Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury www.thalamus.

ro

Laura Spinu
Claudiu Barsila
medical students

Dendritic spines
spines, Rac 1
http://www.neuroscience-bucharest.blogspot.com

and Neuropathic Pain after Spinal Cord Injury

MAPK
KII
CaM
1
Tiam
Par3
5
PSD-9 P

GTP

RAC1
+

GDP

RAC1
+

RAC1
MAPK
GDP
kalirin

RAC1
Par3

+ kalirin
+
1

GTP
Tiam
P

+
II K
CaM

5 -9
PSD

www.thalamus.ro
The Thalamus
neuroscience & medicine

2009 C design & concept by C. Barsila & L. Spinu

medical students
This chapter does not intend to be an “authoritative” article. It represents our educational interest in research and also it
represents our interest in medical graphic design. You are not allowed to sell or use these pages or parts of them in any
circumstances. You can use these pages for personal purposes or for educational purposes. If you use these pages please link
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Spinal cord injury and Rac1 .......................... 2

Dendritic Spines and PSD...............................4

Rho family of GTPases.....................................5

Actin regulatory pathways.........................................8

Dorsal horn neuronal network ......................9

Medication in SCI......................................... 12

Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury

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Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury

www.thalamus.ro
Synaptic plasticity Spinal cord injury (SCI) could determine
induced by SCI may dendritic spines remodeling and can contribute to neu-
appear in the spinal ronal hyperexcitability and neuropathic pain through
cord dorsal horn synaptic changes. Synaptic plasticity induced by SCI may
appear in the spinal cord dorsal horn and may contrib-
and may contribute ute to pain maintenance [1,2]. SCI increases Rac1 mRNA
to pain mainte- expression, which remains elevated for up to 3 months
nance [1,2]. [3]. A role of Rac1, in neuropathic pain after SCI is not
studied enough. Rac1 can modulate dendritic spine mor-
phology and function [4, 5]. Andrew M. Tan et al (2008)
applied the Rac1-specific inhibitor NSC23766 in order to
study the effect of synaptic remodeling in neuropathic
pain after SCI. Rac1-specific inhibitor NSC23766 blocks
guanine exchange factors (GEFs), Trio and Tiam1. Inhi-
bition of the Rac1 signaling cascade ameliorated the
Inhibition of the development of abnormal spine morphologies, reduced
Rac1 signaling cas- neuronal excitability, and normalized nociceptive thresh-
cade ameliorates olds. [6] PSD-95 expression is a marker of sites of synapse
plasticity. Expression of PSD-95 is increased significantly
the deve- lopment in injured spinal cord tissue compared with uninjured
of abnormal spine controls [6]. NSC23766 treatment reduces PSD-95 levels
morphologies, below that of uninjured levels . Cortactin levels did not
reduced neuronal significantly change after NSC23766 treatment compared
excitability, and nor- with intact animals.
malized nociceptive Dendritic spine density increases after SCI. In SCI plus veh
animals (0.9% saline), the density of spines significantly
thresholds. [6] shift toward the cell body compared with the spine den-
sity distribution in intact animals. An increase in spine
density and redistribution of spine location relative to the
cell body, and increases in spine length and head diam-
eter after SCI) occurs after SCI in dorsal horn neurons.

Dendritic spine density increases after experimentaly induced

SCI in rats.
Rac1 (Ras-related C3 botulinum toxin substrate 1) is a
small (~21 kDa) GTPase, and is a member of the Rac
subfamily of the family Rho - family of GTPases. It is
encoded by the gene RAC1.
Dendritic spines contain a cytoskeleton composed mostly of
filamentous actin (F-actin) which determines the shape and
stability/motility of spines. Spines have a small amount of
intermediate filaments and microtubules, ellements that are
present in large mumber in the dendritic shaft .
Barbara Calabrese, Margaret S. Wilson and Shelley Halpain Development and
Regulation of Dendritic Spine Synapses, Physiology 21:38-47, 2006

2
 www.thalamus.ro
Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury

Rac1 could be interpreted as critical in maintaining neuro-

pathic pain through its regulation of dendritic spines. WDR
(Wide-Dynamic Range ) neurons exhibit hyperexcitability
in response to evoked-innocuous and noxious stimulation
Recordings were after SCI. Also increased sensitivity to mechanical stimuli
made in the lombar and reduced thermal nociceptive thresholds are found
region of the rat after SCI.
spine, in the deep NSC23766 is specific for Rac1 and does not interfere with
dorsal horn. cdc42 or RhoA-GEF or Rac1 binding to its effector PAK1.
Andrew M. Tan et al (2008) conclude that a post-SCI shift in
the number of mature spines may contribute to the
strengthening of synaptic inputs, enhanced transmission
fidelity, and potentiation of electrical transduction, which
together may lead to a pathological amplification of
sensory information after SCI [6].

Andrew M. Tan et 1 .Woolf CJ, Shortland P, Coggeshall RE (1992) Peripheral

al (2008) conclude nerve injury triggers central sprouting of myelinated affer-
that a post-SCI ents. Nature 355:75–78.
2. Kim BG, Dai HN, McAtee M, Vicini S, Bregman BS (2006)
shift in the number Remodeling of synaptic structures in the motor cortex follow-
of mature spines ing spinal cord injury. Exp Neurol 198:401– 415.
may contribute to 3. Erschbamer MK, Hofstetter CP, Olson L (2005) RhoA, RhoB,
pathological am- RhoC, Rac1, Cdc42, and Tc10 mRNA levels in spinal cord,
plification of sen- sensory ganglia, and corticospinal tract neurons and long-
sory information lasting specific changes following spinal cord injury. J Comp
Neurol 484:224 –233.
after SCI [6]. 4. Nakayama AY, Harms MB, Luo L (2000) Small GTPases Rac
and Rho in the maintenance of dendritic spines and branches
in hippocampal pyramidal neurons. J Neurosci 20:5329
–5338.
5. Wiens KM, Lin H, Liao D (2005) Rac1 induces the clustering
of AMPA receptors during spinogenesis. J Neurosci
25:10627–10636.
6. Andrew M. Tan, Severine Stamboulian, Yu-Wen Chang,
Peng Zhao, Avis B. Hains,2 Stephen G. Waxman, and Bryan C.
Hains, Neuropathic Pain Memory Is Maintained by Rac1-
Regulated Dendritic Spine Remodeling after Spinal Cord
Injury, The Journal of Neuroscience, 28(49):13173–13183 •
13173
Laminae I to IV comprise the dorsal horn and are concerned with somatosensory afferent
signaling. Lamina I and II (superficial dorsal horn, SDH) receive input largely from thinly
myelinated (Adelta) and unmyelinated (C) fibers of thermoreceptors and various nocicep-
tors. Laminae III and IV (deep dorsal horn, DDH) receive their input from more myelinated
(A) fibers that transmit vibration, touch, and pressure. B. A. Graham, A. M. Brichta, and R. J. Callister,
Moving From an Averaged to Specific View of Spinal Cord Pain Processing Circuits, J Neurophysiol 98: 1057-
1063, 2007.

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Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury

www.thalamus.ro
Dendritic spines are small protrusions from neuronal
dendrites that typically receives input from the presynaptic
component of the excitatory synapses in the central
nervous system. They are located on the dendrites. The
most common morphological type is composed of a
There is a potential bulbous head and a thin neck. The head is connected with
the dendrite through the neck. There is a potential relation
relation between between spine shape and synaptic function, since mor-
spine shape and phological rearrangements of spines have been found in
synaptic function, vitro and in vivo [1,2]. In samples of spines from layer 2/3
since morphologi- pyramidal neurons from mouse primary visual cortex,
cal rearrangements using first Golgi impregnations and then gold-toning and
of spines have been serial thin section electron microscopy, no detectable
correlations between spine head volume and spine neck
found in vitro and in length were found [3]. The area of the PSD is correlated to
vivo [1,2]. the spine head volume and neck diameter and it is uncorre-
lated with the spine neck length. In rat, in CA1 pyramidal
cells, the volume of the spine head was reported to be
proportional to the postsynaptic density (PSD) area and
to the number of presynaptic vesicles [4]. The spine neck
length is correlated to the time constant of calcium com-
partmentalization [3] and also proportional to the filtering
of electrical potentials and it may be involved in calcium
The PSD area is dependent learning rules. There is no correlation between
itself proportional head volume and neck length, although there is a weak
to the number of correlation between head volume and neck diameter [3]. In
postsynaptic recep- neocortical pyramidal neurons spines that were further
tors [8]. The volume away from the soma were longer and had larger heads. In
CA1 pyramidal neurons spines located in the distal
of the spine head is
portions of the apical dendrite had larger heads [6]. Similar
likely to be directly effects were found in Golgi-impregnated CA1 pyramidal
proportional to the neurons, albeit not in neocortical pyramidal cells from
average reliability layers 2/3, 4, 5, and 6 [7].
and strength of its In spines from layer 2/3 pyramidal neurons, no significant
synapse. relation was found between distance from the soma and
spine head volume, total spine volume and PSD area. There
is correlation between spine head volume and the area of
the PSD. It may be a correlation between the volume of the
spine head and the synaptic strength or it may be linked to
the release probability [5]. There is no clear correlation
between the spine head volume and spine neck length.
There is a lack of correlation between head volume and
neck length (since the PSD area is correlated with the head
volume) [5]. The PSD area is itself proportional to the
number of postsynaptic receptors [8]. The volume of the
spine head is likely to be directly proportional to the aver-
age reliability and strength of its synapse. CA1 pyramidal
neurons show a larger spine size with increasing distance
from the soma [7, 6], as if synaptic weight is compensating
for the dendritic electrotonic filtering [5].

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Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury

www.thalamus.ro
1. Dunaevsky A, Tashiro A, Majewska A, Mason C, and Yuste R. Develop-
mental regulation of spine motility in the mammalian central nervous
system. Proc Natl Acad Sci USA 96: 13438–13443, 1999
2. Fischer M, Kaech S, Knutti D, and Matus A. Rapid actin-based plasticity
in dendritic spines. Neuron 20: 847–854, 1998.
3. Barbara Calabrese, Margaret S. Wilson and Shelley Halpain, Develop-
ment and Regulation of Dendritic Spine Synapses, Physiology 21:38-47,
2006
4. Harris KM and Stevens JK. Dendritic spines of CA 1 pyramidal cells in the
rat hippocampus: serial electron microscopy with reference to their
biophysical characteristics. J Neurosci 9: 2982–2997, 1989.
5. Jon I. Arellano, Ruth Benavides-Piccione, Javier DeFelipe,and Rafael
Yuste Ultrastructure of dendritic spines: correlation between synaptic and
spine morphologies, Frontiers in Neuroscience. (2007) vol. 1,
iss. 1,131-143
6. Megias, M., Emri, Z., Freund, T. F., Gulyas, A. I. (2001). Total number and
distribution of inhibitory and excitatory synapses on hippocampal CA1
pyramidal cells. Neuroscience 102, 527–540.
7. Konur, S., Rabinowitz, D., Fenstermaker, V., Yuste, R. (2003). Systematic
regulation of spine head diameters and densities in pyramidal neurons
from juvenile mice. J. Neurobiol. 56, 95–112.
8. Nusser, Z., Lujan, R., Laube, G., Roberts, J., Molnar, E., Somogyi, P. (1998).
Cell type and pathway dependence of synaptic AMPA receptor number
and variability in the hippocampus. Neuron 21, 545–559.

Rac and Cdc42 pro- One of the key regulators of the actin cytoskeleton is the
mote neurite out- Rho family of GTPases. The Rho GTPases function as
molecular switches to turn on or off downstream
growth, RhoA
biochemical pathways depending on the stimuli [1]. This
stimulates retrac- GTP-ases are under control of proteins such as the gua-
tion. nine nucleotide exchange factors (e.g.Kalirin-7) and
the GTPase-activating proteins. Rac and Cdc42 promote
neurite outgrowth, RhoA stimulates retraction. The
balance of these opposing activities of the different Rho
GTPases regulates some functions and the morphology of
GTPases functions: neurons.
cell movement and GTPases functions: cell movement and motility, transcrip-
tion, cell growth and proliferation, as well as cell cycle
motility, transcrip-
progression. Members of the Rho Molecules in GTPase
tion, cell growth family have two states: GTP- and GDP-bound states. The
and proliferation, GTPases are inactivated when the bound GTP is hydro-
as well as cell cycle lyzed to GDP. Rho GTPases have intrinsic GTPase activity
progression. but the hydrolysis is slow. The Rho GTPases are normally
present in cytoplasm, kept here by RhoGDI until a stimuli is
applied to the cell. Well known members of Rho GTPases
are RhoA, Cdc42 and Rac1 [1]. The effector proteins down-
stream of Rac1 in lamellipodia formation are mainly the
WAVE subfamily of the WASP proteins. POR1 may also be
involved in this process [2,3,4].

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Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury

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N-WASP mediates the link between Cdc42 and the Arp2/3
proteins in actin polymerization, and participates in the
formation of filopodia [2, 5] . WAVE1 is a downstream
WAVE1 is a down- effector of Rac1. It is responsible for the number of den-
stream effector of dritic spines in the neurons. Phosphorylation of WAVE1 by
Rac1. It is respon- the cyclin-dependent kinase 5 (Cdk5) inhibits WAVE1’s
sible for the activity and thus limits its capacity to regulate Arp2/3-
dependent actin polymerization [1,6] . Cdk5 and its regu-
number of den-
lator p35 have also been shown to interact with both Rac1
dritic spines in the and PAK leading to downregulation of PAK activity [7]. It
neurons. has long been established that the downstream effects of
RhoA and Cdc42/Rac can be antagonistic to one another
in cells [8] . Cdc42 and Rac are required for neurite forma-
It has long been tion while dominant negative Cdc42 and Rac1 have been
found to inhibit neurite outgrowth in N1E115 cells [9].
established that the Strong Rac1 and Cdc42 activities have also been localized
downstream effects to the tips of the growin neurites in PC12 cells stimulated
of RhoA and with nerve growth factor (NGF) [1,10] . The RhoA-induced
Cdc42/Rac can be neurite retraction was found to be mediated by the
antagonistic to one actions of ROK. Studies on primary neurons have also
another in cells . confirmed the findings that Cdc42 and Rac1 generally
enhance neurite formation and outgrowth whereas RhoA
activity inhibits these activities [1]. However, recent data
have indicated that it is the balance of Rho GTPase activi-
ties that is important in the regulation of neurite
Too much or too outgrowth. Too much or too little Rac1 activity reduces
neurite outgrowth.
little Rac1 activity
reduces neurite out- 1 Cheng-Gee Koh, Rho GTPases and Their Regulators in Neuronal
growth. Functions and Development, Neurosignals 2006–07;15:228–237
2 Miki H, Suetsugu S, Takenawa T: WAVE, a novel WASP-family protein
involved in actin reorganization induced by Rac. EMBO J 1998; 17: 6932-
6941.
3 Miki H, Yamaguchi H, Suetsugu S, Takenawa T: IRSp53 is an essential
intermediate between Rac and WAVE in the regulation of membrane
ruffling. Nature 2000; 408: 732–735.
4 Van Aelst L, Joneson T, Bar-Sagi D: Identification of a novel Rac1-
interacting protein involved in membrane ruffling. EMBO J 1996; 15:
3778–3786.
5 Rohatgi R, Ma L, Miki H, Lopez M, Kirchhausen T, Takenawa T, Kirschner
MW: The interaction between N-WASP and the Arp2/3
complex links Cdc42-dependent signals to actin assembly. Cell 1999; 97:
221–231.
6 Kim Y, Sung JY, Ceglia I, Lee K-W, Ahn J-H, Halford JM, Kim AM, Kwak SP,
Park JB, Ho Ryu S, Schenck A, Bardoni B, Scott JD, Nairn
AC, Greengard P: Phosphorylation of WAVE1 regulates actin polymeriza-
tion and dendritic spine morphology. Nature 2006;
442: 814–817

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 Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury
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7 Nikolic M, Chou MM, Lu W, Mayer BJ, Tsai LH: The p35/Cdk5 kinase is a
neuron-specific Rac effector that inhibits Pak1 activity. Nature 1998; 395:
194–198.
8 Kozma R, Ahmed S, Best A, Lim L: The Rasrelated protein Cdc42Hs and
bradykinin promote formation of peripheral actin microspikes and
filopodia in Swiss 3T3 fibroblasts. Mol Cell Biol 1995; 15: 1942–1952.
9 Sarner S, Kozma R, Ahmed S, Lim L: Phosphatidylinositol 3-kinase,
Cdc42, and Rac1 act downstream of Ras in integrin-dependent neurite
outgrowth in N1E-115 neuroblastoma cells. Mol Cell Biol 2000; 20: 158–
172.
10 Aoki K, Nakamura T, Matsuda M: Spatiotemporal regulation of Rac1
and Cdc42 activity during nerve growth factor-induced neurite
outgrowth in PC12 cells. J Biol Chem
2004; 279: 713–719.

These graphics are orienta- 5

tive and represent the 350
pattern found by Andrew M.
spines/10microm. dendrite

et al 2008. For the original

data see Andrew M. Tan,
Severine Stamboulian, Yu-Wen
Chang, Peng Zhao, Avis B. Hains,2 2,5
0
Stephen G. Waxman, and Bryan C.
Hains, Neuropathic Pain Memory
Is Maintained by Rac1-Regulated
Dendritic Spine Remodeling after
Spinal Cord Injury, The Journal of
Neuroscience,28(49):13173-
13183 • 13173 0
0 350

distance from the soma

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 NMDA Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury
www.thalamus.ro

NMDAR
A
MD
N NM
R DA
DA GluR R
NM
hilin
spinop


CaMKII Ca2+
P
PIIa LCF + PSD-95
CaMKII
A 



PS
D-9
5
+ Par3
integrin
SAPAP/GKAP P
P
A
RhoA

A
A

A
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PAK
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PAK PIX + + RAC1

+
GDP
+
R

+
POR 1

Gro
DA

PIIa
Ca2+/Calmodulin RAC1

wt
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LIMK

Fac
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+
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tor
ROCK

R
ece
A P
GK myosin

pto
P/ p70S6K
PA nk
binding activation
SA

r
ha PIX
cofilin
P /S cofilin P
SA K
+
o PA
Pr P
Src myosin IQGAP
P32/CDK5R1 PIP5K
PAK actin polymerisation

+
-
CN/PP2B
debrin binding activation PLD 1
cortactin + MLCK gelsoline
P67 (Phox)
actin polimerisation

TrkB Arp2/3 Ca2+

PAR-6
cell-cell adhesion
ARHGEF6
+ N-WASP
debrin phosphatidic acid level

+ P NADPH oxidase
myosin PARD3 PI3K
MAPK RAC1 aPKCs RAC1
Raf 1
ROS
GDP
GTP
RAC1
+
Par3

+ kalirin kalirin
NF-KB
+

MTOC orientation
1

GTP
Tiam

Tiam 1
P

+
GDP
II K
CaM

cell proliferation
-95

Posh
RAC1
PSD

MEK1/2
IRSp53
CYFIP2
Hspc300
Abl2 WAVE
WAVE genes MLK3
2009 design & concept by C. Barsila & genes MEKK1
L. Spinu NcKAP1
medical students WAVE
MKK4/7 active

JNK1
Arp2/3

genes

Actin regulationg pathways under the control of ionotropic glutamate receptor.

RhoA (activated) interacts with NMDARs. The effect is the activation of the ROCK/PII complex. The
result is a stable actin after ROCK/PII activation. High levels of CA2+ induce CaMKII-dependent phos-
phorylation of spinophilin. This detaches the spinophilin from the actin and sends it to the mem-
brane. Here spinophilin interacts with Lcf. After this interaction Lcf activates RhoA. The actin-severing
activity of cofilin is controlled by different kinases and phosphatases. LIMK has a negative regulator
effect on cofilin activity. Activation of LIMK depends on Rac-1, through its effector - PAK. NMDA stimuli
increases Rac-1 activity (local) through Rac1 - GEFs PIX and Tiam 1 which increases the activity of
cofilin, wich can lead to higher actin turnover rates.
actin regulatory pathways mediated by non-glutamate receptors
Arp2/3 has actin-polymerizing activity. N-Wasp has actin-polymerizing activity. Both of them (Arp2/3
and N-Wasp) depend on cortactin phosphorylation levels. This levels are controlled in a TrkB and Src
dependent manner. Kalirin is recruited and activated to spines by EphB. Kalirin through Rac and PAK
leads to activation of myosin.

actin regulatory proteins in spines. The actin severing activity of cofilin is dependent on the
balance existing between kinases and phosphatases. - LIMK and CN/PP2B. Cofilin binds to actin and
affects the filament structure. At this moment the debrin afinty for actin is lowered. Debrin has a stabi-
lizing effect on actin. Debrin prevents actin reorganization. The reorganization of actin is due to
myosin binding to acting filaments and by interacting with gelsolin. Myosin stabilizes actin and
contracts F-actine. PAK triggers myosin motor activity. Gelsolin caps the barbed ends of actin. In this
way the actin polimerization is possible. This role of gelsolin is Ca2+ dependent.
Vanessa Schubert and Carlos G. Dotti, Transmitting on actin: synaptic control of
dendritic architecture, Journal of Cell Science 120, 205-212

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 Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury
www.thalamus.ro

Laminae I to IV comprise the dorsal horn and are

concerned with somatosensory afferent signaling. They
link the primary afferent neurons and neurons of CNS.
Lamina I and II (superficial dorsal horn, SDH) receive
input largely from thinly myelinated (A-delta ) and unmy-
elinated (C) fibers of thermoreceptors and various noci-
ceptors. Laminae III and IV (deep dorsal horn, DDH)
receive their input from more myelinated (A) fibers that
transmit vibration, touch, and pressure. [1] Connections
between DDH neurons are predominantly unidirectional
with a majority (69%) of these linkages being inhibitory
in rat. Zheng, Lu, and Perl describe a similar proportion
of inhibitory connections in mouse SDH. Safronov’s
recently reported that only 10% of cell pairs were linked
by inhibitory connections, concluding that excitatory
interneurons dominate in rat lamina II [3]. This differ-
ences may have their roots in the methods used.
Safronov used voltage-clamp recordings, suggesting
that Safronov’s procedures may have underestimated
week connectivity. Schneider found that GABA and
glycine are co-transmitters at inhibitory connections
between DDH interneurons. [1,4]

1. Yan Lu, Synaptic Wiring in the Deep Dorsal Horn. Focus on “Local
Circuit Connections Between Hamster Laminae III and IV Dorsal Horn
Neurons” J Neurophysiol 99: 1051–1052, 2008
2. Lu Y, Perl ER. A specific inhibitory pathway between substantia gelati-
nosa neurons receiving direct C-fiber input. J Neurosci 23: 8752–8758,
2003.
3. Santos SF, Rebelo S, Derkach VA, Safronov BV. Excitatory interneu-
rons dominate sensory processing in the spinal substantia gelatinosa of
rat. J Physiol 581: 241–254, 2007.
4. Schneider SP. Local circuit connections between hamster laminae III
and IV dorsal horn neurons. J Neurophysiol doi:10.1152/jn.00962.2007.
Nociceptive peripheral inputs make monosynaptic
connections with projection neurons in lamina I and
interneurons in laminae I and II [1,2]. Projection neurons in
lamina I transmit nociceptive information at higher levels
in CNS. Most SDH neurons (certainly 95%) are local circuit
interneurons and not projection neurons [1,3,4,5]. These
interneurons are excitatory or inhibitory and receive
inputs from higher brain centers and other local interneu-
rons. These interneurons play a crucial role in setting the
overall excitability level [1]. GFP-labeled population of
neurons in mice in the SDH were exclusively GABAergic
and could be activated during noxious peripheral stimula-
tion of C-fibers [1].

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 Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury
www.thalamus.ro

GFP-positive neurons exhibited tonic firing and were

morphologically identified as central neurons, but label-
ing for GABA-ergic neurons and glycinergic neurons dem-
onstrate more variability in firing pattern and in morphol-
ogy - islet neurons and central neurons. [6, 7]. These stud-
ies indicate that, within the two major inhibitory neuron
classes, subpopulations exist with potentially different
roles in SDH function. Inhibitory connections showed a
single configuration, linking islet to central neurons in
lamina II through a monosynaptic GABAergic synapse.
Both pre- and postsynaptic neurons received monosyn-
aptic C-fiber primary afferent input, although the inputs
studied always arrived first at the presynaptic neuron.
Inhibitory connections were always islet to central [1]. The
central and lamina I neurons receive C-fiber primary affer-
ent input, whereas vertical neurons received A delta-fiber
input. The connection pattern seems to be - central
neuron to vertical neuron and vertical to projection. The
central neuron is common in islet to central neuron circuit
and to the excitatory circuit. [1]

1. B. A. Graham, A. M. Brichta, and R. J. Callister, Moving From

an Averaged to Specific View of Spinal Cord Pain Processing
Circuits, J Neurophysiol 98: 1057–1063, 2007.
2. Light AR, Perl ER. Re-examination of the dorsal root projec-
tion to the spinal dorsal horn including observations on the
differential termination of coarse and fine fibers. J Comp
Neurol 186: 117–131, 1979
3. Polgar E, Hughes DI, Riddell JS, Maxwell DJ, Puskar Z, Todd
AJ. Selective loss of spinal GABAergic or glycinergic neurons
is not necessary for development of thermal hyperalgesia in
the chronic constriction injury model of neuropathic pain.
Pain 104: 229–239, 2003.
4. Spike RC, Puskar Z, Andrew D, Todd AJ. A quantitative and
morphological study of projection neurons in lamina I of the
rat lumbar spinal cord. Eur J Neurosci 18: 2433–2448, 2003.
5. Willis WD, Coggeshall RE. Sensory Mechanisms of the
Spinal Cord. New York: Kluwer Academic/Plenum Publishers,
2004.
6. Heinke B, Ruscheweyh R, Forsthuber L, Wunderbaldinger
G, Sandkuhler J. Physiological, neurochemical and morpho-
logical properties of a subgroup of GABAergic spinal lamina
II neurones identified by expression of green fluorescent
protein in mice. J Physiol 560: 249–266, 2004.
7. Zeilhofer HU, Studler B, Arabadzisz D, Schweizer C, Ahmadi
S, Layh B, Bosl MR, Fritschy JM. Glycinergic neurons express-
ing enhanced green fluorescent protein in bacterial artificial
chromosome transgenic mice. J Comp Neurol 482: 123–141,
2005.

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www.thalamus.ro
The dorsal horn neuropil There is a particular inhibitory connection between two
is a region of complex kinds of SG neurons that is related to primary afferent
synaptic interactions that C-fiber input. . Both neurons of this circuit are located
mediates convergence near the interface between laminae IIo and IIi. The presyn-
from many sensory aptic element seems to be the islet type of SG neurons.
inputs. The extent to These islet cells send a monosynaptic inhibitory projec-
which any connection tion to a nearby neuron whose features match those of
specificity between the transient type of central neuron. The finding that both
mechanosensory afferent the presynaptic islet cell and postsynaptic central cell
systems and central neu- receive monosynaptic connections from different
rons is preserved by the segments of the primary afferent C-fiber spectrum, is
intrinsic dorsal horn significant. This circuit implies that afferent input from
circuitry is unknown. An one part of the C-fiber spectrum, through excitation of
unusually high incidence islet cells, inhibits neurons receiving excitatory input from
of connections by inhibi- a different subset of primary afferent C-fibers.
tory interneurons was
found and these connec- Yan Lu and Edward R. Perl, A Specific Inhibitory Pathway between
tions involve multiple Substantia Gelatinosa Neurons Receiving Direct C-Fiber Input, 2003 •
23(25):8752– 8758
types of neurons in many
combinations.

C fiber

islet cell Adelta fiber

other cellular types vertical cell

C fiber

lamina I
excitatory
inhibitory
neurons neuron
projection
neuron

vertical
neuron
descending excitatory small C fiber
inputs neuron islet cells
lamina II 0
transient large C fiber
neuron

lamina II i excitatory
neuron

inhibitory islet cells

neurons

vertical transient
neuron
neuron
excitatory
projection
neuron
neuron

Spinal lamina II (substantia gelatinosa) neurons plays an important role in process-

ing of nociceptive information from primary afferent nerves. Anatomical studies
suggest that neurons in the outer (lamina IIo) and inner (lamina IIi) zone of lamina II
receive distinct afferent inputs.
11
 Dendritic Spines, RAC 1 and Neurophatic Pain after Spinal Cord Injury
www.thalamus.ro

First-line Medications for Neuropathic Pain

Medication Beginning Dosage Titration Maximum Dosage Duration of Adequate Trial

Gabapentin 100-300 mg every night or Increase by 100-300 mg 3600 mg/d (1200 mg 3-8 wk for titration plus
100-300 mg 3 times daily 3 times daily every 1-7 d 3 times daily); reduce if 1-2 wk at maximum
as tolerated low creatinine clearance tolerated dosage
5% Lidocaine patch Maximum of 3 patches daily None needed Maximum of 3 patches daily 2 wk
for a maximum of 12 h for a maximum of 12 h
Opioid analgesics* 5-15 mg every 4 h After 1-2 wk, convert total No maximum with careful 4-6 wk
as needed daily dosage to titration; consider
long-acting opioid evaluation by pain
analgesic and continue specialist at dosages
short-acting medication exceeding 120-180 mg/d
as needed
Tramadol hydrochloride 50 mg once or twice daily Increase by 50-100 mg/d in 400 mg/d (100 mg 4 times 4 wk
divided doses every 3-7 d daily); in patients older
as tolerated than 75 y, 300 mg/d
in divided doses
Tricyclic antidepressants 10-25 mg every night Increase by 10-25 mg/d 75-150 mg/d; if blood level 6-8 wk with at least 1-2 wk
(eg, nortriptyline every 3-7 d as tolerated of active drug and its at maximum tolerated
hydrochloride or metabolite is 100 dosage
desipramine ng/mL, continue titration
hydrochloride) with caution

*Dosages given are for morphine sulfate. !! do not self-medicate. consult a specialist befor taking any medication. !!
Robert H. Dworkin et al, Advances in Neuropathic Pain Diagnosis, Mechanisms, and Treatment Recommendations ,
Arch Neurol. 2003;60:1524-1534

Dextromethorphan may be Pregabalin, like gabapentin, was shown to be effective

used as a Preventive Treatment
in several models of neuropathic pain [1,2,3,4], incisional
for Neuropathic Pain after SCI
injury , inflammatory injury , and formalin-induced injury
[1]. It is also effective in the treatment of anxiety, and is
also a sleep-modulating drug [1]. Pregabalin increases
the duration of nonrapid eye movement and also
decreases rapid eye movement sleep in rats [5]. Its main
site of action appears to be on one subunit of presynap-
tic, voltagedependent calcium channels [6]. Pregabalin
produce an inhibitory modulation of neuronal excitabil-
ity , particularly in areas of the central nervous system
dense in synaptic connections. [7,8,9]. In contrast to vera-
pamil (Dihydopyridines) , pregabalin has no effect on
arterial blood pressure or cardiac function. [1]

1.Noor M. Gajraj, Pregabalin: Its Pharmacology and Use

in Pain Management,Anesth Analg 2007;105:1805–15
2.Partridge B, Chaplan S, Sakamoto E, Yaksh T. Characterization of the effects of
gabapentin and 3-isobutyl- -aminobutyric acid on substance P-induced
thermal hyperalgesia. Anesthesiology 1998;88:196–205
3. Jun J, Yaksh T. The effect of intrathecal gabapentin and 3-isobutyl aminobu-
tyric acid on the hyperalgesia observed after thermal injury in the rat. Anesth
Analg 1998;86:348–54
4. Nozaki-Taguchi N, Chaplan SR, Higuera ES, Ajakwe RC,
Yaksh TL. Vincristine-induced allodynia in the rat. Pain
2001;93:69–76
5.Kubota T, Fang J, Meltzer LT, Krueger JM. Pregabalin enhances nonrapid eye
movement sleep. J Pharmacol Exp Ther 2001;299:1095–105
6.Belliotti T, Capiris T, Ekhato I, Kinsora J, Field M, Heffner T, Meltzer L, Schwarz J,
Taylor C, Thorpe A, Vartanian M, Wise L, Zhi-Su T, Weber M, Wustrow D.
Structure-activity relationships of pregabalin and analogues that target the
alfa(2)-delta protein. J Med Chem 2005;48:2294–307
7. Chizh BA, Gohring M, Troster A, Quartey GK, Schmelz M, Koppert W. Effects of
oral pregabalin and aprepitant on pain and central sensitization in the electri-
cal hyperalgesia model in human volunteers. Br J Anaesth 2007;98:246–54
8. McClelland D, Evans R, Barkworth L, Martin D, Scott R. A study comparing the
actions of gabapentin and pregabalin on the electrophysiological properties of
cultured DRG neurones from neonatal rats. BMC Pharmacology 2004;4:14
9. Hill D, Suman-Chauhan N, Woodruff G. Localization of
12 [3H]gabapentin to a novel site in rat brain: autoradiographic studies. Eur J
Pharmacol 1993;244:303–9
 or.sumalaht.www
Inhibition of Rho or Rho-kinase,
downstreameffector of Rho,
promotes axon regeneration in
vivo. These findings establish
Rho and Rho-kinase as key play-
ers in inhibiting the regenera-
tion of the central nervous
system, and launched a new
wave of studies that aim to
promote regeneration of injured
axons by modulating this inhibi-
tory pathway.
Tanaka H, Yamashita T, Yachi K,
Fujiwara K, Yoshikawa K, and
Tohyama M (2004) Cytoplasmic
p21Cip1/WAF1 enhances axonal
regeneration and functional
recovery after spinal cord injury in
rats. Neurosci 127, 155-164.

Protein kinase C-related kinase 1 (PRK1 or PKN) is involved in regulation of the intermediate
filaments of the actin cytoskeleton, as well as having effects on processes as diverse as mitotic
timing and apoptosis.
Modha R, Campbell LJ, Nietlispach D, Buhecha HR, Owen D, Mott HRThe Rac1 polybasic region
is required for interaction with its effector PRK1J. Biol. Chem. v283, p.1492-1500

13

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2009 C design & concept by C. Barsila & L. Spinu
medical students