Transcript Slide 1

BDNF Mediates Chronic Pain
Tori Collins
Pain is OK
• Pain has a protective role
• Elicits behavioral responses to minimize tissue
damage
• Hypersensitivity in wounded tissue helps avoid any
contact with the damaged area
• However chronic pain has no biological advantage
Pain
• Neuropathic pain: maladaptive pain resulting from
injury to NS
• Pharmacotherapy largely ineffective
– Treated with antidepressants or anticonvulsants
– Undesirable side effects
– Limited efficacy
Symptoms
•Stimulus-independent pain: shooting, burning
-Spontaneous firing in C fibers
-Disinhibition of dorsal horn neurons
•Stimulus-evoked pain: hyperalgesia, allodynia
•Low-threshold Aβ fibers
•Reduced threshold of peripheral terminals
•Tingling, numbness/loss of sensation
Central Sensitization
• Nociceptive neurons in the dorsal horns of the spinal
cord become sensitized by peripheral tissue damage
or inflammation.
• Neurons are more easily excited (NMDAr).
• A possible mechanism for chronic pain
– NMDA antagonists abolish pain hypersensitivity
Brain-derived neurotrophic factor drives the
changes in excitatory synaptic transmission in
the rat superficial dorsal horn that follow
sciatic nerve injury
Van B. Lu, James E. Biggs, Martin J. Stebbing, Sridhar
Balasubramanyan, Kathryn G. Todd, Aaron Y. Lai,William F.
Colmers, David Dawbarn, Klaus Ballanyi and Peter A. Smith
CCI
• Chronic constriction injury (CCI) of the sciatic
nerve is a model for neuropathic pain
• CCI is associated with an increase in neuron
excitability in the dorsal horn (central
sensitization)
• CCI produces changes in synaptic excitation in
different neuronal phenotypes as characterized
by an electrophysiological signature
• CCI causes release of BDNF from microglia
BDNF
• Sequestration of BDNF decreases pain
behaviors
• Concentration of BDNF is elevated for days
after injury, producing a similar
electrophysiological signature to CCI
• Hypothesis: CCI/BDNF decrease excitation of
inhibitory neurons and increase excitation of
excitatory neurons
Briefly, Methods
• Sciatic nerve of 20-day-old male rats was
subjected to CCI
• Organotypic cultures were made and aged
matched to CCI rats
• Acute and organotypic slices contained
substantia gelatinosae
substantia ge·lat·i·no·sa
• n. “The apical part of the posterior horn of the
gray matter of the spinal cord, composed largely
of very small nerve cells and whose gelatinous
appearance is due to its very low content of
myelinated nerve fibers. It functions in the
integration of sensory stimuli that give rise to the
sensations of heat and pain. Also called Rolando's
gelatinous substance.”
The American Heritage® Medical Dictionary Copyright © 2007, 2004 by Houghton
Mifflin Company. Published by Houghton Mifflin Company. All rights reserved.
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Figure 1
Major populations: tonic islet/central neurons (TIC)-INHIBITORY and radial irregular delay discharge
neurons (RID)--EXCITATORY
Figure 2
Figure 3
Radial delay (RD) neurons in organotypic
slices were compared to RID neurons in
acute slices. TIC and RD are major
populations in the BDNF group.
Figure 4
BDNF’s effects on TIC and RD neurons
Figure 5
• CCI and BDNF produce similar changes in IEI in
both neuronal populations.
• TIC=inhibitory
• RID=excitatory
Figure 5
Figure 6
No significant change in excitability, n=3
Why GAD?
HOOC-CH2-CH2-CH(NH2)-COOH
↓ GAD
CO2 + HOOC-CH2-CH2-CH2NH2
GAD converts glutamate to GABA and CO2
Figure 6
BDNF decreased frequency and amplitude of sEPSCs in
GAD+ cells and increased amplitude in GAD- cells.
Figure 7
• BDNF increases Ca2+ response to K+ challenge
Figure 7
• Microglia activation happens early after
peripheral nerve injury
• If BDNF is responsible, the effect should be
prevented byTrkB-d5
Figure 7
• TrkB-d5 added to organotypic cultures prior to
aMCM exposure or to aMCM itself reduced
the effect of aMCM
Figure 8
• BDNF’s excitatory effect may be due to
disinhibition
• BDNF still increases excitability when GABAA
receptors are blocked
Figure 8
• Ca2+ response should be mediated by
glutamate release
• Glur antagonists reduced Ca2+ response in
BDNF group
Conclusions
• CCI increases excitation of putative excitatory
neurons and decreases excitation of putative
inhibitory neurons
– CCI→loss of excitatory synaptic terminals of nonpeptidergic nociceptive fibers, which associate
with GABAergic neurons→decreased firing
Conclusions
• BDNF and CCI produce a similar pattern of
changes
– However BDNF, not CCI, reduced sEPSC amplitude
in TIC (inhibitory) cells
– Some of the neurons selected in organotypic
cultures may be from cell populations outside
lamina II
• BDNF/CCI effects may reflect increased
contribution of AMPA receptors
Conclusions
• BDNF’s actions in RD (excitatory) neurons
appear to be presynaptic while its actions in
TIC (inhibitory) neurons are both pre- and
postsynaptic
• Some effects may be mediated by TrkB-d5
while others are mediated by p75
Conclusions
• Long-term exposure to BDNF increases overall
dorsal horn excitability
• Activated microglia may be a source of BDNF
– Cl- gradient
• BDNF “necessary and sufficient” for CCI
induced changes that lead to central
sensitization