Module 7 - Neuropharm Flashcards
1
Q
What is the primary excitatory neurotransmitter in the CNS and also has important actions in the PNS?
A
Glutamate
2
Q
Where does glutamate come from?
A
Either from glucose metabolism in the Kreb’s Cycle or from GABA metabolism in the glial cells
3
Q
What does glutamate bind to what type of receptors?
A
AMPA and NMDA
4
Q
How is glutamine synthesized?
A
from GABA metabolism* in the glial cells of the CNS (astrocytes, mainly).
5
Q
What is glutamate metabolism related to?
A
formation of glutamine or α-ketoglutarate (which are not neurotransmitters) or GABA (an inhibitory neurotransmitter)
6
Q
What is the synthetic enzyme of glutamine?
A
Glutaminase to make glutamate
7
Q
What is the enzyme that turns glutamate back into glutamine?
A
Glutamine synthetase
8
Q
True or False
Glutamate levels in the brain are tightly controlled
A
T
9
Q
After glutamate activates its receptors, it is rapidly removed from the synaptic cleft between neurons by _________ _______________ __________located on neurons and astrocytes.
A
glutamate transporters (EAATs)
10
Q
In astrocytes, what is glutamate covered to glutamine by?
A
Glutamine synthase
11
Q
What is considered the most important neurotransmitter in the brain?
A
Glutamate
12
Q
What is glutamate required for excitation?
A
waking behavior, learning and memory storge and recall, and management of planning activities
many reflexes, primarily, the afferent limb of reflex activity.
13
Q
What is the first receptor of glutamate to be characterized?
A
AMPA site
14
Q
What happened when the glutamate is bound to AMPA receptor?
A
acts very quickly to open non-specific channels to both Na+ and K+.
15
Q
Where are the NMDA receptors in the brain located? What are they necessary for?
A
NMDA receptors in the brain, particularly the hippocampus, are necessary for the process called “long term potentiation”, which underlies the production of long-term memory
16
Q
What receptors are requiring the other to complete complex actions of excitation?
A
AMPA and NMDA
17
Q
______ sites help keep _____ sites from allowing too much calcium from entering the cell.
A
AMPA; NMDA
18
Q
What can happen if too much Ca2+ comes into the cell?
A
Too much Ca2+ coming into the cell causes excitotoxicity: concussion and hypoxia
19
Q
What happens if there is not adequate ATP due to respiratory hypoxia or other decrease in O2?
A
there won’t be an adequate way to get rid of the excess Ca2+
20
Q
What can happen if there is too much glutamate due to increased excitation?
A
(caused by concussion or TBI), intracellular levels of Ca++ can cause cell death by apoptosis.
21
Q
What can help mitigate the effects of ROS driven by Ca2+
A
Antioxidants and glutathione (GSH)
22
Q
What is the major inhibitory neurotransmitter in the central nervous system (CNS)?
A
GABA
23
Q
How is GABA synthesized?
A
in neurons, mainly from glutamic acid (glutamate) derived from the Kreb’s cycle…. See the next slide.
24
Q
What enzymes causes inactivation of GABA?
A
Reuptake and GABA-T (GABA-transaminase)
25
What is the synthetic enzyme of GABA?
Glutamic Acid (Glutamate)
Decarboxylase (GAD)
26
What is the implicated receptor site involved in anxiety disorder? What are they permeable to?
GABAa receptor
Only to chloride
27
What types of disorders do the GABA sites have been implicated?
Generalized anxiety disorders, depression, sleep, and seizure disorders.
28
What are the common BDZs?
diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan)
29
What happens when the conductance of chloride to benzodiazepine site is bound?
It will DOUBLED
30
What is the BDZ to the GABA activity receptor?
Modulator
31
What herbs have been shown to have an action on chloride conductance at the GABA-a receptor site?
Valerian and Kava
32
What does glutaminase covert glutamine to?
Glutamate
33
What is epilepsy?
is a chronic brain disorder characterized by recurrent seizures, which are brief episodes of abnormal brain activity that can cause involuntary movements, loss of consciousness, or other symptoms.
34
What happens is someone has a seizure in the frontal lobe? Occipital lobe? Parietal lobe? Temporal lobe?
Frontal lobe: loss of motor control, a change in behavior, or change in language expression
Occipital lobe: see multi-colored shapes, such as circles and flashes, or experience temporary loss of vision
Parietal lobe: a person to feel numbness or tingling, or feel burning or cold sensation
Temporal lobe: experience an odd smell, odd taste, buzzing or ringing in the ears, fear or panic, deja vu, or abdominal discomfort
35
What happens if you dampen 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:
36
What are the anti-seizure drugs?
Sodium channel: Phenytonin, Carbamazepine, Oxcarbazepine, Lamotrigine
Potassium channel: Retigabine
Calcium channel: Pregabalin, Gabapentin, Etosuximide
GABA receptor: Barbiturates, benzodiazepines, tiagabine, vigabatrin
Glutamate receptor: Valproic acid, Topiramate, Perampanel
37
What is Cortical Spreading Depression (CSD)?
When one small area of the brain is “hyper-irritable”, likely from hypoxia… and too much glutamate is released, and there is a breakdown of the Na/K pumps and the Ca++ pumps, the depolarizing currents formed can initiate rolling depolarization in neighboring cells… resulting in more release of glutamate into the soup of chemicals in the brain…
38
How do things like seizure and Migraine and other types of pain syndromes get started in the brain?
From an ectopic focus of excitation… and too much glutamate… and the connectedness of the neurons… the depolarization spreads through the various pathways in the brain…
39
What happens if too much glutamate release at the caudate?
usually uses GABA to support control and inhibition of random movement: excitotoxicity and destruction of GABA neurons… MUCH MORE complex than this!
40
What causes 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
41
Enkephalins bind opiate receptors that use __________ as the agonist and ______________ as the antagonist.
Morphine; naloxone
42
What are the mutiple opiate receptors?
delta, mu, and others.
43
What is Enkephalins involved in
pain modulation, respiratory and GI control
also acts as a growth factor and regulates many immune system functions
44
What do mu receptors act as postsynaptically? Presynaptically?
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.
45
Where are these receptors predominate?
the dorsal horn, the respiratory control centers, the enteric system of the gut, and parts of the limbic system
46
What is a well-known function of opiate binding?
Narcotic analgesia system
47
What can morphine do to the respiratory system?
Morphine (like enkephalin) can cause respiratory depression (stop breathing).
48
What happens in the body when opioids binds to the opioid receptors?
can help relieve pain, but also cause sedation and hypoventilation.
49
What happens in the body when naloxone binds to the opioid receptors?
"pushes" opioids off the receptors, thereby reversing their effects, and blocks further binding.
50
Where do A-delta and C-fiber afferent axons carry the information to?
The dorsal horn via peripheral nerves, spinal nerves, and eventually, the dorsal root. The cell bodies of these primary afferents are in the dorsal root ganglia.
51
Where do second-order afferent axons cross the midline in the spinal cord?
In the spinal cord before ascending as the spinothalamic tract
52
What tract carries pain information to the brain?
The spinothalamic tract.
53
Where does the spinothalamic tract terminate?
In the thalamus.
54
What type of neurons are excited in the thalamus?
Third-order neurons.
55
Which part of the brain receives pain information for conscious perception?
The postcentral gyrus of the parietal lobe.
56
What is the role of the dorsal horn in pain processing?
It modifies incoming pain information before it is sent to the brain.
57
At what levels can pain processing be modified?
The dorsal horn, spinothalamic tract, thalamus, and cortex.
58
What factors influence pain perception?
The current situation and past experiences with tissue damage.
59
Why is pain considered an unreliable symptom between patients?
Because it is influenced by multiple physiological and psychological factors.
60
What is still at a basic level in our understanding of pain?
The complex circuits and modifications involved in pain perception.
61
What are primary afferent neurons that respond to tissue damage called?
Nociceptors
62
What types of nociceptor fibers exist, and how are they classified?
C-fibers (unmyelinated, slow conduction, high threshold) and A-delta fibers (thinly myelinated, faster conduction).
63
What is the difference in conduction speed between C-fibers and A-delta fibers?
A-delta fibers conduct faster due to thin myelination, while C-fibers are slower due to lack of myelination.
64
What are two well-studied neuropeptides involved in pain processing and neurogenic inflammation?
Substance P and CGRP (Calcitonin Gene-Related Peptide).
65
What is the function of substance P in pain perception?
It enhances pain signaling and contributes to neurogenic inflammation.
66
How does CGRP contribute to the pain process?
It plays a role in vasodilation and neurogenic inflammation
67
Are nociceptors found in all tissues?
Yes, they are distributed throughout all tissues
68
Why is somatic pain more localized than visceral pain?
Somatic nociceptors have direct and well-defined central connections, whereas visceral nociceptors do not.
69
Does all nociceptive activation reach conscious awareness?
No, some nociceptive signals do not reach conscious perception.
70
What is the role of substance P in pain processing?
It enhances pain transmission and promotes neurogenic inflammation.
71
How does substance P contribute to neurogenic inflammation?
It induces vasodilation, increases capillary permeability, and recruits immune cells.
72
How many types of NK (neurokinin) receptors are known?
Three types.
73
Which receptor does substance P (SP) primarily bind to?
NK-1 receptor
74
What is the general action of NK-1 receptor activation?
Second messenger-managed excitation.
75
What is the function of NK-1 receptor activation in pain processing?
Enhances pain signaling and contributes to neurogenic inflammation.
76
How is CGRP produced?
It is created from alternate RNA processing of the calcitonin gene.
77
What is one of the strongest vasodilators in the body?
CGRP
78
What conditions are associated with CGRP due to its vasodilatory effects?
Inflammation, headache, and other vasodilation-related conditions.
79
With which neuropeptide is CGRP co-released from primary afferent axons in the periphery?
Substance P (SP)
80
What ion channels activate the release of CGRP and SP in the periphery?
TRPV-1 (transient receptor potential vanilloid) and TRPA-1 (transient receptor potential ankyrin).
81
Where is CGRP co-released with SP centrally, and what is its function there?
In the dorsal horn, where it modulates ascending pain pathways.
82
What are the primary functions of CGRP?
Vasodilation, migraine involvement, heart function regulation, inflammation and immunity modulation, and tissue damage signal transmission.
83
How does CGRP contribute to migraines?
By causing vasodilation and modulating pain pathways in the brain.
84
What effect does CGRP have on the heart?
It influences heart function, likely through vasodilation and effects on cardiac cells.
85
How does CGRP impact inflammation and immunity?
It affects monocytes, macrophages, dendritic cells, endothelial cells, and various epidermal cells, contributing to immune regulation and inflammation.
86
What role does CGRP play in the transmission of tissue damage signals?
It has a complex relationship with substance P (SP) in pain signaling and neurogenic inflammation.
87
Which cells are affected by CGRP in the immune system?
Monocytes, macrophages, Langerhans cells (LCs), dendritic cells (DCs), and neutrophils.
88
Which epidermal cells are influenced by CGRP?
Keratinocytes, melanocytes, and fibroblasts.
89
What is EMT, and how might CGRP be involved in it?
EMT stands for epithelial-mesenchymal transition, a process involved in wound healing, fibrosis, and cancer progression. CGRP may influence this through its effects on fibroblasts and immune cells.
90
What is FMT, and how might CGRP play a role in it?
FMT stands for fibroblast-to-myofibroblast transdifferentiation, a process in tissue repair and fibrosis that CGRP may modulate.
91
What triggers an orthodromic action potential in nociceptive afferents?
Injury and/or injury products.
92
What happens when an action potential invades local collaterals and terminal endings unaffected by the original insult?
It can trigger neurotransmitter release, increasing capillary permeability and promoting inflammation.
93
Which channels are activated when action potentials reach the nerve terminals?
Voltage-gated calcium channels (Ca++ channels).
94
What is the role of calcium entry in neurotransmitter release?
It activates SNARE proteins, leading to vesicle fusion and neurotransmitter release.
95
What are some outcomes of excitatory neurotransmitter release from nociceptive afferents?
Excitation of nearby afferent terminals, increased capillary permeability, and mast cell degranulation.
96
How can inhibitory neurotransmitters affect pain signaling?
They can presynaptically reduce neurotransmitter release from nearby terminals, decreasing pain transmission.
97
What are some key neurotransmitters involved in neurogenic inflammation?
Substance P (SP), CGRP, glutamate (Glu), serotonin (5-HT), galanin (Gal), and somatostatin (SST).
98
Which receptor does substance P bind to in neurogenic inflammation?
Neurokinin-1 receptor (NK1r)
99
What role do SNARE proteins play in neurotransmitter release?
They mediate vesicle fusion, allowing neurotransmitters to be released into the synapse.
100
What is neurogenic inflammation?
A complex inflammatory response mediated by neuropeptides released from C-fibers in response to injury.
101
How are the nervous system and immune system interconnected?
They interact through neuromodulators, neurotransmitters, and cytokines that influence inflammation and pain signaling.
102
What are two classical neuropeptides involved in initiating inflammation?
Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP).
103
What type of axon is a C-fiber?
An unmyelinated sensory afferent axon.
104
What is the usual (orthodromic) direction of action potential conduction in C-fibers?
Toward the spinal cord, initiating pain perception pathways.
105
What is antidromic conduction, and what does it cause?
Reverse action potential conduction in C-fibers, leading to the peripheral release of pro- and anti-inflammatory neuropeptides.
106
How do SP and CGRP contribute to inflammation?
They bind to endothelial cells and mast cell receptors, increasing vascular permeability (causing swelling/edema) and vasodilation (causing redness and heat).
107
What substances are released from mast cells during neurogenic inflammation?
Histamine (vasoactive, increases mucus secretion) and serotonin (5-HT, vasoconstrictive, initiates hemostasis).
108
What neurotransmitter is co-released with CGRP and SP?
Glutamate.
109
How does glutamate amplify the inflammatory response?
It excites adjacent C-fibers, leading to increased peptide and glutamate release, spreading the inflammatory response (wheal and flare).
110
What receptor reacts to tissue-damaging stimuli and triggers the release of Substance P (SP) peripherally?
Transient Receptor Potential Vanilloid-1 (TRPV-1)
111
Besides SP, what other neuropeptide is released upon TRPV-1 activation?
Calcitonin Gene-Related Peptide (CGRP).
112
What types of stimuli activate TRPV-1 receptors?
Heat, cold, and capsaicin.
113
Why are TRPV-1 receptors clinically significant?
Because their activation can be used therapeutically for pain relief.
114
How does capsaicin relieve pain despite activating TRPV-1?
It initially triggers pain and neuropeptide release but later desensitizes the receptors, reducing pain signaling.
115
What happens when heat, cold, or capsaicin is applied to the skin?
It causes the release of Substance P (SP) and CGRP.
116
How does the release of SP and CGRP contribute to pain relief?
The release depletes these neurotransmitters, making them less available for the inflammatory process, reducing inflammation and pain.
117
Why are heat, cold, and capsaicin considered anti-inflammatory treatments?
They deplete pro-inflammatory neuropeptides (SP and CGRP), reducing inflammation.
118
What are the two main types of thermoreceptors on primary afferent terminals?
Cold receptors and warm receptors.
119
At what temperature range do cold receptors respond?
Between 5°C and 35°C, and also above 45°C (“paradoxical cold”).
120
At what temperature range do warm receptors respond?
Between 30°C and 45°C.
121
How do thermoreceptors respond to temperature changes?
They are rapidly adapting, meaning they respond best when temperature is changing.
122
How do certain chemicals cause the sensation of warming or cooling on the skin?
They activate thermoreceptors that mimic temperature changes, such as menthol activating cold receptors and capsaicin activating heat receptors.
123
What does menthol activate in the body to create a cooling sensation?
Menthol activates cold receptors, specifically the TRPM8 receptors, creating a cooling sensation.
124
Which receptor does capsaicin activate to create a sensation of heat?
Capsaicin activates the TRPV1 receptors, which are responsible for detecting heat.
125
What is the role of TRPM8 receptors?
TRPM8 receptors are responsible for detecting cool temperatures and are activated by substances like menthol.
126
What sensation does capsaicin produce in the body?
Capsaicin produces a burning or heat sensation, even though no physical heat is present.
127
How do menthol and capsaicin mimic temperature changes?
Menthol mimics a cooling sensation by activating cold receptors, and capsaicin mimics a burning heat sensation by activating heat receptors.
128
What neurotransmitters are involved in the regulation of tissue damage and pain processing in the dorsal horn?
Substance P (SP), Glutamate, and Calcitonin Gene-Related Peptide (CGRP) are involved in the regulation of tissue damage and pain processing in the dorsal horn.
129
What type of primary afferent fiber is responsible for “fast pain”?
“Fast pain” is carried by A-delta fibers, which are high-threshold mechanoreceptive nociceptors.
130
What is “slow pain,” and how is it different from “fast pain”?
“Slow pain” is not as well localized, has larger receptive fields, lasts longer, and has a delayed onset. It often involves allodynia, where previously non-painful stimuli now cause pain. It is carried by C-fiber polymodal nociceptors.
131
What is the difference between “acute first pain” and “delayed second pain”?
“Acute first pain” is immediate, well-localized, and often the result of a mechanical injury, while “delayed second pain” is achy, hyper-sensitive, and occurs later, often involving allodynia.
132
What is “allodynia”?
Allodynia is a condition where previously non-painful stimuli cause pain, often occurring after an injury and associated with slow pain mechanisms.
133
How is “slow pain” thought to be mediated in the dorsal horn?
Slow pain is likely mediated by slow excitatory postsynaptic potentials (EPSPs) generated by Substance P at NK-1 receptors in the dorsal horn.
134
What is the role of descending control mechanisms in the pain experience?
Descending control mechanisms can alter the pain experience, such as through counter-irritation, which can modify the perception of pain after an injury.
135
What receptors and ion channels are involved in the complex regulation of tissue damage and pain?
The complex regulation involves multiple receptors (like NK-1 receptors) and ion channels, as well as neurotransmitters like Substance P, Glutamate, and CGRP.
136
What is the simple pathway for pain transmission?
The simple pathway for pain transmission involves the primary afferent, which sends signals to the second-order afferent in the dorsal horn, and then those signals are relayed to higher centers.
137
How does pain processing stop after an injury?
Pain processing can stop through mechanisms like counter-irritation, and likely, opiates play a role in modulating this process
138
What is counter-irritation, and how does it help with pain?
Counter-irritation is when a non-painful stimulus is applied to an area to decrease pain perception, such as rubbing or applying pressure to reduce pain intensity.
139
What is the first thing you do after hitting your finger with a hammer, and why?
The first thing you do is stop and focus on the pain, as the pain response stops you from continuing the activity to protect the injury.
140
Why is it necessary for pain to stop enough to allow you to take action after an injury?
It is necessary for pain to stop enough so that you can take action, such as addressing the injury, performing first aid, or avoiding further damage.
141
What likely plays a role in stopping pain in the dorsal horn?
Opiates likely play a role in stopping pain by modulating pain transmission at the dorsal horn.
142
What happens when tissue damage first occurs in terms of C-fiber input?
The C-fiber input stimulates the ascending pathway but inhibits the interneurons that would normally inhibit the ascending pathway, likely using inhibitory transmitters like enkephalin or GABA.
143
What role do A-beta fibers play in pain modulation?
A-beta fibers are low threshold neurons that, when stimulated (e.g., by rubbing or touching the injured part), excite inhibitory interneurons, “closing the gate” and reducing the conscious experience of pain.
144
How does rubbing or touching an injured area help reduce pain according to gate control theory?
Rubbing or touching an injured area activates A-beta fibers, which excite inhibitory interneurons in the dorsal horn, effectively “closing the gate” to the ascending pain pathway and reducing the perception of pain.
145
What neurotransmitters are involved in inhibiting pain in the dorsal horn?
Enkephalin and possibly GABA are involved in inhibiting pain by modulating the activity of interneurons in the dorsal horn.
146
How did the understanding of pain processing evolve from the gate control theory?
The gate control theory was proposed before substances like enkephalin, Substance P (SP), and glutamate were understood to play roles in pain modulation, though current research has provided more insight, still leaving some gaps.
147
Where do enkephalins act after being released in the pain pathway?
Enkephalins likely act within the dorsal horn, specifically at the “gate neuron,” where they inhibit activity in second-order neurons to reduce pain transmission.
148
What is the role of opiates like morphine, fentanyl, and tramadol in pain modulation?
Opiates act to hyperpolarize the membrane of second-order neurons in the spinothalamic tract or decrease the release of excitatory neurotransmitters like glutamate, Substance P (SP), and CGRP, thereby reducing pain transmission.
149
How do glutamate and Substance P contribute to pain transmission in the dorsal horn?
Glutamate activates AMPA and NMDA receptors on second-order neurons, leading to increased pain signaling, while Substance P binds to NK-1 receptors, which activate protein kinase C (PKC) and indirectly increase NMDA receptor activity, further promoting pain transmission.
150
What effect does CGRP have in the dorsal horn during pain transmission?
CGRP binds to specific receptors on second-order neurons, altering receptor expression and function, which can contribute to central sensitization and chronic pain.
151
How do opioids reduce pain in the dorsal horn?
Opioids bind to μ-opioid receptors (MOR) on both pre- and post-synaptic neurons. They close voltage-gated calcium channels on primary afferent fibers, reducing neurotransmitter release, and open potassium channels on second-order neurons, causing hyperpolarization and reducing their sensitivity to excitatory inputs.
152
What is central sensitization, and how do neurotransmitters like glutamate, SP, and CGRP contribute to it?
Central sensitization is a phenomenon where the nervous system becomes more sensitive to pain, often contributing to chronic pain. Glutamate, SP, and CGRP contribute by increasing calcium influx and neurotransmitter release, enhancing pain signaling.
153
What specific effect do opioids have on calcium and potassium channels in pain transmission?
Opioids close voltage-gated calcium channels on primary afferent fibers, reducing calcium influx and neurotransmitter release, while opening potassium channels on second-order neurons, leading to hyperpolarization and reduced sensitivity to pain.
154
How do tissue-damaging techniques like trigger point therapy and myofascial release work in terms of pain modulation?
Tissue-damaging techniques like trigger point therapy and myofascial release are intentionally painful to stimulate descending inhibitory systems, which reduce pain by inhibiting both primary and secondary afferent axons.
155
What neurotransmitters are involved in the descending pain control system?
The descending pain control system uses serotonin and norepinephrine (NE) as its neurotransmitters, which are typically associated with mood regulation and depression.
156
How might selective serotonin reuptake inhibitors (SSRIs) affect pain perception?
SSRIs, which potentiate the action of serotonin, also have an analgesic effect, likely by acting on the descending pain control system to inhibit pain transmission.
157
What is the relationship between serotonin, norepinephrine, and depression in terms of pain modulation?
A lack of serotonin and norepinephrine can contribute to depression, and their role in the descending pain control system suggests that insufficient levels may affect the system’s ability to inhibit pain.
158
How might depression influence the effectiveness of pain treatments like trigger point therapy?
Individuals with depression may have insufficient serotonin and norepinephrine levels, which could reduce the effectiveness of treatments like trigger point therapy, as these treatments rely on the descending pain control system.
159
What areas of the brain are involved in descending pain control?
The raphe nuclei (medulla), pontine reticular areas (pons), and periaqueductal gray (midbrain) are involved in descending pain control, releasing serotonin and norepinephrine to modulate pain.
160
Front:
How do descending systems inhibit pain through neurotransmitters like serotonin and NE?
Descending systems release serotonin and norepinephrine, which excite the release of enkephalin, an inhibitory neurotransmitter that helps reduce pain perception by acting on primary and secondary afferent axons.
161
How can counter-irritation and descending mechanisms influence pain perception?
Both counter-irritation and descending mechanisms can “close the gate” to pain by stimulating inhibitory pathways, with descending systems releasing serotonin and NE to activate the release of enkephalin and reduce pain.
162
What role does serotonin play in the descending pain control system?
Serotonin is released from descending systems and binds to 5HT-1A receptors on primary afferent neurons, hyperpolarizing the membrane and closing calcium channels. This reduces the release of excitatory neurotransmitters like glutamate and Substance P, thereby inhibiting the ascending pain pathway.
163
How do SSRIs (selective serotonin reuptake inhibitors) affect serotonin in the descending pain control system?
SSRIs inhibit the reuptake of serotonin, allowing serotonin to act for a longer period of time, which enhances its antinociceptive effects by potentiating the inhibition of pain signals in the ascending pathway.
164
What is the effect of serotonin binding to 5HT-1A receptors on primary afferent neurons?
Binding serotonin to 5HT-1A receptors on primary afferent neurons hyperpolarizes the membrane and closes calcium channels, reducing the release of neurotransmitters like glutamate and Substance P, which leads to less activation of the ascending pain pathway.
165
How does serotonin contribute to pain modulation at higher centers in the brain?
At higher centers in the brain, serotonin plays complex roles that contribute to both antinociceptive and antidepressant effects, depending on the receptor type activated (autoreceptors or heteroreceptors).
166
What are the steps involved in the descending pain control system?
1. Primary afferent neurons stimulate the dorsal horn, activating ascending pain pathways.
2. The ascending tracts stimulate the periaqueductal gray matter in the midbrain, which activates the pons and raphe systems.
3. These descending systems release serotonin and norepinephrine, which modulate the actions of enkephalin to inhibit pain signals.
167
How does serotonin influence the action of enkephalin in pain modulation?
Serotonin, released from descending systems, enhances the action of enkephalin by stimulating its release from gate interneurons, which in turn inhibits pain signals by blocking the release of excitatory neurotransmitters like glutamate and Substance P.
168
How do SSRIs enhance serotonin’s antinociceptive action?
SSRIs prolong the action of serotonin by inhibiting its reuptake, thereby allowing serotonin to remain active longer and more effectively inhibit the pain signals through descending pathways.
169
What is the concept of “central biasing” in pain perception?
Central biasing refers to the influence of conscious or unconscious factors, such as past experiences, circumstances of the injury, and the chronicity of pain, on how pain is perceived and managed by the brain and nervous system.
170
Why is pain management considered a complex system?
Pain management is complex because it involves not only the spinal cord and brainstem areas but also the consciousness, with factors like past pain experiences, injury context, and chronicity influencing the perception and management of pain.
171
What is central sensitization, and how does it contribute to chronic pain?
Central sensitization is a process in which excitation of primary afferents, compounded by ongoing glutamate release and increased inflammation, leads to a chronic “depolarization” of cells. This reduces the need for additional glutamate release to generate action potentials, causing the perception of pain without further tissue damage. It is one of the mechanisms behind chronic pain.
172
How does Substance P contribute to central sensitization?
Substance P is released from the peripheral terminals of primary afferents, mediating inflammation and causing action potentials in C-fibers. This results in the release of glutamate and Substance P at the central terminal, creating generalized excitation in the dorsal horn and contributing to central sensitization.
173
What role does inflammation play in central sensitization?
Chronic inflammation increases the release of glutamate and Substance P, which potentiates the excitatory circuits involving glutamate, Substance P, and CGRP, sensitizing the dorsal horn and leading to the perception of pain even without continued peripheral stimulus.
174
How does central sensitization affect the dorsal horn and pain perception?
Central sensitization causes generalized excitation in the dorsal horn, where it sensitizes the tract cells in the nucleus proprius. This results in the transmission of pain information to the thalamus through the spinothalamic tract, even without ongoing tissue damage.
175
What neurotransmitters are involved in the central sensitization process?
Glutamate, Substance P, and CGRP are key neurotransmitters involved in central sensitization. Their release and interaction in the dorsal horn contribute to the heightened pain response and chronic pain conditions.
176
What is the impact of central sensitization on pain pathways?
Central sensitization “sensitizes” the dorsal horn, meaning that pain pathways are activated even without continued peripheral injury. This leads to the chronic perception of pain and may be responsible for conditions like chronic pain and fibromyalgia.
177
How does the spinothalamic tract relate to central sensitization?
The spinothalamic tract carries pain signals from the dorsal horn to the thalamus. In central sensitization, the tract cells in the nucleus proprius of the dorsal horn become overly excited, transmitting pain signals even without new peripheral injury.
178
Why is central sensitization considered complex?
Central sensitization involves multiple mechanisms, including potentiation of excitatory neurotransmitters like glutamate, Substance P, and CGRP, which “sensitize” the dorsal horn, leading to chronic pain. These processes are not fully understood and are studied in more detail in advanced courses.
179
What neurotransmitters are released by primary afferent neurons in the spinal dorsal horn during neuropathic pain?
Primary afferent neurons release neurotransmitters including glutamate (Glu), interleukin-1 beta (IL-1β), substance P, ATP, tumor necrosis factor alpha (TNF-α), nerve growth factor (NGF), and others.
180
How do glutamate (Glu) and IL-1β contribute to central sensitization?
Glu and IL-1β activate NMDAR (N-Methyl-D-Aspartate Receptors) on secondary neurons, leading to calcium (Ca2+) influx, which plays a key role in central sensitization.
181
What is the role of P2X4R activation in central sensitization?
Activation of P2X4R on secondary neurons by ATP intensifies NMDAR activation and leads to downstream activation of c-Jun N-terminal kinase (JNK), P38, and MAPK, contributing to central sensitization and synaptic remodeling.
182
How does microglial activation affect central sensitization?
Microglial activation, triggered by IL-1β, ATP, and TNF-α, results in the release of brain-derived neurotrophic factor (BDNF) and increased IL-1β levels. BDNF activates TrkB receptors on secondary neurons, enhancing NMDAR activation and contributing to central sensitization.
183
What are the downstream effects of BDNF activation on secondary neurons?
BDNF activates TrkB receptors on secondary neurons, triggering signaling pathways like MAPK/ERK and PI3K/Akt-CREB, which enhance NMDAR activation and contribute to central sensitization.
184
How does ATP activate astrocytes in the process of central sensitization?
ATP activates the P2X7 receptor (P2X7R) on astrocytes, inducing the release of further ATP. Additionally, ATP can activate metabotropic glutamate receptors (mGluRs) on astrocytes, leading to the release of IL-1β and TNF-α, exacerbating central sensitization.
185
What role does glutamate (Glu) play in the activation of astrocytes during central sensitization?
Glutamate activates metabotropic glutamate receptors (mGluRs) on astrocytes, which leads to the release of pro-inflammatory cytokines like IL-1β and TNF-α, contributing to central sensitization.
186
How does central sensitization lead to increased sensitivity to non-painful stimuli?
Prolonged activation of central systems increases sensitivity to excitatory neurotransmitter release, causing non-painful peripheral stimuli or descending stimuli to activate the central pain perception pathway.
187
Why is central sensitization considered complex?
Central sensitization involves multiple signaling pathways and cell types, including primary afferent neurons, secondary neurons, microglia, and astrocytes, with complex interactions between neurotransmitters like glutamate, substance P, and cytokines, leading to heightened pain perception.
188
What is the basic central pathway for creating pain perception?
The basic central pathway consists of a three-neuron series:
1. Action potentials are generated in the tissues at the C-fiber and travel to the spinal cord.
2. The signal synapses in the spinal cord, crosses the midline, and ascends to the thalamus.
3. After another synapse in the thalamus, the signal reaches the cerebral cortex, where the perception of pain occurs.
189
How is pain perception related to the side of the body and the cerebral cortex?
Pain from the right side of the body is processed by the opposite (left) cerebral cortex. This cross-body processing is thought to be due to evolutionary coordination of the two sides of the nervous system, allowing them to function cooperatively.
190
What are the tracts that stay on the same side of the nervous system, and what kind of information do they carry?
Some tracts stay on the same side of the nervous system and carry unconscious or stereotypical information. These pathways do not typically reach the level of the cortex.
191
What are some hypotheses explaining why pain processing is typically contralateral (processed on the opposite side of the body)?
One hypothesis suggests that as separate body parts developed, the two sides of the nervous system needed to coordinate to support each other. This may have led to the need for cross-body processing of sensory information, including pain.
192
How do primary afferents release neurotransmitters both peripherally and centrally?
Primary afferents release neurotransmitters both at their peripheral terminals and centrally:
• Peripherally: Release of substances like Substance P (SP) and CGRP contributes to neurogenic inflammation.
• Centrally: These neurotransmitters initiate the pathway for pain perception in the spinal cord and brain.
193
Can chiropractic treatment influence the activation of primary afferents?
Yes, chiropractic treatment, such as spinal adjustments, could influence primary afferents. Irritation or “subluxation” of the spinal nerve can activate these afferents and lead to the peripheral release of mediators like SP, CGRP, and others that contribute to inflammation.
194
What is the difference between the Axon Reflex and Orthodromic Activation?
•Axon Reflex (Antidromic Activation): The release of pro- and anti-inflammatory mediators at the peripheral terminal of the primary afferent.
• Orthodromic Activation: The central release of neurotransmitters that initiate the pain perception pathway.
195
How might chiropractic adjustments help manage pain and disease?
Chiropractic adjustments might help manage pain and disease by affecting the primary afferents, potentially reducing inflammation and altering the pain perception pathways through both peripheral and central mechanisms.
196
Can the afferent axon be excited at a point other than the end?
Yes, afferent axons can be excited at points other than their peripheral terminals, such as in the dorsal root ganglion. When this happens, an action potential is generated in both orthodromic (toward the CNS) and antidromic (toward the periphery) directions.
197
What can cause afferent axons to be excited in ways other than at the peripheral terminal?
Afferent axons can be excited due to mechanical irritation, such as from disc herniation, facet degeneration, or mechanical fixation. This can lead to pain (referred from the neuron’s receptive field) and peripheral inflammation.
198
How does chiropractic treatment help with pain and inflammation?
Chiropractic adjustments can help by addressing the irritation of afferent axons, reducing pain and inflammation. By correcting issues like mechanical fixation, the adjustments may prevent the unnecessary excitation of axons, helping manage both pain perception and peripheral inflammation.
