Sensitization of nociceptive pathways II Flashcards
How is peripheral sensitization studied?
- Single-cell analysis (electrophysiological recording, Ca imaging, etc.)
- Nerve-skin preparations
- Whole animal studies (e.g., knockout models)
- Human studies using stimuli like capsaicin
- Short-term models (e.g., carrageenan injection)
- Long-term models (e.g., complete Freund adjuvant injection)
- Outcome measurements, including responses to thermal and mechanical stimulation, electrophysiological recordings, and molecular analysis
Do the intracellular signaling pathways that trigger peripheral sensitization eventually converge, or do they remain parallel?
- evidence is conflicting
- understanding this is crucial for developing analgesics.
How is the specificity of the response achieved in peripheral sensitization, where neurons can respond differently to signals that should activate the same intracellular pathway?
- Specificity may result from location of receptors, channels & signalling molecules in distinct membrane domains.
- Some receptors can produce different intracellular pathways depending on the context (e.g., PKC or PKA pathways) but comprehensive understanding still needed
What is the role of NGF in pain modulation?
- NGF (Nerve Growth Factor) increases pain either locally or systemically depending on the dose and route of administration.
- Increased NGF expression in injured/inflamed tissues is associated with elevated pain levels.
How does the inhibition of NGF affect pain?
- Inhibiting NGF (as shown in a study with tanezumab (an NGF inhibitor) for osteoarthritis patients) led to a significant decrease in pain compared to a placebo.
- The reduction in pain ranged from 45-62% with tanezumab compared to 22% with the placebo
Is peripheral sensitization only relevant in cases of persistent inflammation?
- Peripheral sensitization might not resolve completely once inflammatory stimulus removed.
- can have long-term consequences, leaving nerves in a primed state to respond more significantly to inflammatory stimuli, potentially leading to amplified pain responses
What is the term for the state in which an animal or human, after an inflammatory stimulus, returns to apparent normalcy but is primed to respond more strongly to a smaller stimulus in the future?
“priming,” and it can lead to increased hyperalgesia upon subsequent stimulation
Does peripheral sensitization contribute to neuropathic pain?
- Yes
- as it reflects both peripheral and central sensitization mechanisms.
- Abnormal signals can arise from both injured axons and intact nociceptors that share the innervation territory of the nerve injury
What is central sensitization primarily triggered by in the context of nociceptive inputs?
- nociceptive inputs, leading to the activation of AMPA and NMDA receptors.
- this activation can result in increased spontaneous activity, a reduction in threshold for activation, and an enlargement of the neuron’s receptive field
What are some of the challenges and issues associated with studying central sensitization?
- complexity of the system
- the involvement of various players like nociceptors peripheral tissue, immune cells, peripheral afferents, descending influences, microglial cells & astrocytes.
- this complexity makes it difficult to unravel the specific cellular & molecular mechanisms and to determine which element is the most fundamental & crucial in central sensitization
How long can central sensitization be maintained once established?
- extremely long periods of time once established, making it a basis for chronic pain
Is there a difference in susceptibility to develop central sensitization among individuals, and what factors may influence this susceptibility?
- Variability in susceptibility to central sensitization can exist among individuals
- this susceptibility may be influenced by genetic & environmental factors
What is the role of the NMDA receptor in central sensitization, and why is it considered important?
- The NMDA receptor (tetramer composed of 2 NR1 subunits and 2 NR2 subunits (A, B, C, or D))
- allows calcium influx and is associated with phosphorylation, which increases the open channel probability and promotes receptor insertion in the membrane
What are the phosphorylation sites on NMDA receptor subunits, and which kinases phosphorylate them?
- Multiple residues on NMDA receptor subunits can be phosphorylated by various kinases, including PKA, PKC, CaMKii, and src.
- Examples incl. Tyrosine1472 and PKA/PKC phosphorylation of the NR1 subunit
Is there a consensus on which NMDA receptor subunit (NR1 or NR2) must be phosphorylated for sensitization, and does it vary with different types of insults?
- disagreement in scientific community on whether NR1 or NR2 subunit phosphorylation necessary for sensitization
- It’s possible that different insults or contexts may involve different subunits.
What is the role of NR2B receptor antagonists in blocking C fiber long-term potentiation (LTP) in the dorsal horn?
- NR2B receptor antagonists can block induction of C fiber LTP in the dorsal horn, demonstrating the presence of these receptors and their involvement in LTP
How does phosphorylation of the NR2B subunit of the NMDA receptor change in the carrageenan model of inflammatory pain?
- Phosphorylation of the NR2B subunit in the carrageenan model of inflammatory pain can vary, with some studies reporting decline in phosphorylation while others show an increase
- role of NR2B phosphorylation in inflammatory pain is complex.
What effect does blocking NR2B phosphorylation with the src inhibitor PP2 have on hyperalgesia?
- Blocking NR2B phosphorylation with the src inhibitor PP2 can also block hyperalgesia
- suggesting a role for this phosphorylation in pain sensitization
Which site on the NR1 subunit is phosphorylated following noxious heat exposure, and by what kinase?
- Following noxious heat exposure, the NR1 subunit is phosphorylated at the PKC-dependent site, serine-896, by PKC kinase
Define peripheral sensitisation
- Increased sensitivity of sensory nerve endings in the periphery
- Often due to tissue injury or inflammation
- Lower threshold for nerve activation
- Amplified response to various sensory stimuli
- Contributes to heightened pain perception & hyperalgesia
