Chronic Pain Flashcards
What is pain?
an unpleasant sensory emotional experience associated with actual or potential tissue damage, or described in terms of such damage
What is the dorsal root ganglion (DRG)?
afferent senesory neurons, fron neck –> tailbone
Describe the myelination status, if the neuron perceives proprioception or nociception, and if it is a “large light” or “small dark” primary afferent neuron: A(alpha) and A(beta) fibres; A(delta) fibre; C fibre
A(alpha) and A(beta): myelinated (conduct impulses quickly), proprioceptive, large light
A(delta): lightly myleinated, small dark, nociceptive
C: unmyelinated, small dark, nociceptive
For the following sensory fibres, where do they project in the dorsal spinal column: A(beta), A(delta), C. What do the interneurons connect to, what’s the purpose of this structure?
A(beta): project to deep lamina (III, IV, V)
A(delta): project to superifical (I, II) and deep (V)
C: project to superifical (I, II)
interneurons connect II to WDR
WDR = wide dynamic range; gating mechanisms; gets various kinds of inputs
Does pain on your right side get processed in your right or left brain?
left - pain is processed on the contraleteral side
What are the two major pathways from the spinal cord to the brain? What is the pathway from the brain to the spinal cord?
spinal cord to brain:
1. spinoreticular tract
2. spinothalamic
brain to spinal cord:
1. PAG –> RVM –> dorsal horn
Describe two modes of sensitization. What is the purpose of sensitizing pain? Does sensitization occur in the periphery or central?
- hyperalgesia: signals are amplified (e.g. hit your thumb the first time –> ow; hit your thumb the second time –> OWWW)
- allodynia/paradoxical pain: responses to previously innocuous stimuli may emerge; (alpha)(beta)/AB now being active
purpose = protective function
sensitization can occur in both the PNS and CNS
What main immune cells are involved in pain, how do they function?
ICs: mast cells, T cells, and macrophages
- produce and secrete inflammatory and growth factors
- cytokines: IL-1B, IL-6, IL-17, NGF (impact sensitivity of nociceptors)
- can affect neuronal activity directly or indirectly
How does PKA activation affect neuronal sensitivity?
activation of PKA –> sensitization
phosphorylates NA+ channels –> channel stays open for longer –> larger APs –> increased pain
Describe how macrophages can potentiate sensitization?
macrophages infiltrate into the DRG and produce TNFs and IL-1B –> sensitivity
How does IL-1B affect nociceptor excitability in the periphery (3)?
- changes AP threshold
- increases AP output
- increases AP frequency
Describe normal pain transmission vs sensitization in the CNS
normal
- normal EAA (excitatory amino acid) release
- activation of AMPARs (glutimate R; ion channel)
- NMDARs (glutumate R) “silent” due to Mg2+ block (needs more stimulus to remove Mg2+)
sensitizated
- enhanced EAA release (pre-synaptic)
- recruitment of NMDARs (post-synaptic)
- Ca2+ entry: phosphorylation of PKA/PKC (now active) –> phosphorylate NMDARs –> more sensitive (ACUTE)
- Ca2+ entry: gene transcription –> more Rs (LONG TERM)
- reduced threshold & larger output
Describe the classical view of CNS immune cells (glial cells) vs the new view
classical
- “glue” of the CNS – keeps neurons in place
- mediators of homeostasis that “listen” to neurons
- increase responsiveness to pertubations – become “reactive”
new
- now acknowledge as capable of “talking” to neurons
Why does ATP activate microglia?
extracellular ATP is a DAMP
What can prevent the proliferation and activation of glial cells?
metabolic inhibitors – e.g. flurocitrate and minocycline
Describe CSF-1 levels in the dorsal horn after PNI
injured sensory neurons express CSF-1 –> CSF-1 is transported to spinal cord –> CSFR-1 is exclusively expressed by microglia in the spinal dorsal horn
What do glial cells produce in response to injury/disease?
cytokines and BDNF
How do afferent (pre-synaptic) neurons activate microglia?
- CCL21, CCL2, CX3CL1
- ATP
- CSF-1 (most critical)
Descrobe how microglia derived factors lead to disinhibition and pain: compare and contrast normal to pathological states
normal
- KCC2 is a K+-Cl- exchanger
- KCC2 extrudes Cl- –> intracellular [Cl-] is low
- GABA binding –> influx of Cl- –> inhibition
pathological
- microglia derived BDNF lowers KCC2 –> intracellular [Cl-] increases
- GABA binding –> efflux of Cl- –> disinhibition
When can neuropathic pain develop in life, what is it dependent on?
the emergence of NeP phenotype correlaes with the maturation of the IS, especially dependent on T cells
Describe the sexual dimorphic aspect of pain: which sex is more sensitive to pain, why?
males are more sensitive –testosterone + functional TLR4 –> allodynia
