Neuropharmacology 2 (MODULE 7) Flashcards
What is glutamate?
• Glutamate is the primary excitatory neurotransmitter in the CNS and also has important actions in the PNS, as well.
• It is an amino acid, and it can come from two sources: either
from glucose metabolism in the Kreb’s Cycle or from GABA
metabolism in the glial cells
• It binds several type of receptors… the two most important
for us:
• AMPA and NMDA
What major enzymes are involved in glutamate synthesis?
What do they individually do?
NOTE: glutamate synthesis and cycling between neuron’s and glia. The action of glutamate released into the synaptic cleft is terminated by uptake into neuron’s and surrounding glial cells via specific transporters. Within the nerve terminal, the glutamine released by glial cells and taken up by neuron’s is converted back to glutamate.
*Gluaminase = enzyme that catalyses the conversion of glutamine back to glutamate.
*Glutamine synthase = enzyme that catalyses the conversion of glutamate and ammonia into glutamine. This helps regulate the balance of nitrogen in the body.
*Glutamate dehydrogenase (GDH) = enzyme that plays a key role in the metabolism of glutamate. It catalyzes the reversible oxidative deamination of glutamate to form NH4+. This regulates nitrogen in metabolism.
Where does glutamate synthesis happen?
Presynaptic terminal of the cell
What are EAATs? What do they do?
Glutamate transporters located on the neurons and astrocytes. This regulates the amount of glutamate and prevents excitotoxicity. Responsible for the reuptake of glutamate from the synaptic cleft into nearby cells, such as neurons and glial cells.
Why is glutamate considered to be the most important neurotransmitter in the brain?
It is required for excitation and waking behaviour, learning and memory storage and recall, and management of planning activities. It is also crucial in many reflexes, primarily the Afferent limb of reflex activity. It acts at several types of receptors, notably the AMPA and NMDA sites.
What is the AMPA receptor? What does it do?
The AMPA receptor, when bound by glutamate, acts very quickly to open non-specific channels to both Na+ and K+.
Depolarization (fEPSPs) occur and helps to regulate all types of excitatory activity in the brain and spinal cord.
(*α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor)
What are NMDA receptors and what does they do?
Long term potentiation! Underlies the process of long term memory.
It allows both sodium (Na+) and calcium (Ca2+) to enter the cell and potassium (K+) to leave the cell.
Mg2+ will regulate how quickly Ca2+ can come into the cell.
T or F
There are fewer NMDA receptors than AMPA receptors at excitatory synapses.
T
AMPA sites help keep NMDA sites from allowing too much calcium from entering the cell.
Too much Ca++ coming into the cell causes excitotoxicity: concussion and hypoxia
What is excitotoxixity and how can it occur?
Occurs when too much Ca2+ comes into a cell or there is not enough O2 to run the Ca2+ pumps.
T or F
GABA is inhibitory
T
While calcium transport via NMDA receptors is necessary for long term potentiation (LTP) associated with memory production and neuroplasticity.. too much can lead to?
Too much calcium inside the cell can lead to cellular death via the activation of apoptotic enzymes.
How does antioxidants and glutathione (GSH) help mitigate the effects of ROS driven by Ca2+?
Glutathione is often discussed as an adjunctive treatment for free radicals and ROS created by excess Ca2+
Usually cells have highly active calcium pumps that remove excess calcium from cell if levels are too high if there is not adequate ATP do to respiratory hypoxia or other decreases in O2 there will not be an adequate way to get rid of the excess calcium. Therefore if too much glutamate is released do to increased excitation cause by concussion or TBI intracellular levels of calcium can cause cellular death by apoptosis. What can help mitigate these affects and why?
Antioxidants and glutathione can help reduce the affects of ROS that are driven by calcium.
—> Calcium-induced ROS production can cause significant cellular damage, but antioxidants, particularly glutathione, help to neutralize these harmful species, protecting the cell from oxidative damage. Glutathione and other antioxidants work together to reduce ROS levels, maintain cellular function, and prevent long-term damage to cellular structures.
Longer Explanation:
Calcium ions (Ca²⁺) are involved in numerous cellular processes, including signal transduction, muscle contraction, neurotransmitter release, and enzyme activation. However, when calcium levels become dysregulated (e.g., during oxidative stress or injury), excessive calcium can activate pathways that lead to increased ROS production.
Calcium overload can activate enzymes such as phospholipase A2 and NADPH oxidase, both of which contribute to the generation of ROS, particularly in mitochondria and cell membranes.
Antioxidants are molecules that neutralize ROS, preventing them from causing oxidative damage to cells. Antioxidants include enzymes like superoxide dismutase (SOD), catalase, and glutathione peroxidase, as well as non-enzymatic molecules like vitamin C, vitamin E, and polyphenols.
What are ROS (reactive oxygen species)?
Reactive molecules containing oxygen that can play both beneficial and harmful roles in the body. While they are involved in important processes like cell signalling and immune defuse, excessive ROS can cause oxidative stress, leading to damage to cells and tissues. balancing ROS levels with antioxidants is crucial for maintaining good health.
T or F
Too much glutamate in the cell will overproduce glutathione.
F
Too much glutamate inside the cell will inhibit the cells ability to make glutathione.
What is gamma amino butyric acid (GABA)?
It is known to be the primary inhibitory transmitter in the brain. Synthesis: in neurons, mainly from glutamic acid (glutamate) derived from the Kreb’s cycle
Most GABA is synthesized
from glutamic acid derived from the Kreb’s cycle
The synthetic enzyme is: Glutamic Acid (Glutamate)
Decarboxylase (GAD)
Glutamate will become GABA using what enzyme?
Glutamic acid decarboxylase (GAB)
What are GABA-a receptors? How do they function?
-GABAa receptors are known to be permeable only to chloride.
-It is a complex receptor, however, requiring two ligands to bind to bring about full conductance to chloride.
GABA and an endogenous benzodiazapine must both bind
How does inactivation occur involving GABA?
Inactivation occurs by reuptake (GABA transporters) either into glial cells or back into the presynaptic terminal directly.
In the mitochondria of the glial cells, GABA-Transaminase (GABA- T) transforms GABA back into glutamate, and from there, back to glutamine.
This can be transported back into the “GABA neuron” where glutamine enters the mitochondria to rejoin the Kreb’s cycle.
The brain makes _______ and ________. Both are necessary for what?
GABA and benzodiazepines
Both are necessary for full chloride ion conductance (Cl-) (g)…
Further explained
- when GABA is present, benzodiazepines amplify GABA’s inhibitory effects, making neurons even less likely to fire.
If something inhibits or reduces the function of GABA (e.g., by blocking GABA receptors or reducing GABA production), it can lead to increased neuronal excitability. This hyperexcitability is linked to mood disorders, including anxiety and depression
If there is an issue with benzodiazepine function—for example, in the case of benzodiazepine receptor antagonists or reduced receptor sensitivity—the calming, anxiolytic effects of the drug are diminished. This would result in ineffective treatment for anxiety and potential worsening of symptoms in individuals who rely on benzodiazepines for symptom management.
If Cl- comes into a cell this will cause ________. Why is this significant in the context of GABA?
Hyperpolarization,
GABA is an inhibitor transmitter. GABA + benzodiazepine = the standard amount of Cl- ion necessary for no anxiety.
***diagram on slide 19
T or F
Benzodiazepines (BDZs) are modulators of GABA and NOT agonists
T
What two herbs have been shown to have an action on chloride conductance at the GABA-a receptor site?
Valerian and kava
In the waking times there are higher levels of _______ and during the sleeping time there are higher levels of ______.
Waking = glutamate
Sleeping = GABA
What is epilepsy?
Many forms of seizure disorder— grand mal seizures —> absence seizures
Often the cause is unknown… though TBI, stroke, infections, tumors, and other events affecting the brain can result in seizures.
Depending on the area of the brain affected, different signs and symptoms can be manifested.
In frontal lobe
What are anticonvulsants? How do they work?
- medications used to prevent or control seizures in individuals with epilepsy or other seizure disorders.
All are aimed at decreasing random facilitation of excitatory synapse in the brain…
Damping glutamate: lethargy, decreased learning and memory… we’ve gotten better at this the more we learn about the action of NTXs in the brain. As we have learned more about these drugs and the brain, many of them seem to cause: Interruption of “cortical spreading depression”… spreading DEPOLARIZATION in the brain… many applications.
What is Huntington’s disease?
-autosomal dominant inherited disease
-mutant gene encodes “huntingtin”, a protein containing many copies of glutamine: excitotoxicity at GABA neurons in the caudate nucleus
-choreiform spastic motor activity, and profound dementia
**it destroys the basil nuclei in the brain
Endogenous Opiate Neurotransmitters.
Overview.
Several endogenous opiate NTXs exist: enkephalin and dynorphin are two
examples. Methionine enkephalin is produced from pro-enkephalin (from which
four met-enkephalin molecules are cleaved; it has a five amino acid structure.
There are multiple opiate receptors: delta, mu, and others . Enkephalins are involved in pain modulation, respiratory and GI control… Enkephalin also acts as a growth factor and regulates many immune system
functions
Enkephalins bind opiate receptors that use morphine as the __________ and naloxone as the __________.
Morphine as the agonist
Naloxone as the antagonist
Enkaphalins are involved in pain modulation respiratory and GI control..
What do they do to the respiration?
Decrease or depression of respiration (stop breathing)
What is the role of mu opiate receptors on the neuron?
- Pre and postsynaptic configurations… mu
receptors act to create fIPSPs
postsynaptically by the opening of specific K+
channels.
• Presynaptically, the mu receptor can act to
inhibit Ca++ influx, reducing the amounts of
NTX released.
Within discussion of the pain system what are the three neurotransmitters?
glutamate
substance P
enkephalin
Pain is a perception triggered by tissue damage. The conscious awareness of pain occurs after several synaptic processes occur, allowing action potentials to realise neurotransmitters at the level of the cerebral cortex.
This process is influenced by MANY things, including…?
The current situation and your past experiences of tissue damage
Primary Afferent neurons that respond to tissue damage are called?
Nociceptors (high threshold, unmyelinated axons, C-fibers and thinly myelinated A-delta fibers)
T or F
Nociceptors are distributed to all tissues.
T
For example, somatic activation results in well-localised perception of pain, while visceral activation does not
What is Substance P? Overview of Substance P.
— It is understood to be one of the
primary neurotransmitters involved in primary afferent delivery of
information about tissue damage, and subsequently, involved in neurogenic
inflammation…
— Substance P binds Neurokinin Receptors: there are three type of NK receptors known… SP binds NK-1 receptors. These are complex, but the general action is second messenger managed excitation
Substance P results in..
A. EPSP
B. fEPSP
C. sEPSP
C
CGRP or Calcitonin Gene-Related Peptide is what?
One of the strongest vasodilators in the body; participating in
inflammation, headache, and other conditions subject to vasodilation
It is released from primary afferent axons in the periphery with SP on
activation by TRPV-1 and TRPA-1 (transient receptor potential
vanilloid or ankyrin) ion channels where it is involved in neurogenic
inflammation
It is also co-released with SP centrally in the dorsal horn where it
modulates the ascending pathways.
T or F
Substance P and CGPR are released individually
F
They are almost always released together
CGRP functions are ?
Wide and varied!
• Vasodilation
• Migraine
• Heart function
• Inflammation and Immunity
• Transmission of tissue damage information where it has a complex relationship with SP
Overview of neurogenic inflammation:
• Neurogenic Inflammation
is mediated by
neuropeptides released
from C-fibers
• A complex series of
molecular events
triggered by peripheral
release of neuroactive
substances initiate
inflammation.
GCRP and SP are pro-inflammatory mediators. Travel to mast cell and get mast cell to release contents that contribute to inflammation
Substance P and CGRP are Released Peripherally by Activation of _______ ___________.
TRPV receptors.
• Transient Receptor Potential Vanilloid-1
and other receptors react to various
tissue damaging stimuli to cause the
release of SP peripherally.
• CGRP and other peptides are also
released in this way. • Clinically, these receptors are
important to us, as they are activated
by heat, cold, and capsaicin: all
employed by us to relieve pain.
Explain why heat, cold, or capsaicin are used on the skin to release SP and CGRP.
This caused the transmitters to be
depleted– thus less available to be used in the inflammatory process—
This is at least one reason why
these simple treatments are anti
inflammatory.
Tissue damage results in two major neurological actions: ____________ ________ of ____________ ___________— Sp and CGRP and other substances are released to mediate inflammation.
Peripheral induction of neurogenic inflammation
Centrally, the action potential causes release of all
three: SP, Glutamate, and CGRP… and others.
Binding of these transmitters causes excitation of
the central pathways.
Fast pain vs Slow pain
“Fast pain”: acute, well-localized, immediate experience of “pain”, most often a familiar, mechanical incident… contusion, laceration, tearing… primary afferent: A-delta fiber high threshold mechanoreceptive nociceptors.
“Slow pain: not as well localized, larger receptive fields… Lasts longer, has a somewhat delayed onset… “allodynia”– previously non- painful stimuli result in pain… Primary afferent: C-fber polymodal nociceptors.
What is counter- irritation?
Mediated by low threshold primary
afferent input by circuitry called the “gate theory” of pain modulation.
Not a painful stimulus
Ex: after you crush your thumb w a hammer = you stick your thumb in your mouth
What is the gate theory?
Slide 33 on review notes
SSRI are potentiators of __________ or (5-HT)
Serotonin
SSRI (selective serotonin reuptake inhibitors)
Activation of autoreceptors does what?
Activation of deters receptors does what?
AR = decreases release of 5_HT in the DHS
HR = decreases release of nociceptive nxt to reduce pain signal
What is central sensitisation?
Basically, long activation of central systems causes increased sensitivity to excitatory transmitter release.
Thus, non-painful peripheral stimuli, or descending stimuli… can cause activation of the central pain perception pathway.
T or F
Afferent axons can be activated in the dorsal root ganglion area, and at other points as well.
T
Once this
occurs, action potential will be generated in
both the orthodromic and antidromic
directions!
Which of these is known to be the most common excitatory amino acid in the brain and the spinal cord?
GABA
Acetylcholine
Glutamate
Enkephalin
Glutamate
In the synthesis pathway of glutamate from glutamine, what is the enzyme necessary?
glutaminase
glutamic acid decarboxylase
GABA decarboxylase
glutamine synthetase
Glutaminase
Glutamate can be synthesized from at least two different substances. Choose which two of these are potential sources.
A. tyrosine
B. glutamine
C. alpha-ketoglutarate
D. glycine
B and C
Glutamate uses two different receptors coupled to non-specific ion channels. Which of these receptors increases conductance to Ca++ as well as Na+ and K+?
Nicotinic cholinergic
AMPA
NMDA
GABA-a
NMDA
What is the inactivation mechanism for Glutamate?
A. Excitatory amino acid transporters carry glutamate quickly into astrocytes
B. Glutamate is taken into the postsynaptic cell and used for gluconeogenesis
C. There is no process as these are amino acids
D. Most is broken down into component molecules by postsynaptic enzymes
A
Which of these is a function of glutamate in the central nervous system?
A. long term potentiation resulting in learning and memory
B. all of the above
C. managing excitatory motor control systems in the CNS
B
What is GABA’s primary role in the nervous system?
A. causing fIPSPs, managing rest, and well-being
B. potentiating fEPSPs via NMDA and AMPA receptors
C. causing excitation in pain systems
D. causing sIPSPs and managing autonomic responses in the CNS
A
Which of these disease processes are managed by / influenced by GABA?
A. epilepsy
B. generalized anxiety disorder
C. all of the above
D. sleep
C
How is GABA synthesized?
A. using GABA-transaminase
B. from alpha-ketoglutarate directly using glutamine synthase
C. from tyrosine and tryptophan
D. from glutamate using glutamic acid decarboxylase (GAD)
D
What is the function of benzodiazepines in relationship to GABA?
A. they are potentiators of GABA
B. they are inhibitors of GABA
C. they are agonists of GABA
A
Which one of these are endogenous opiate neurotransmitters?
A. naloxone
B. morphine
C. enkephalin
C
Which one of these is a mechanism of action of enkephalin?
A. binding GABA-a receptors causing fIPSPs via increased Cl- conductance
B. binding mu-receptors and causing fIPSPs via increased K+ conductance
C. binding NMDA receptors and causing fEPSPs via non-specific channels
D. binding AMPA receptors and causing fEPSPs via non-specific channels
B
Which of these conditions may be influenced by the concept of cortical spreading depression?
A. migraine headache
B. all of these
C. chronic pain
D. epilepsy
B
Which of these is the antagonist at mu and delta opiate sites?
A. morphine
B. naloxone
C. aspirin
D. enkephalin
B
Which one of these is an eleven amino acid peptide known to be involved in both the peripheral and central processing of the pain experience?
A. Enkephalin
B. Glutamate
C. Substance P
D. CGRP
C
Which of these is the receptor binding Substance P?
A. TRPV-1
B. AMPA
C. NK-1
D. Mu receptor
C
Which two of these axonal classes can be associated with the transmission of nociception? Choose TWO.
A. A-beta fibers
B. A-delta fibers
C. C-fibers
D. Ia fibers
B and C
Which of these is a 37 amino acid peptide causing the strong vasodilation in neurogenic inflammation?
A. CGRP
B. Enkephalin
C. Endorphin
D. Substance P
A
CGRP is co-released with which of these in the periphery to mediate the process of neurogenic inflammation?
A. Substance P
B. GABA
C. Acetylcholine
D. Enkephalin
A
These receptors are found on the surfaces of primary afferent terminals in the periphery. They are activated by heat and cold.
A. TRPV1 and TRPA
B. AMPA
C. NK-1
D. Muscarinic cholinergic
A
In the dorsal horn, which of these mediates the process leading to the perception of fast pain?
A. CGRP
B. Substance P
C. Enkephalin
D. Glutamate
D
When you put your finger in your mouth after hitting it with a hammer, by what mechanism is the perception of pain reduced?
A. counter-irritation
B. cortical spreading depression
C. Direct inhibition of A-delta fibers
D. descending inhibitory control
A
In the process called counter-irritation, what type of axon causes the increase in the activity of the inhibitory interneurons?
A. high threshold, A-delta
B. low threshold, Ia
C. low threshold, A-beta
C
What type of peripheral stimulus is required for the process called descending noxious inhibitory control?
A. low threshold, chemoreceptive
B. low threshold, mechanoreceptive
C. low threshold, thermoreceptive
D. high threshold, nociceptive
D
What type of physical therapy / massage / body work would stimulate pain relief by counter-irritation? Choose all that apply.
A. strong tissue manipulation meant to cause inflammation
B. Trigger point therapy, myofascial release
C. gentle palpation of the surrounding tissues
D. Swedish massage, healing touch
C and D
What type of physical therapy / massage/ body work would stimulate pain relief by descending noxious inhibitory control mechanisms?
A. use of non-noxious heat or cold
B. Swedish massage, healing touch
C. gentle palpation of the tissues surrounding an area of injury
D. Trigger point therapy, myofascial release
D
What mechanism likely plays a role in chronic pain at the level of the spinal cord dorsal horn?
A. too much serotonin being released
B. central sensitization
C. too much enkephalin being released
B
The glutamate - glutamine cycle takes place where?
Astrocyte (glial cell)
Astrocyte (glial cell)
