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6BBYN302 Perspectives on Pain and Nervous System Disorders > Sensitization of nociceptive pathways I > Flashcards

Sensitization of nociceptive pathways I Flashcards

Overall aim of the sensitisation lectures: to provide a conceptual framework to support the understanding of the mechanisms underlying plastic changes in peripheral nociceptors and in neurons of the dorsal horn of the spinal cord, which lead to increased nociception, and may underlie persistent pain states.

1
Q

What is sensitization in the context of nociceptors?

A
  • involves reduction in threshold, increased response magnitude to noxious stimuli & the potential for previously ineffective stimuli to become effective
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2
Q

What often leads to the sensitization of nociceptors?

A
  • typically develops as a consequence of tissue insult and inflammation
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3
Q

What additional feature can develop in sensitized nociceptors?

A
  • may exhibit spontaneous activity
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4
Q

What defines the peptidergic subpopulation of nociceptors?

A
  • presence of one or both of the neuropeptides substance P and CGRP
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5
Q

How is the peptidergic subgroup further defined?

A
  • further defined by the expression of the NGF receptor TrkA
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6
Q

What defines the non-peptidergic nociceptors?

A
  • defined by the expression of Ret
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7
Q

Which type of afferents, notably peptidergic nociceptors, can release substances from their peripheral terminals?

A
  • can release substances from their peripheral terminals
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8
Q

Where are the cell bodies of nociceptors located?

A

DRG

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9
Q

What do nociceptors innervate?

A
  • Nociceptors have both central and peripheral axon branches, innervating target organs and the spinal cord, respectively
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10
Q

What happens when intense stimuli are detected by nociceptors?

A
  • nociceptors can generate acute pain, and in cases of persistent injury, both peripheral & CNS components of the pain transmission pathway exhibit plasticity
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11
Q

What is central sensitization?

A
  • Central sensitization is a state of hyperexcitability in the CNS.
  • It leads to enhanced processing of nociceptive messages.
  • It results in increased sensitivity to pain.
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12
Q

How does central sensitization contribute to pain processing in the CNS?

A
  • Central sensitization involves release of glutamate from nociceptors’ central terminals.
  • Glutamate activates AMPA receptors in second-order dorsal horn (DH) neurons.
  • This process contributes to primary hyperalgesia
  • It also leads to secondary hyperalgesia, where innocuous stimulation near the injury site can cause pain.
  • Secondary hyperalgesia involves heterosynaptic facilitation, with Ab afferents engaging pain transmission circuits.
  • It results in profound mechanical allodynia
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13
Q

What are Ad fibers, and how many types are there?

A
  • a type of sensory nerve fiber.
  • two types: Type I, which is associated with high-threshold mechanical (HTM) pain and likely mediates first pain
  • Type II, which has a lower heat threshold but a high mechanical threshold.
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14
Q

Are C fibers homogenous or heterogenous, and what is their sensitivity?

A
  • heterogenous
  • most of them are polymodal, meaning they’re sensitive to both heat and mechanical stimuli
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14
Q

What commonly results in peripheral sensitization, and how does it occur?

A
  • commonly results from inflammation-related changes in the chemical environment of nerve fibers
  • tissue damage often accompanied by accumulation of endogenous factors, collectively known as the “inflammatory soup,” (includes various signalling molecules)
  • Nociceptors express receptors capable of recognizing & responding to these pro-inflammatory agents, enhancing the excitability of the nerve fibers
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15
Q

What is the role of NGF (Nerve Growth Factor) in sensory neurons during embryogenesis and in adults?

A
  • NGF required for survival & development of sensory neurons during embryogenesis.
  • In adults, it’s produced in response to tissue injury as part of the inflammatory response.
  • NGF acts directly on peptidergic C fibers, which express its TrkA receptor & activates downstream signaling pathways, including PLC, MAPK, and PI3k.
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16
Q

How does central sensitization contribute to pain processing in the CNS?

A
  • central sensitization involves release of glutamate from nociceptors’ central terminals
  • Glutamate activates AMPA receptors in second-order DH neurons.
  • this process contributes to primary hyperalgesia
  • it also leads to secondary hyperalgesia, where innocuous stimulation near injury site can cause pain
  • Secondary hyperalgesia involves heterosynaptic facilitation, with Ab afferents engaging pain transmission circuits
    -,results in profound mechanical allodynia
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17
Q

What is the significance of GABAergic and glycinergic inhibitory interneurons in pain processing?

A
  • GABAergic and glycinergic inhibitory interneurons are found in the superficial dorsal horn (DH).
  • play a crucial role in gate control theory of pain
  • loss of function of these inhibitory interneurons can lead to ↑ pain perception
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18
Q

What are some components that contribute to the pain experience?

A
  • Context, including pain beliefs, expectations, and placebo effects.
  • Cognitive set, including hypervigilance & attention.
  • Mood, including depression and anxiety.
  • Chemical & structural factors e.g. neurodegeneration & distraction
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19
Q

What is sensitization, and how can it occur in the context of pain?

A
  • can occur either peripherally or centrally
  • often follows injury or inflammation in peripheral tissues or CNS
  • Sensitization involves 2 features:
    a decreased threshold to respond to a smaller stimulus AND an amplified magnitude of response.

Both peripheral and central sensitization can contribute to the perception of ↑ pain

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20
Q

How can you distinguish between peripheral and central sensitization?

A
  • If injury/inflammation had stimulus applied peripherally & resulted in a greater response (e.g., increased pain), it’s difficult to determine if it’s due to peripheral, central sensitization, or both.
  • BUT, if stimulus applied some distance from injured area, where peripheral terminals haven’t been affected & still leads to an ↑ response likely due to central sensitization bc peripheral sensitization tends to be localized to area of injury/inflammation.
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21
Q

What are the three main types of pain?

A
  • Nociceptive pain (results from tissue damage activating nociceptors)
  • Inflammatory pain (caused by inflammatory mediators, with underlying mechanisms of peripheral & central sensitization)
  • Neuropathic pain (often due to peripheral nerve injury, involving central sensitization & ectopic activity)
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22
Q

What is the difference between inflammatory pain and neuropathic pain in terms of sensitization mechanisms?

A
  • Inflammatory pain involves both peripheral & central sensitization.
  • Neuropathic pain characterized by more central sensitization & occurrence of ectopic activity.

Ectopic activity can generate action potentials at various locations along the axon or in the cell body of the dorsal horn (rather than typical peripheral terminal)

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23
Q

What were the key findings of Dmitrieva’s 1996 study regarding the effects of NGF on primary afferent neurons innervating the rat urinary bladder?

A
  • Dmitrieva’s study focused on adult rat urinary bladder afferent neurons.
  • When the bladder filled with NGF (Nerve Growth Factor), sensitization occurred.
  • Normally, afferents responded to bladder distension with ↑ in firing correlated with ↑ bladder volume.
  • With NGF, the nerves exhibited a lower threshold of activation and ↑ firing even at lower bladder volumes.
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24
Q

What is long-term potentiation (LTP) in the context of neuronal synapses?

A
  • the persistent strengthening of synapses based on patterns of activity.
  • results in a long-lasting ↑ in signal transmission between two neurons
  • Neurons in dorsal horn of spinal cord have varying potential to develop LTP
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25
Q

What is the significance of spinoparabrachial tract neurons in the context of pain processing?

A
  • Spinoparabrachial tract neurons in the spinal cord project and terminate in the parabrachial nuclei of the brain.
  • These neurons are involved in pain processing (but precise function remains unknown)
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26
Q

How can spinoparabrachial tract neurons be potentiated?

A
  • Potentiation of these neurons can occur through conditioning synapses at high frequencies, resulting in an ↑ response.
    The physiological accuracy of this high-frequency potentiation is not within the normal firing rate of C fibers.
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27
Q

What is the role of the periaqueductal gray (PAG) in pain processing?

A

-PAG is a major center for descending pathways that modulate spinal cord activity
- It responds to low-frequency stimulation with long-term potentiation (LTP), which occurs within the normal physiological range

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28
Q

What is the primary target of peripheral sensitization in pain processing?

A
  • primarily targets the transduction process, which involves converting thermal, mechanical, or chemical signals into electrical signals in primary sensory neurons
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29
Q

What is the typical cause of peripheral sensitization?

A

tissue inflammation

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30
Q

How does peripheral sensitization affect the electrical response of primary sensory neurons?

A
  • increases the electrical response of primary sensory neurons, making them more excitable
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31
Q

Can peripheral sensitization be caused by individual components of the “inflammatory soup”?

A
  • Yes, individual components of the inflammatory soup, such as NGF (Nerve Growth Factor), can cause peripheral sensitization
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32
Q

Which cellular components do these inflammatory molecules act on in peripheral sensitization?

A
  • These molecules act on specific receptors present on the primary sensory neurons
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33
Q

What are examples of ligand-gated channels involved in pain signalling?

A

TRPV1 (sensitive to heat, H+, and capsaicin)
P2X3 (activated by ATP)
ASIC (responsive to changes in extracellular pH)

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34
Q

How do ligand-gated channels function in pain signaling?

A
  • they open when bound by specific ligands, allowing influx of positive ions into the neuron, which directly depolarizes the neuron
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35
Q

What are examples of G protein-coupled receptors (GPCRs) involved in pain processing?

A

PGE2 (activating EP receptors)
Bradykinin (stimulating B2 receptors)
Adrenaline (acting on B2 receptors)
ATP (involving P2Y receptors)

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36
Q

How do G protein-coupled receptors (GPCRs) impact pain signaling?

A
  • GPCRs modulate activity of pain-sensing neurons.
  • They don’t directly depolarize the neurons but influence channel activity and signalling pathways
37
Q

What is the role of NGF (Nerve Growth Factor) in pain processing?

A
  • NGF activates TrkA receptor, a membrane-bound receptor. - It triggers autophosphorylation & activates members of the MAPK (Mitogen-Activated Protein Kinase) pathway, which is essential for initiating intracellular signaling pathways
38
Q

How does inflammation impact neurons in terms of channels and receptors?

A
  • During inflammation, neurons can regulate the expression of channels & receptors
  • they may upregulate or downregulate existing channels, express new channels, and modify neurochemical nature of neurons, leading to plasticity in response to injury or inflammation
39
Q

How does the neurochemical nature of neurons change in response to long-term injury or inflammation?

A
  • In a system with long-term injury/inflammation, neurons can undergo significant changes in their neurochemical properties
  • may involve upregulation, downregulation, or de novo expression of channels & receptors
40
Q

What is the major consequence of ligand-activated channels in pain processing?

A
  • Ligand-activated channels allow the influx of Ca2+, which activate various Ca2+-dependent enzymes and initiate intracellular pathways
41
Q

How do GPCRs function in pain processing?

A
  • GPCRs coupled to specific G proteins.
  • In general, many GPCRs in pain processing activate adenylyl cyclase, leading to ↑ production of cAMP and subsequent activation of protein kinase A (PKA)
42
Q

How does activation of GPCRs in pain processing lead to increased calcium levels in neurons?

A
  • Activation of GPCRs can stimulate phospholipase C (PLC), which triggers the production of inositol trisphosphate (IP3).
  • IP3 induces the release of Ca2+ from intracellular stores, ultimately increasing Ca2+ levels in neurons
43
Q

What is the hypothesis regarding the role of PKA and PKC in triggering peripheral sensitization?

A
  • Independent activation of either PKA (Protein Kinase A) or PKC (Protein Kinase C) is believed to be sufficient to induce peripheral sensitization in the nervous system.
44
Q

Is it possible that some receptors require the activation of both PKA and PKC for sensitization?

A
  • yes
  • it’s possible that sensitization of certain receptors may necessitate the concurrent activation of both PKA and PKC
45
Q

Can some receptors activate different pathways under specific circumstances, and can sex hormones influence this process?

A
  • Yes
  • certain receptors, e.g. B2 adrenaline receptor and PGE2 acting on its EP receptor, can activate different signaling pathways under specific conditions
  • Sex hormones, like estrogen, can modulate this process
46
Q

Is it known whether all these signaling pathways are necessary for peripheral sensitization, or if they converge at some point?

A
  • currently unclear whether all these signaling pathways are required for peripheral sensitization or if they converge at some point in process
47
Q

What are the rapid changes that occur upon activation of pain pathways?

A
  • phosphorylation of receptors and channels, leading to increased membrane excitability and sensitization of these receptors and channels. It can also lead to the rapid insertion of channels into the membrane
48
Q

How does the activation of pain pathways affect the pools of receptors inside the cell?

A
  • can phosphorylate pools of receptors present in vesicles inside the cell
  • which can then be rapidly inserted into the cell membrane.
49
Q

What are the longer-term changes in gene expression that can result from the activation of pain pathways?

A
  • can lead to longer-term changes in gene expression, including increased expression of channels, receptors & neurotransmitters
  • this can result in the increased release of neurotransmitters in the spinal cord & expression of channels & receptors not previously present in the cell
50
Q

What is central sensitization?

A
  • an activity-dependent enhancement of the strength of synaptic connections between primary afferent & secondary neurons in the spinal cord
  • this phenomenon can also occur at higher processing locations in brainstem & brain, ultimately leading to an increased experience of pain
51
Q

What is homosynaptic facilitation in the context of transmission?

A
  • a phenomenon where only the synapse that has been activated becomes potentiated.
  • It is a system for amplifying the signal at that specific synapse
52
Q

How does central sensitization differ from homosynaptic facilitation in terms of synaptic potentiation?

A
  • Central sensitization is a mechanism that goes beyond homosynaptic facilitation.
  • While homosynaptic facilitation involves the potentiation of the active synapse, central sensitization aims to amplify the pain signal more broadly, including nearby synapses - this mechanism is adaptive, as it encourages healing and helps to rest the injury
53
Q

What is heterosynaptic facilitation in the context of synaptic potentiation?

A
  • a phenomenon where the stimulation of one synapse also stimulates another synapse
  • this results in the amplification of both synapses, leading to increased synaptic strength
54
Q

How does central sensitization affect the receptive field of dorsal horn neurons?

A
  • can lead to an expansion of the receptive field of DH neurons
  • Areas surrounding the original receptive field, which would not have triggered an action potential under normal conditions, can now lead to neuronal activation
55
Q

Describe the impact of central sensitization on parallel pathways for pain and touch

A
  • In central sensitization, response of nociceptive-specific neurons to stimulus from periphery is enhanced, leading to hyperalgesia.
  • Stimulation of low-threshold mechanoreceptors e.g. Ab fibers by light touch, which wouldn’t have affected pain pathway in normal conditions, can now activate the neuron.
  • results in a shift from a nociceptive-specific neuron to a wide dynamic range neuron capable of responding to various stimuli (including noxious & innocuous ones) leading to perception of pain
56
Q

What type of stimuli can neurons undergoing central sensitization now respond to?

A
  • Neurons undergoing central sensitization can now respond to low-threshold mechanical stimuli, including innocuous touch
57
Q

Describe short-term changes in central sensitization

A
  • phosphorylation-dependent and transcription-independent
  • they involve immediate phosphorylation through activation of signalling pathways related to receptors & channels
58
Q

Primary neurotransmitter in normal nociception?

A

Glutamate

59
Q

Name some receptors involved in nociception?

A

AMPA, Metabotropic Glutamate Receptors, and NMDA receptors

60
Q

What is the primary subunit of AMPA receptors in nociception?

A

GluR2 (GluR2 subunits make AMPA receptors primarily permeable to sodium ions)

61
Q

Under normal circumstances, what prevents NMDA receptors from being activated by glutamate?

A

Magnesium (Mg) block

62
Q

When glutamate acts on AMPA receptors, what ions enter the cell?

A

Sodium (Na) ions

63
Q

What is the main outcome of glutamate acting on AMPA receptors?

A

A short-lived influx of sodium (Na) ions

64
Q

What are the two major contributors to the onset of central sensitization?

A

AMPA and NMDA receptors

65
Q

What happens to AMPA and NMDA receptors in central sensitization?

A
  • they become phosphorylated, leading to the insertion of new receptors in the membrane
66
Q

How does central sensitization affect the response to stimuli?

A
  • causes a much greater influx of ions, increased depolarization, a significant rise in calcium levels, and further activation of signaling pathways
67
Q

What non-receptor tyrosine kinase is activated by the NMDA receptor via TrkB?

A

Src

68
Q

What is the potential result of uncoupling Src from the NMDA receptor in pain conditions?

A
  • It could lead to the reversal of hyperalgesia & allodynia in both inflammatory & neuropathic pain
69
Q

What did Liu et al. find regarding the clinical use of NMDAR blockers?

A
  • clinical use of NMDAR blockers is limited due to side effects associated with suppression of physiological NMDAR functions
70
Q

How did they reverse pain hypersensitization induced by inflammation and peripheral nerve injury? Was this intervention effective for acute nociception (thermal/mechanical/chemical pain)?

A
  • They reversed pain hypersensitization by inhibiting the interaction of Src (protein tyrosine kinase) with its anchoring protein in the NMDAR complex.
  • No, it had no effect on acute nociception
71
Q

In what types of pain conditions is Src coupling of fundamental importance?

A
  • neuropathic and inflammatory pain, specifically in hyperalgesia & allodynia
  • It’s not important in the transmission of normal noxious stimuli
72
Q

Do all dorsal horn (DH) neurons have the same receptors and pathways for pain processing?

A

No, not all DH neurons have the same receptors and pathways for pain processing

73
Q

What happens when you activate a nociceptive neuron in the DH?

A

leads to an excitatory signal in the spinal cord

74
Q

In the DH, are there only excitatory neurons?

A
  • No, in the DH, there are both excitatory and inhibitory neurons
75
Q

What percentage of DH neurons are projection neurons (sending signals to the brain)?

A
  • Only a very small percentage of DH neurons are projection neurons; the majority are local interneurons
76
Q

Can an excitatory interneuron work through activating an inhibitory interneuron?

A
  • Yes
  • Therefore, even if it’s an excitatory neuron, you won’t always know if activating it will increase or decrease the pain signal
77
Q

Why is it challenging to determine the exact location and function of neurons in the DH in many studies?

A
  • Many studies homogenize data to find levels of phosphorylated receptors and other markers, but can’t always pinpoint exact location of these changes within the DH.
  • This limitation means they can’t differentiate between various cell types e.g. glial cells or specific types of neurons.
78
Q

Provide at least two definitions of central sensitization

A
  1. the activity-dependent alteration of synaptic connectivity within the spinal cord, leading to an enhanced responsiveness of neurons in CNS to their normal afferent input.
  2. the enhanced perception of pain, which may or may not be due to the increased excitability of dorsal horn neurons.
79
Q

What are some mechanisms that can lead to an increased response in central sensitization?

A
  • Classical central sensitization (heterosynaptic)
  • Long-term potentiation (LTP, homosynaptic)
  • Wind-up (homosynaptic).

Wind-up is similar to LTP but shorter-lived, resulting from high-intensity, low-frequency repeated stimulation, leading to short-lived potentiation of that synapse.

80
Q

What are the two mechanisms of increased response contributing to central sensitization?

A
  • enhanced responsiveness of neurons in CNS to their normal afferent input
  • enhanced pain perception
81
Q

How does a reduction of tonic inhibition in the spinal cord contribute to central sensitization?

A
  • it can lead to hyperalgesia & allodynia.
  • Neuropathic pain associated with decreased GABAergic inhibition, while inflammatory pain involves reduced glycinergic inhibition, often mediated by prostaglandins
82
Q

What role do glial cells play in central sensitization?

A

e.g. microglia & astrocytes
- influence central sensitization by regulating pain signalling in CNS.
- Changes in glial activity can lead to the release of pro-inflammatory molecules & altered synaptic function

83
Q

How do descending pathways from the brain contribute to central sensitization?

A
  • can either inhibit or facilitate pain signal transmission in the spinal cord
  • Modifications in these pathways influence pain perception & may contribute to central sensitization.
  • These pathways also mediate placebo effect
84
Q

What structural changes in the central nervous system are associated with chronic pain?

A
  • Chronic pain linked to structural plasticity in CNS including increased dendritic spine neurons with more synapses & the sprouting of afferent nerve fibers
  • These changes contribute to long-term alterations in pain perception
85
Q

What distinguishes long-term changes related to central sensitization from short-term changes?

A

Long-term changes associated with central sensitization are transcription-dependent
- they involve induction of gene expression, often occurring in peripheral neurons & less frequently, in DH neurons

86
Q

How does inflammation influence gene expression at various levels of the ascending nociceptive pathway?

A
  • Inflammation typically results in new gene expression throughout ascending nociceptive pathway, contributing to central sensitization
  • this gene expression occurs at both peripheral (e.g., DRG) & central (e.g., dorsal horn) levels
87
Q

Which mediators are likely involved in central sensitization, and how do they influence neurons?

A
  • Substances such as SP, cGRP, and BDNF
  • they act on receptors, initiating intracellular pathways that sensitize neurons
  • These mediators are upregulated in the DRG with prolonged exposure to noxious stimuli
88
Q

What is the role of substances like SP and cGRP in the process of peripheral sensitization?

A
  • Substances like SP and cGRP, when upregulated, increase NT release in DH, leading to greater signal in post-synaptic neurons
  • this contributes to peripheral sensitization
89
Q

What are the long-term changes in post-synaptic neurons related to central sensitization, and what is the role of ERK1/2 and CREB in this process?

A
  • Long-term changes in post-synaptic neurons involve activation of ERK1/2 and CREB, leading to expression of various genes.
  • Notable genes include cFOS, NK1, and COX2, which plays a role in synthesis of prostaglandins that can contribute to spread of sensitization
90
Q

How does the activation of various receptor molecules in DH impact sensory input processing in the spinal cord?

A
  • The activation of diverse receptor molecules in the DH can result in sensitized processing of sensory inputs in the SC
91
Q

What are the consequences of the activation of intracellular signalling pathways in DH neurons?

A
  • phosphorylation of membrane receptors
  • translocation of receptors to membrane
  • and later new gene transcription & translation

6BBYN302 Perspectives on Pain and Nervous System Disorders (11 decks)

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