CPPS 325 VERGE 2025 Pain Signalling #14 #15 to upload (1) Flashcards
What is the role of cytokine signaling in melanoma cancer cells?
Cytokine signaling gone awry can lead to changes in melanoma cancer cells that make them more prone to metastasize.
What does RNAi stand for?
RNA interference.
What is nitric oxide (NO) known for in terms of therapeutics?
Knowledge of nitric oxide pathways has led to some very useful therapeutics.
What anatomical pathways interpret pain states?
Several anatomical pathways are involved in interpreting pain states.
What happens to regions of the body when tissue is injured or inflamed?
Regions rapidly sensitize to sensory input.
What are inflammatory agents that regulate TRPV1?
Inflammatory agents regulate TRPV1 through direct and indirect mechanisms and pathway crosstalk.
What initiates action potentials in sensory neurons signaling pain?
Generator potentials resulting from the inward flow of positively charged ions (cations).
Who provided early insights into pain transmission?
René Descartes.
What is the significance of pain in terms of survival?
Pain serves a functional role for survival.
What risk do people lacking pain receptors face?
They are at great risk for damage without sensing it.
What type of responses do pain stimuli induce?
Species-typical escape and withdrawal responses.
True or False: Pain can involve an emotional component.
True.
What does proprioception refer to?
Capacity to sense position of joints, direction, and velocity of movement.
What is nociception?
The detection of painful and thermal stimuli.
What is a major regulator of inflammatory pain?
Nerve growth factor (NGF).
Where are the cell bodies of primary afferent sensory neurons located?
In the dorsal root ganglia (DRG).
What are nociceptors?
Pain receptors that respond to intense pressure, thermal stimuli, and chemicals.
Fill in the blank: Pain receptors are activated by _______.
mechanical, chemical, thermal, and cold stimuli.
What is hyperalgesia?
Increased pain sensation.
What mediators are involved in the pain response?
- ATP
- Acetylcholine
- Serotonin
- Prostaglandin E2
- Bradykinin
What happens to the area beyond the original burn zone?
It also becomes sensitized.
What is the significance of nerve growth factor (NGF) in pain transmission?
NGF binds to trkA receptors on sensory neurons and regulates gene expression and activity of channels such as TRPV1.
What are the effects of inflammatory mediators?
They cause peripheral vasodilation, increased vascular permeability, and increased pain sensation.
What does the activation of the trkA receptor lead to?
Activation of the MAPK pathway and transcription of proteins involved in pain transmission.
Fill in the blank: Increased levels of NGF are produced by _______.
keratinocytes, fibroblasts, and immune cells.
What is a major driver of inflammation-associated pain states?
NGF through its binding to and activation of trkA
NGF (Nerve Growth Factor) is crucial for the development of hyperalgesia.
What happens when NGF’s actions on sensory neurons are blocked?
The hyperalgesic/sensitized pain state does not develop or is abolished.
What is sensory neuron sensitization?
A rapid process that occurs within minutes following tissue/nerve damage or induction of an inflammatory state.
What is a common feature of pathologies involving sensory neuron sensitization?
Tissue acidosis, characterized by decreased pH (increased protons).
What ion channels are activated due to increased proton drive in sensory neurons?
Proton-sensitive ion channels such as TRPV1 and acid sensing ion channels (ASICs).
What does the activation of proton-sensitive ion channels cause in sensory neurons?
It causes nerve cells to fire/depolarize, increasing trkA mobilization to the neuronal membrane.
What did Geoff Bray’s 2013 study demonstrate?
Extracellular pH and neuronal depolarization serve as dynamic switches to mobilize trkA to the membrane of adult sensory neurons.
What is the effect of exposing adult rat sensory neurons to a slightly acidic environment (pH 6.5)?
It results in rapid mobilization of trkA to the membrane.
What methodology was used to assess trkA mobilization in sensory neurons?
Immunofluorescence under non-permeabilizing conditions.
What was observed in sensory neurons after exposure to pH 6.5?
Increased detection of trkA over the membranes of cell bodies and neurites.
What does increased cell surface levels of trkA indicate?
It heightens the response of sensory neurons to NGF.
What was the result of challenging neurons with NGF after mobilizing trkA?
A significantly larger activation of trkA was observed in the pH 6.5 group.
What role does BDNF play in the study?
BDNF can activate trkB, which has the same phosphorylation site as trkA.
What significant increase was observed in sensory neurons exposed to acidic media?
Increased levels of phosphorylated trkA and phospho-p38MAPK.
What is the significance of the rapid mobilization of trkA in response to acidosis?
It may be an adaptive response contributing to rapid sensitization of sensory neurons under inflammatory conditions.
What do inflammatory agents do to sensory neurons?
They bind to specific receptors and initiate various signaling cascades affecting rapid changes.
True or False: Acidosis results in decreases in trkA localized to sensory neuron membranes.
False.
Fill in the blank: The inward flow of _______ initiates action potentials in sensory neurons.
cations.
What is sensitization of sensory neurons?
The process by which sensory neurons become more responsive to stimuli under inflammatory conditions.
Sensitization involves changes in signaling pathways that increase neuron responsiveness.
What molecules bind to sensory neuron endings during inflammation?
Molecules in the inflammatory soup bind to specific receptors on sensory neuron endings.
These receptors initiate signaling cascades that alter neuron function.
What is hyperalgesia?
An increase in the magnitude of pain induced by a normally painful stimulus.
For example, warm water from a shower feels hotter on a burned area.
What is allodynia?
When a usually nonpainful stimulus becomes painful.
An example is light touch feeling painful on a burned area.
Which ion channel is primarily involved in detecting noxious heat?
TRPV1 (transient receptor potential vanilloid 1).
TRPV1 channels are sensitive to heat and protons released at injury sites.
How do inflammatory agents regulate TRPV1?
Through direct and indirect mechanisms and pathway crosstalk.
This involves various signaling pathways that modulate TRPV1 activity.
What effect does phosphorylation by PKA and PKC have on TRPV1?
It significantly increases TRPV1 activity upon stimulation with capsaicin or heat.
Phosphorylation enhances the channel’s sensitivity to stimuli.
What is the role of AKAP in TRPV1 signaling?
AKAP organizes a multiprotein complex to enhance phosphorylation efficiency of TRPV1 channels.
This positioning allows for better signaling and response.
What happens to TRPV1 channels when PIP2 is broken down?
The PIP2 gate is removed, allowing TRPV1 channels to become fully activated.
This process is mediated by PLC pathways activated by various ligands.
What is the effect of neurogenic inflammation related to TRPV1 sensitization?
It enhances calcium influx in response to TRPV1 activation, leading to increased pain sensitivity.
This contributes to the overall hyperalgesic state.
What does NGF binding to trkA do in relation to TRPV1?
Increases TRPV1 membrane trafficking via phosphatidylinositol 3-kinase (PI3K).
More TRPV1 channels in the membrane heighten responses to stimuli.
Fill in the blank: The increase in pain sensation that characterizes hyperalgesia results from an increase in the sensitivity of the ion channels responsible for the membrane depolarization of the _______.
nociceptor nerve endings.
What is the role of PKA in TRPV1 and Nav1.7 channel activity?
PKA phosphorylates TRPV1 and Nav1.7 channels to increase their activity.
This phosphorylation enhances the channels’ responses to stimuli.
What is the significance of the NaV1.7 channel in sensory neurons?
It amplifies generator potentials that lead to action potentials conveying pain information to the brain.
Increased NaV1.7 activity is critical for pain sensation.
True or False: Inflammation can lead to a reduction in trkA receptor mobilization to the membrane.
False.
Inflammation can increase trkA receptor mobilization, enhancing pain signaling.
What are the outcomes of increased generator potentials in sensory neurons?
They can result in neuronal depolarization and firing in nociceptors, indicating increased pain sensation.
This firing conveys pain signals to the spinal cord and brain.
