors, categorized as either D1-like or D2-like

• D1-like dopamine receptors include D1 and D5, usually excitatory and increase action potential firing

• D2-like dopamine receptors include D2-D4, usually inhibitory and decrease both action potential firing and neurotransmitter release

Nigrostriatal Pathway: substantia nigra to striatum

• the substantia nigra is located in the midbrain

• crucial for movement regulation, primarily involved in the coordination of voluntary motor control

• significantly impacted by Parkinson’s disease where dopamine-producing neurons degenerate

Mesocortical Pathway: connects the ventral tegmental area to the prefrontal cortex

• plays a key role in cognitive functions like attention, executive functions, and emotional responses

• related to the pathophysiology of schizophrenia, with dysregulation affecting cognitive and emotional control

Mesolimbic Pathway: runs from the ventral tegmental area to the nucleus accumbens (and other parts of limbic system)

• primarily associated with the reward system, reinforcing behaviors that are pleasurable

• significantly involved in the development of addiction and mood disorders

Cocaine & Amphetamines!

• cocaine orignates from the leaf of the coca plant, primarily grown in northwestern South America

  • indigenous inhabitants have chewed coca leaves for 5000 years, and coca leaves were initially used ceremonially by the ruling class

• arrival of conquistadors made coca leaves more widespread

  • the effects of increased endurance and suppressed hunger was useful for laborers and helped increase its popularity

• 1850 - german scientists successfully extract cocaine from the coca plant with a high purity

mild effects: euphoria, dysphoria, insomnia, restlessness, inflated self esteem, anger, talkativeness, mild anorexia, increased libido

severe effects: irritability, anxiety, fear, extreme energy or exhaustion, rambling, incoherent speech, total anorexia, delusions of grandeur, extreme violene, disjointed ideas.

mechanism of action:

• cocaine antagonizes dopamine receptors, blocking dopamine reuptake at the synaptic cleft

  • coke can additionally impact norepinephrine and serotonin reuptake

• Cocaine indirectly activates the mesolimbic pathway

  • more dopamine is released by the nucleus accumbens when coke blocks norepinephrine reuptake and the increased glutamatergic activity stimulates the ventral tagmental area’s dopamingergic neurons

Amphetamines (an umbrella term for a class of stimulants)

• amphetamine is a parent term for synthetic stimulants that act on the dopamine system

  • ephedrine and cathinone are two naturally occurring stimulants that act in a similar manner to amphetamines

    • cathinone is found in an evergeen shrub called Khat, and has been used as a stimulant for centuries in africa and the arabian peninsula

    • ephedrine is found in an herb and has been used in chinese medicine for thousands of years

      • products containing ephedrine were disregulated in the USA after an Orioles’ pitcher died from related complications

Amphetamine’s mechanism of action:

• unlike cocaine, amphetamines can be imported into the presynaptic terminal in dopamine neurons via the dopamine transporter

• it causes the dopamine transporter to work in reverse, releasing large amounts of dopamine into the synapse

• mesolimbic pathway augmentation leads to addiction

Therapeutic vs Side Effects of Amphetamines:

• therapeutic: when dosed and composed correctly, amphetamines treat several disorders including obesity, narcolepsy, and ADHD

• undesirable: changes in eating habits, sleeping habits, libido, mood swings, tachychardia, exhaustion/fatigue

• chronic use: neurotoxicity in the nigrostriatal pathway; dopamine neurons in this pathway get damaged and eventually die from chronic amphetamine exposure.

Anesthesia
- Difference/positives vs. negatives between Local, Regional, General anesthesia

- General anesthesia- unconsciousness, analgesia, amnesia, akinesia
- The discovery of curare and its importance as a paralytic during surgery- effects
on nicotinic acetylcholine receptors
- Discovery of inhaled anesthetics- nitrous oxide in oral surgery and the ether
dome in Mass General!
- Theories of the mechanism of action of inhaled general anesthetics: Meyer-
Overton hypothesis (i.e. membrane/lipid hypothesis) vs. protein hypothesis
(direct interaction with membrane proteins- GABA receptors being a major target)
- Minimum alveolar concentration as it relates to potency, ED50, and age of a
person
- Therapeutic range vs. therapeutic index. How we calculate therapeutic index

Serotonin/Hallucinogens/Antidepressants

Serotonin synthesis in the body- Requirement of tryptophan, how tryptophan
makes its wat into the body/brain//Understanding how blocking certain enzymes
prevents serotonin synthesis.
- Serotonin packaging an release from pre-synaptic terminals, binding to receptors
(pre and post-synaptic) that are neuromodulatory (indirectly increase or decrease
the likelihood of firing an AP)
- Turning off serotonin signals- SERT and MAO- where they are located and what
they do. Know that 5-HIAA is the major metabolic product of serotonin
breakdown.
- Genetic vs. pharmacologic manipulation of the serotonin system.
- Serotonin impact on aggression- Resident Intruder Test- Depleting serotonin vs
enhancing serotonin synthesis
- Serotonin in the gut- Majority of serotonin release- Too much serotonin = IBS-D/
Too little serotonin IBS-C. Use of a partial agonist to more tightly regulate
serotonin signaling in IBS patients.
- Hallucinogens- Some are naturally occurring while others are synthesized/ Most
act as agonists at the 5-HT2 receptor/ potency can vary widely across different
hallucinogens.
- Hallucinogens can promote synesthetic states in users. Define synesthesia.
- Direct vs. indirect activation layer 5 pyramidal neurons in the frontal lobe of the
cortex as the primary driver of hallucinogenic states.
- Affective disorder- Major depressive disorder (MDD) vs. bipolar disorder
- Increase in MDD incidence in the population over the last century
- How the drug reserpine provided the evidence leading to the Monoamine
Hypothesis for MDD.
- Evidence for the Serotonin Hypothesis for MDD
- Mechanisms for increasing available serotonin in the brain (SSRI and MAOI)

- Serotonin synthesis in the body- Requirement of tryptophan, how tryptophan
makes its wat into the body/brain//Understanding how blocking certain enzymes
prevents serotonin synthesis.
- Serotonin packaging an release from pre-synaptcated and what
they do. Know that 5-HIAA is the major metabolic product of serotonin
breakdown.
- Genetic vs. pharmacologic manipulation of the serotonin system.
- Serotonin impact on aggression- Resident Intruder Test- Depleting serotonin vs
e