Chemical anatomy of pain (1) Flashcards
To discuss neurochemical variety of DRG neurons (particularly nociceptors); To highlight the progressive changes in our understanding of the characteristics of nociceptors, in relation to technical developments; To discuss the issue of the functional specificity of different identifiable subpopulations of nociceptors To draw attention to the areas of uncertainty/controversy in the field.
How are innocuous stimuli transmitted in the somatosensory system?
- through Abeta fibers and travel via the dorsal column medial lemniscus
How are noxious stimuli transmitted in the somatosensory system?
- through C and Adelta fibers and travel via spinothalamic tract
How does the somatosensory system process sensory information, especially in the context of pain?
- somatosensory system comprises parallel pathways (for processing various sensory info e.g. touch, pain, temp)
- convergence of pathways can occur, where different types of sensory info are integrated & processed together
What is the primary role of the dorsal root ganglia (DRG) in the somatosensory system?
- acts as a cluster of sensory nerve cell bodies that transmit sensory info from periphery to CNS
What type of neurons are found in the DRG?
- DRG contains pseudo-unipolar sensory neurons, which have a single process extending from the cell body that bifurcates into both peripheral and central branches
What is the first step in somatosensory processing, and where does it occur?
- first step is transduction, (takes place in periphery) where DRG neurons convert various sensory stimuli into electrical signals
What happens after transduction in somatosensory processing?
sensory signals are transmitted to CNS via the central branch of DRG neurons
What part of the central nervous system processes and interprets somatosensory information?
- cerebral cortex is responsible for the perception and interpretation of somatosensory input
What is the role of DRG neurons in modulation within the somatosensory system?
- involved in the modulation of sensory information, influencing how we perceive sensations like pain
What are the fundamental processes involved in sensation within the somatosensory system?
- Sensation involves transduction of stimuli from the periphery
- DRG neurons play a role in this process
Describe the steps of sensory signal processing in the somatosensory system
- Transmitted signals are sent to CNS
- Perception occurs in the cerebral cortex, enabling conscious awareness of the sensory input
How can the perception of sensation, especially pain, be modulated within the somatosensory system?
- Modulation processes can change how sensations perceived - incl. pain
- Sensory neurons use neurotransmitters like glutamate (NMDA/AMPA/mGluR) for signal transmission.
- Neuromodulators like substance P, acting via NK1 receptors, can influence sensory processing
What are the characteristics of cutaneous nociceptors in terms of localization and sensations?
Back:
- well-localized
- can produce sensations like pricking, stabbing, and burning
How do muscle and visceral nociceptors differ from cutaneous nociceptors in terms of localization and sensations?
- Muscle & visceral nociceptors are much more poorly localized
- can generate sensations such as aching, cramping, fullness, dullness & vagueness
What contributes to the differences in localization and sensation between cutaneous and visceral nociceptors?
- influenced by the distribution of C-fiber components in the skin compared to visceral afferents & their connections to central and peripheral terminals
Where do the peripheral processes of dorsal root ganglion (DRG) neurons innervate receptors?
- the skin, muscle, and viscera
How can the peripheral processes of some DRG cells influence vascular activity?
- Some DRG cells’ peripheral processes release vasoactive mediators that change vascular permeability, indicating efferent as well as afferent activity
What are A fibers, and what types of input do they process?
- sensory nerve fibers with low threshold input sensitivity, primarily processing mechanosensation
- they’re myelinated & conduct signals rapidly
What are C fibers, and what types of input do they process?
- sensory nerve fibers with high-threshold sensitivity, processing mechanical, thermal, and chemical (polymodal) stimuli
- they’re unmyelinated & have slower conduction velocities
What are the two main subgroups of C fibers?
- peptide-rich
- peptide-poor
What neuropeptides are released by C fibers in the periphery, and what are their functions?
- C fibers (particularly peptide-rich subpopulation) release substances such as substance P and CGRP in the periphery
- these neuropeptides have vasoactive properties & can promote inflammatory responses
How were polymodal nociceptors initially proposed to be divided into two groups?
- suggested to be divided into 2 groups based on their content of peptide and fluoride-resistant acid phosphatase (FRAP)
- as well as their termination sites within the spinal cord
Majority of C-fibers are what?
- polymodal & responds to all
forms of noxious stimuli (thermal, mechanical and chemical) - with varying degrees of sensitivity
Is there any overlap between Aβ fibers and nociceptors? If so, what type of pain do they typically transmit?
-Yes, there is some overlap
- Aβ fibers can transmit mechanical, prickling, fast pain that is often localized
What happens to C fiber classes (peptidergic and non-peptidergic) as they develop, and how do they differ in terms of neurotrophic support requirements?
- C fiber classes (peptidergic and non-peptidergic) diverge during development
- Non-peptidergic fibers become responsive to glial cell-derived growth factors, and this responsiveness is influenced by target tissues.
What is the role of Nerve Growth Factor (NGF) in relation to nociceptors?
- NGF levels increase in inflamed tissues
- and it plays a significant role in nociceptor sensitization and pain modulation
What are the major DRG subgroups based on their trophic factor response?
- A fibers, C fibers (divided into peptide-rich and peptide-poor)
- each of which responds to specific trophic factors for development and survival
What is the characteristic response of peptide-poor C fibers?
- Peptide-poor C fibers preferentially respond to ATP, contributing to their nociceptive function
What is a common neurotransmitter among these different DRG subgroups, and how do they differ in terms of transporters?
- Glutamate is a common neurotransmitter in these subgroups
- they use different transporters for glutamate uptake, which can influence their synaptic functions
How are C fibers divided into two groups based on their characteristics?
one group:
- expressing receptors for GDNF
- terminating in the deeper parts of the substantia gelatinosa (laminae 2) of the spinal cord
other group:
- synthesizing peptides like substance P,
- expressing NGF receptor TrkA
- terminating more superficially in the dorsal horn
How can neurons in the ascending nociceptive pathway change their phenotype in response to sustained peripheral injury?
- Neurons in the ascending nociceptive pathway can change their phenotype in response to sustained peripheral injury
- leading to new gene expression in the spinal cord and brain
- resulting in a new pattern of gene expression that changes substantially over time
What ion channels are involved in nociceptor function?
- Nociceptors involve various ion channels, including:
- Transient Receptor Potential (TRP) family for detecting a wide temperature range.
- TRP channels predominantly expressed in nociceptors & associated with tissue injury & inflammation.
- e.g. TRPV1 is upregulated in inflammatory conditions
What are the roles of Acid-Sensing Ion Channels (ASIC) in nociceptors?
-play a significant role in pain and inflammation
- activated when extracellular pH decreases & are responsible for gating nociceptors
Which ion channel is crucial for rapidly adapting mechanically activated currents in nociceptors, particularly in Merkel cells?
- Piezo2 ion channels = vital for rapidly adapting mechanically activated currents in nociceptors, with a specific role in Merkel cells - associated with fine touch sensation.
What role does the mass-related G protein-coupled receptor family play in nociceptors?
- mass-related G protein-coupled receptor family is less understood, but used as a marker to differentiate non-peptidergic C fibers into groups
- this differentiation allows for genetic modifications to study the loss of specific sensory sensations
Which sodium channels are involved in nociceptor function?
- Nociceptors utilize sodium channels, including Nav1.9 and Nav1.8, in their signal transmission
- these channels are important for nociceptive processes
What is the role of MrgprD in nociceptive neurons?
- MrgprD = marker for non-peptidergic nociceptive neurons, representing approximately 75% of IB4-expressing neurons
- exclusively innervate the skin & terminate in lamina II of the dorsal spinal cord
- MrgprD neurons mainly function in mechanical nociception, indicating specificity in their sensory functions
How does genetic ablation of C fibers expressing MrgprD affect sensitivity to different noxious stimuli?
- genetic ablation of C fibers expressing MrgprD reduces behavioral sensitivity to noxious mechanical stimuli while leaving heat or cold sensitivity unaffected
- suggests that brain distinguishes between different noxious stimulus modalities early in sensory processing
What happens when TRPV1 nociceptors are selectively ablated?
- abolishes sensitivity to noxious heat pain
- but their elimination, when combined with ablation of MrgprD-expressing C fibers, results in an additive phenotype, indicating the brain’s early differentiation of various noxious stimulus modalities
What anatomical differences suggest unique sensory functions for MrgprD neurons?
- MrgprD neurons innervate the most superficial layers of the skin’s epidermis, specifically the Stratum granulosum
- peptidergic CGRP neurons innervate the underlying Stratum spinosum.
These anatomical distinctions indicate that MrgprD neurons may have unique sensory functions.
How do MrgprD neurons contribute to mechanical and thermal nociception?
- they’re essential for full expression of mechanical nociception (but don’t play significant role in thermal nociception)
- specific post-synaptic targets in the spinal cord’s lamina II (substantia gelatinosa) with which MrgprD neurons synapse remain unknown
What is the method used to study MrgprD neurons’ function?
- a method involved genetically targeting the light-activated ion channel ChR2-venus to the MrgprD locus.
- these afferents terminate in laminae II of the spinal cord, suggesting their innervation of substantia gelatinosa (SG) neurons
- this approach allowed precise control of a subset of nociceptors
What did the study by Cavanaugh et al. in 2009 reveal about ChR2-venus expression?
-study by Cavanaugh et al. in 2009 found that ChR2-venus was expressed in non-peptidergic MrgprD DRG neurons
- indicating their involvement in optogenetic control of nociceptor activity
How do MrgprD neurons contribute to responses to extreme cold and heat?
- Pogorzala et al.’s 2013 study demonstrated that MrgprD neurons contribute to painful responses to extreme cold & heat.
- While eliminating MrgprD neurons alone doesn’t affect behavioural responses to temperature, when combined with the ablation of TRPV1/8 cells, it significantly ↓ responses to extreme heat and cold
What is the proposed role of Mrgprd C-11?
- Mrgprd C-11 is thought to be involved in anti-nociception upon ligand binding
How does TRPM8 knockout (KO) affect temperature sensitivity in mice?
- In mice, the knockout of TRPM8 C fibres, associated with cooling sensation, results in an inability to discern temperature differences until they become noxious
What happens when TRPV1 is knocked out in adult rats?
- In adult rats, knocking out TRPV1 causes them to sit in noxious heat without realizing it
- They still maintain cooling sensitivity.
What is the function of the Merkel cell-neurite complex in the skin?
- serves as a gentle touch receptor in the skin, mediating slowly adapting responses of Aβ sensory fibers to encode fine details of objects
How does Piezo2 affect Merkel cells’ mechanosensitivity?
- Merkel cells’ mechanosensitivity is completely dependent on Piezo2
- Engineered mice deficient in Piezo2 in the skin show moderately ↓ behavioural responses to gentle touch
What are the key conclusions regarding nociceptors and sensory processing?
- A fibers and C fibers are morphologically, physiologically, and neurochemically distinct, supporting the idea of parallel sensory processing
How many populations of nociceptors are there? and what are they?
3
- Ad/b HTM nociceptors (A-delta and C-fibers associated with high-threshold mechanoreceptors for fast pain).
- C-fibers comprising peptide-rich subpopulations.
- C-fibers comprising peptide-poor subpopulations.
What is the role of Ad/b HTM nociceptors?
NOTE; Ad/b HTM = Ad and C-fibers (b) that are associated with high-threshold mechanoreceptors (HTM)
- Ad/b HTM nociceptors are associated with fast pain transmission
What are the two subpopulations of C fibers in the context of peptide content?
- C fibers can be divided into peptide-rich & peptide-poor subpopulations
How does the complexity of sensory integration affect perception?
- it reflects the intricacies of perception & leads to various structure-function relationships between afferent phenotypes & target tissues
