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Transcript
Annals of Anatomy 193 (2011) 347–353
Contents lists available at ScienceDirect
Annals of Anatomy
journal homepage: www.elsevier.de/aanat
Effects of activity-dependent strategies on regeneration and plasticity after
peripheral nerve injuries
Esther Udina a,b , Stefano Cobianchi a,b , Ilary Allodi a,b , Xavier Navarro a,b,∗
a
Group of Neuroplasticity and Regeneration, Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology,
Universitat Autònoma de Barcelona, Bellaterra, Spain
b
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain
a r t i c l e
i n f o
Article history:
Received 9 December 2010
Received in revised form 14 February 2011
Accepted 24 February 2011
Keywords:
Exercise
Nerve regeneration
Neuropathic pain
Reinnervation
Spinal reflexes
Treadmill
s u m m a r y
Peripheral nerve injuries result in loss of motor, sensory and autonomic functions of the denervated limb,
but are also accompanied by positive symptoms, such as hyperreflexia, hyperalgesia and pain. Strategies
to improve functional recovery after neural injuries have to address the enhancement of axonal regeneration and target reinnervation and also the modulation of the abnormal plasticity of neuronal circuits. By
enhancing sensory inputs and/or motor outputs, activity-dependent therapies, like electrostimulation or
exercise, have been shown to positively influence neuromuscular functional recovery and to modulate
the plastic central changes after experimental nerve injuries. However, it is important to take into account
that the type of treatment, the intensity and duration of the protocol, and the period during which it is
applied after the injury are factors that determine beneficial or detrimental effects on functional recovery. The adequate maintenance of activity of neural circuits and denervated muscles results in increased
trophic factor release to act on regenerating axons and on central plastic changes. Among the different
neurotrophins, BDNF seems a key player in the beneficial effects of activity-dependent therapies after
nerve injuries.
© 2011 Elsevier GmbH. All rights reserved.
1. Introduction
Peripheral nerve injuries result in loss of motor, sensory and
autonomic functions in the denervated territory. Moreover, as a
consequence of the nerve injury positive symptoms also appear,
such as hyperreflexia, due to enhanced spinal motor responses,
and hyperalgesia and pain, influenced by plastic changes of afferent projections in the spinal cord, in addition to the development
of distorted central somatotopic maps of the reinnervated regions
(Lundborg, 2003; Navarro et al., 2007). The functional loss can
be recovered if injured axons grow into the distal stump and
reestablish functional connections with appropriate peripheral target organs. The degree of reinnervation primarily depends on the
severity of the injury, related to length of nerve disruption and misalignment of nerve stumps, and on the repair procedure applied
(Valero-Cabré and Navarro, 2002). The ultimate goal of peripheral
nerve repair is an effective functional recovery, which requires a
sufficient amount of regenerated axons, but also appropriate tar-
∗ Corresponding author at: Facultat de Medicina, Universitat Autònoma de
Barcelona, E-08193 Bellaterra, Spain. Tel.: +34 935811966; fax: +34 935812986.
E-mail address: [email protected] (X. Navarro).
0940-9602/$ – see front matter © 2011 Elsevier GmbH. All rights reserved.
doi:10.1016/j.aanat.2011.02.012
get reinnervation, and restitution of adequate central connectivity
in spinal circuits.
Various forms of exercise training are used in rehabilitation medicine to help maintaining muscle properties during
denervation or paralysis and to promote functional recovery
after neural injuries and in neurodegenerative diseases. During
the regeneration-reinnervation period, enhanced sensory inputs
and/or motor activity by means of electrostimulation or exercise
have been shown to positively influence the neuromuscular functional outcome after experimental nerve injuries (Al-Majed et al.,
2000; Asensio-Pinilla et al., 2009; Marqueste et al., 2004; Vivo
et al., 2008). Furthermore, activation of sensory afferents via electrical stimulation can result in modulation of spinal reflex circuits
(Vivo et al., 2008) and amelioration of neuropathic pain (Nam
et al., 2001; Sun et al., 2004). Intensive programs of sensory reeducation after nerve injury can improve tactile discrimination
and threshold perception, although this effect may wane after
cessation of training (Shieh et al., 1998). Combined rehabilitation of motor and sensory functions by passive or active exercise
programs may eventually lead to a better coordination of sensorymotor tasks and restoration of adequate circuitry at the spinal level.
This review is focused on the effects of activity-dependent treatments, particularly exercise training, on peripheral nerve function
348
E. Udina et al. / Annals of Anatomy 193 (2011) 347–353
Table 1
Summary of activity-induced effects in animal models of peripheral nerve injuries.
Activity
Injury
Duration
Nerve regeneration
Swimming
SNC
3d
↑ Axonal growth
Collateral sprouting
25 m/d, 7 wk
Wheel running
Treadmill running
Intact
2 h/d, 3–6 wk
1–2 h/d, 4–6 wk
3, 7 or 28 d
↓ Reinnervation
↑Reinnervation
↓MAG, ↑PKA
↑BDNF, GAP-43, CREB
SNC
3, 7 d
SNF
17/34 wk
↑Regeneration
↑BDNF, NT3, GAP-43
↑Degeneration in
tibialis a. (2 wk),
↑Regeneration in
soleus muscle
(8–12 wk)
L4T, L5T
8 h/d, 4 wk
LGST
30 or 90 d
↑Contraction
Intact
1 h/d, 4 wk
9 h, 1–7 wk
PNTR
CCI
L4T
3 h/d, 10 wk
1 h/d, 1 wk
1 h/d, 8 wk
10 wk pre-injury
↑BDNF, NT4, TrkB
↑Sprouting ↑ Fiber type
change
↑ CNAPs
↑ Regeneration
L4T, L5T
8 h/d, 3–28 d
SNC
1–2 h/d, 2–6 wk
1 h/d, 14 d
SNTR
1 h/d, 4 wk
20 m/d, 2 wk
60 m/d, 2 wk
1 h/d, 4 wk
Bicycle training
Mechanical
stimulation
PNC
2 h/d, 4 d
SNTR
1 h/d, 4 wk
FcTR
Daily, 8 wk
MTR
DCNT
2 wk
Neuropathic pain
Reference
↓ Allodynia 5–7 wk
Gutmann and Jakoubek
(1963)
Hutchinson et al.
(2004)
Herbison et al. (1974)
Ghiani et al. (2007);
Gomez-Pinilla et al.
(2002)
Molteni et al. (2004);
Ying et al. (2005)
Irintchev and Wernig
(1987)
↓Sprouting in tibialis a.
muscle
↑ MU enlargement
Tam et al. (2001)
Seburn and Gardiner
(1996)
Skup et al. (2002)
Wernig et al. (1991)
↓ Allodynia; ↑Allodynia
↑Sprouting in plantaris,
↓in solueus
↓ Sprouting and
Schwann cells bridging
↑Type II fibers in
plantaris muscle
↑ DRGs neurite growth,
Schwann cells
proliferation, ↑GAP-43
↑ Regeneration and
reinnervation
↑Axonal elongation
and sprouting
↑Axon elongation but
not sprouting
↑Regeneration and
reinnervation
↑ Sprouts and
reinnervation
↑Regenerated axons
and reinnervation
↑ Reinnervation
Marqueste et al. (2004)
Cobianchi et al. (2010)
Gardiner et al. (1984)
Tam and Gordon
(2003)
Herbison et al.
(1980a,b)
Seo et al. (2009)
↑Sensory recovery
Asensio-Pinilla et al.
(2009)
Sabatier et al. (2008)
Sabatier et al. (2008)
↓H-reflex excitability
Udina et al. (2011)
↓H-reflex excitability
Pachter and Eberstein,
(1989)
Udina et al. (2011)
Angelov et al. (2007)
No effect
↑Sprouting nociceptive
fibers
↑Sensitivity
Sinis et al. (2008)
Nixon et al. (1984)
Injury: SNC: sciatic nerve crush; SNF: sciatic nerve freezing; L4T: spinal L4 root transection; L5T: spinal L5 root transection; LGST: lateral gastrocnemius-soleus nerve
transection; PNTR: peroneal nerve transection and repair; CCI: chronic constriction injury of sciatic nerve; SNTR: sciatic nerve transection and repair; PNC: peroneal nerve
crush; FcTR: facial nerve transection and repair; MTR: median nerve transection and repair; DCNT: dorsal cutaneous nerve transection. Duration: m: minutes; h: hours; d:
days; wk: weeks. Others: ↑: enhancement or increase; ↓: reduction or decrease; MU: motor units; CNAPs: compound nerve action potentials; DRGs: dorsal root ganglia.
and regeneration and on plastic changes in spinal circuits (see
Table 1).
2. Effects of exercise training on neuromuscular function
Peripheral nerve lesion or spinal cord injuries induce inactivation and subsequent paralysis of affected skeletal muscles.
Denervation or disuse leads to a progressive atrophy of skeletal
muscles, with marked loss of muscle mass, decreased crosssectional area of muscle fibers and changes in the mechanical and
biochemical muscle characteristics (Boudriau et al., 1996; Gordon
and Mao, 1994; Marqueste et al., 2006). These adaptations are most
evident in muscles predominantly of slow-twitch, which show the
highest rate of recruitment during normal activity. Amongst the
fast-twitch muscles, the ones that are normally more active (e.g.,
extensors versus flexors in the hind limb) are also more affected by
inactivity (Roy et al., 1999). In general, slow muscles become faster
and fast muscles become slower following disruption of their nerve
supply (Pette and Staron, 2001). Reinnervation of a previously
denervated muscle partially restores its phenotype, indicating the
importance of neural activity in the maintenance of muscle fiber
types (Wang et al., 2002).
However, activity is not the only factor that influences the quality of the muscle. Alterations in the muscle are more marked after
peripheral nerve injuries than after spinal cord lesions (Roy et al.,
2002). The disruption of the neuromuscular unit after nerve lesion
leads to the loss of both activity-dependent and -independent neural influences on the muscle.
E. Udina et al. / Annals of Anatomy 193 (2011) 347–353
Artificially maintaining muscle activity during denervation/paralysis may improve neuromuscular rehabilitation.
Electrostimulation of denervated muscle, passive exercise and
locomotion training have been shown to be effective strategies in
retarding muscle atrophy and improving contractile response after
reinnervation (Eberstein and Pachter, 1986; Hennig and Lomo,
1987; Marqueste et al., 2004; Pachter and Eberstein, 1989; Soucy
et al., 1996). In contrast to inactivity, increased neuromuscular
activity or overloading (increased load to a muscle induced by
surgical ablation of synergistic muscles) elicits fiber type transition from fast to slow (Pette, 2002). Muscle activity induced by
stimulation may result in an autocrine release of trophic factors,
thus avoiding the disuse effect following nerve or central lesions
(Goldspink and Yang, 2001; McKoy et al., 1999). Muscle fibers are
also capable of adjusting their phenotypic properties in response
to muscle or nerve electrical stimulation (Marqueste et al., 2006;
Pette and Vrbova, 1992), static stretching (Sakakima and Yoshida,
2003) and also to exercise (Booth and Thomason, 1991). To this
respect, it was suggested that induced activity mimicking physiological motion would produce better preservation/recovery of
muscle functional properties than conventional electrical stimulation (Marqueste et al., 2004, 2006). However, both forced exercise
and electrical stimulation of the injured nerve had positive effects
in promoting muscle reinnervation after nerve injury in rats
(Asensio-Pinilla et al., 2009). Rather than the amount of electrical
activity received, the effects seem to be mainly influenced by
shortening or lengthening of the muscles (Gordon and Pattullo,
1993; Gordon et al., 2004).
3. Effects of exercise on peripheral nerve regeneration
An overview of the literature shows conflicting evidence on
beneficial and deleterious effects of exercise on peripheral nerve
regeneration and muscle reinnervation. Variations in the type of
nerve injury, the exercise applied, time and intensity of training
appear to be the main factors explaining the controversial results
reported.
The amount and intensity of training play a key role in the positive effects of exercise after nerve injury. Hines (1942) reported
beneficial results of daily running in a wheel only during the period
of denervation, as trained rats showed a slightly but consistent
increase in muscle mass and isometric muscle strength. Gutmann
and Jakoubek (1963) found an early (3 days) increase in the axonal
growth rate after bilateral sciatic nerve crush in rats forced to swim
compared with that of sedentary controls. Nevertheless, long term
hyperactivity induced by tenotomy (tendon section) of synergist
muscles (Herbison et al., 1973), intensive swimming (Gutmann
and Jakoubek, 1963; Herbison et al., 1974), or treadmill running
(Herbison et al., 1980a,b) for 2–6 weeks after crush lesion of the
sciatic nerve in rodents tended to show deleterious effects on muscle function recovery. On the other hand, mice running voluntarily
after their sciatic nerves were cut and re-sutured, initially demonstrated a delayed reinnervation, whereas at later stages postlesion
nerve maturation was improved (Badke et al., 1989). Voluntary running produced a decreased weight and force in extensor digitorum
longus muscles but an increased force and weight in soleus muscles
(Irintchev et al., 1990, 1991). These changes are typical of endurance
training and could be interpreted as beneficial. Consistent with
these observations, van Meeteren et al. (1997a) reported beneficial
effects of exercise training, in the form of voluntary static standing
on both hindpaws, on the recovery of motor and sensory functions
during the early phase of reinnervation after sciatic nerve crush.
After 10 weeks of standing exercise (van Meeteren et al., 1997a)
or treadmill training (Marqueste et al., 2004) fast nerve fibers
increased in proportion and improved their conduction velocity. In
mice, continuous moderate or intermittent high-intensity training
349
promote axonal elongation after autograft repair (Sabatier et al.,
2008). Besides, low but not high intensity treadmill training potentiates Schwann cell proliferation in the regenerating sciatic nerve
in rats (Seo et al., 2009).
It can be hypothesized that, when initiated in the denervation
phase, moderate exercise results in accelerated functional sensorimotor recovery, because exercise might be beneficial for axonal
outgrowth, nerve maturation, and recovery of muscle contractile
properties, whereas forced intense exercise tends to have a detrimental effect, especially on muscle function, and overwork may
even damage partially denervated muscles (Herbison et al., 1973;
Irintchev et al., 1991; van Meeteren et al., 1997a). It is important
to note that, in most of the studies on laboratory rodents, these
were submitted to exercise from 3 to 5 days after nerve lesion, to
avoid possible damage to the sutured nerve, and also due to the
lack of clear evidence that exercise is beneficial at very early stages
of regeneration.
Little is known about the possible differential effects of passive, voluntary or forced exercise paradigms, differences that might
affect the interpretation of results. Swimming and treadmill running increase physical activity, but may not merely represent
physical overload, and, stress-related changes influence the results
of training experiments (van Meeteren et al., 1997b). Some studies
have shown that passive exercise of the denervated muscle before
their reinnervation preserves the structure of the end-plates and
enhance reinnervation (Pachter and Eberstein, 1989). In contrast,
continuous passive motion of the hindlimb after tibial nerve section did not influence nerve regeneration, when this treatment was
performed only during the first 14 days after injury (Kim et al.,
1998). Recently, it has been demonstrated that daily brief manual
stimulation (5 min/day for 2 months) of whisker pad muscles following section and repair of the pure motor facial nerve resulted
in improved restoration of facial movements (whisking) and a
reduction in motor endplate poly-innervation (Angelov et al., 2007;
Guntinas-Lichius et al., 2007), indicating that activation of the intact
sensory afferents could enhance motor regeneration. However, the
same procedure did not influence the recovery, the degree of axonal
sprouting or the extent of polyinnervation of motor endplates when
applied to the mixed median nerve injured in the forelimb (Sinis
et al., 2008).
In a recent study, both passive and active exercise produced similar slight improvement in regeneration of the rat sciatic nerve,
as indicated by increased recovery of compound muscle action
potentials (CMAPs) a higher number of regenerated axons in the
distal nerve, and a reduction in the increased excitability of spinal
reflexes after nerve injury (Udina et al., 2011). Interestingly, there
were differences in the recovery of flexor (gastrocnemius) and
extensor (tibialis anterior) muscles depending on the type of exercise. Treadmill walking prevented hyperreflexia in both muscles,
whereas, with passive cycling, it was only observed in the gastrocnemius muscle (Fig. 1). Cycling mainly acts by alternating
lengthening and shortening of the triceps surae (Houle et al.,
1999), whereas in active running, both extension and flexion of
the ankle are alternated by the animal. The differential effects of
exercise training on different muscle responses have been also
reported in spinalized animals (Roy et al., 1998, 2005). On the
other hand, cycling exercise is able to prevent muscle atrophy after
spinal cord lesion but not the transition of soleus myofibers from
slow to fast (Houle et al., 1999), whereas treadmill training prevents both atrophy and conversion of myofiber type (Roy et al.,
1999).
Regarding the mechanisms of action, Molteni et al. (2004) found
that dorsal root ganglia (DRG) neurons exhibited increased neurite outgrowth when cultured from animals that had undergone
3 or 7 days of exercise compared with sedentary animals; neurite
length in culture directly correlated with the distance that animals
350
E. Udina et al. / Annals of Anatomy 193 (2011) 347–353
Fig. 1. Plots of the recovery of compound muscle action potential (M wave) amplitude (top), and of the H/M ratio (ratio between the amplitude of the H reflex wave
and the amplitude of the direct M wave after electrical nerve stimulation; bottom)
of the tibialis anterior muscle after sciatic nerve transection and suture repair in the
rat. One group received treadmill training at 5 m/min and another group received
cycling exercise at 45 rpm, matching the number of step cycles in both activities.
Note the increased levels of reinnervation in the late phase and the reduction of
hyperreflexia during early phase of reinnervation (modified from Udina et al., 2011).
ran. DRGs from exercised animals had higher levels of BDNF, NT3,
and GAP43 mRNAs than DRGs from sedentary animals. Inhibition
of Trk neurotrophin receptor activity before exercise attenuated
the exercise-dependent increase in neurite growth, indicating that
activation of neurotrophin signaling pathways during exercise
plays a critical role in promoting plasticity and growth of neurons.
Moreover, exercise significantly decreased the levels of myelinassociated glycoprotein (MAG), a potent axonal growth inhibitor,
suggesting that downregulation of MAG is part of the mechanism through which exercise reduces growth inhibition (Ghiani
et al., 2007). This effect was suppressed by blocking the action
of BDNF during exercise, suggesting a potential role of BDNF in
mediating the effects of exercise on axonal growth (Chytrova et al.,
2008).
4. Effects of exercise on motoneurons and reflex motor
responses
Spinal motoneurons are sensitive to increased chronic activity and respond with phenotypic changes, which influence the
manner in which these cells behave during voluntary recruitment (Gardiner et al., 2006). Motoneurons can adapt several
functional relevant properties without losing the phenotype that
designate them as fast or slow motoneurons. Some adaptations
seem designed to have functional consequences during endurance
exercise (increased capacity for axonal transport and for neurotransmitter release). Intense or mild endurance training in rats
cause biophysical changes, such as hyperpolarized resting membrane potential and voltage threshold, and increase amplitude of
afterhyperpolarization (Beaumont and Gardiner, 2003). This hyperpolarization may reduce the level of excitability for prolonged
inputs. It is thus possible that exercise adapts motoneurons to a
lower state of excitability. Although reflex responses evoked during
voluntary contractions are potentiated following strength training,
the corresponding H reflexes (i.e., the reflex response evoked by
electrical stimulation of sensory afferents) and the F responses (late
response induced by antidromic electrical stimulation of motor
axons) at rest are not, suggesting that changes in intrinsic motoneuronal excitability are not involved in these responses (Sale et al.,
1983).
Changes in spinal reflexes persist after nerve injury and reinnervation, and may impair motor unit activation and control
of movement, accounting in part for the poor clinical outcome
achieved after severe nerve injuries (Valero-Cabré and Navarro,
2001). Forcing the activity of the injured neurons, by either passive or active exercise, decreases the hyperreflexia observed after
peripheral nerve lesions (Fig. 1) (Asensio-Pinilla et al., 2009; Udina
et al., 2011). This attenuation of hyperreflexia can be due to regulatory actions from the increased expression of neurotrophic
factors in the spinal cord (Vaynman and Gomez-Pinilla, 2005)
or to the beneficial effects of exercise on the muscles. Altered
neuronal excitability of injured motoneurons is recovered after
reinnervation (Foehring et al., 1986), suggesting that functional
contact with muscle is required for the full expression of the
normal neuronal electrical properties. Exercise, by maintaining
the trophism and normal properties of the muscle can facilitate
the expression of still unknown muscular signals to the innervating axons and attenuate the post-injury hyperreflexia. Even
during the denervation period, exercise of the limbs stimulates
muscle afferents of proximal innervated muscles, which may influence the axotomized motoneurons by spinal synaptic connections
normally silent (Koerber et al., 2006). The effects observed with
exercise training on the spinal H reflex are not likely caused
by actions on motoneuronal excitability during the reinnervation phase. Probably, alterations in segmental inhibition, mainly
involving modulation of Ia presynaptic inhibition, may serve as a
mechanism responsible for chronic training-induced adaptations
in the H reflex (Zehr, 2006).
The effects of activity-dependent treatments on adaptive plasticity of spinal motor reflexes have been studied mostly after spinal
cord injury, which usually leads to hyperreflexia and spasticity.
Using an acute and chronic pattern of treadmill locomotor training, the enlarged H/M ratio (ratio between the amplitude of the H
reflex wave and the amplitude of the direct M wave after electrical nerve stimulation) could be significantly suppressed in patients
with spinal cord injury (Trimble et al., 2001). Passive bicycle exercise can also restore the frequency-dependent depression of spinal
H reflex in a time-dependent manner following complete spinal
transection in rats (Liu et al., 2010; Reese et al., 2006). Cycle training
can likely be considered functionally equivalent to walking training
in this context.
Recent research on the effects of activity on functional recovery after neural injuries is focused on the importance of afferent
information from the periphery as a source of control of posture or
locomotor tasks, in conjunction with the spinal circuitry to which
central pattern generation is routinely attributed (Edgerton et al.,
2008). Expression of brain-derived neurotrophic factor (BDNF),
neurotrophin-4 (NT4), their receptor tyrosine kinase B (trkB), and
growth-associated protein-43 (GAP-43) are all increased in lumbar
spinal cord and DRG neurons by voluntary exercise and decreased
in muscle paralysis (Gomez-Pinilla et al., 2002; Skup et al., 2002).
Then, it can be hypothesized that maintenance of denervated muscle activity increases the release of trophic factor that will benefit
E. Udina et al. / Annals of Anatomy 193 (2011) 347–353
axonal regeneration and induce plastic changes in central synaptic
connections.
5. Effects of exercise on collateral sprouting
After a peripheral nerve injury, neighboring intact nerve fibers
are able to extend collateral branches into regions previously
occupied by nerve fibers that have undergone degeneration. This
phenomenon allows reinnervation of denervated targets as an
adaptive mechanism to functionally rescue muscle and sensory
targets.
Within partially denervated muscles, collateral sprouts emerge
from the nodes of uninjured myelinated motor fibers above the
motor nerve terminal to reinnervate nearby denervated muscles
(Griffin and Thompson, 2008; Son and Thompson, 1995). The effects
of neuromuscular activity on axonal sprouting and motor units
enlargement have been controversial due to the conflicting findings of previous studies, which used different activity regimes and
different muscles. Prolonged treadmill exercise was shown to have
a preferential effect on promoting enlargement of fast-fatigable and
fast-intermediate motor units in the partially denervated gastrocnemius (Einsiedel and Luff, 1994) and plantaris muscles (Gardiner
et al., 1984). Since there was no evidence of muscle hypertrophy,
the increased muscle force was attributed to changes in the extent
of axonal sprouting. In contrast, other studies have reported that
activity (wheeling exercise or functional overload) had no effects
on motor unit enlargement by axonal sprouting in the plantaris
muscle (Gardiner and Faltus, 1986; Michel and Gardiner, 1989).
A thorough evaluation of active and passive neuromuscular
activity on muscles subjected to different extent of partial denervation (Tam et al., 2002; Tam and Gordon, 2003) showed that daily
protocols of high activity (8 h daily running exercise or functional
electrical stimulation of the nerve) constrained axonal sprouting
and consequent motor unit enlargement in extensively denervated muscles. The same detrimental effect was not evident in
moderately denervated muscles, where motorunit size increased
normally following partial denervation. They further demonstrated
that the inhibitory effect of increased neuromuscular activity takes
place at the early onset of axonal sprouting in extensively denervated muscles (Tam and Gordon, 2003). Following denervation,
terminal Schwann cells elaborate a network of long processes that
grow from the vacant end plate, forming “bridges” to nearby innervated end plates. Activity seems to alter at least two responses
triggered by denervation in muscles: the ability of the processes of
terminal Schwann cells to form bridges with innervated synaptic
sites (Love et al., 2003; Tam and Gordon, 2003), and the growth of
axons along these processes (Love et al., 2003). Therefore, increased
activity during the early phase of denervation after nerve injury can
be detrimental for axonal sprouting and collateral reinnervation of
denervated muscles. On the other hand, neuromuscular inactivity
also reduces the degree of motor axon sprouting (Tam et al., 2002).
Thus, present evidence is that too much or lack of neuromuscular
activity is counterproductive for effective collateral reinnervation
in partially denervated muscles.
Regarding collateral sprouting of sensory axons, unmyelinated
and thin myelinated fibers show a strong capacity to sprout and
enlarge their innervation territory (Diamond and Foerster, 1992;
Nixon et al., 1984), whereas large myelinated fibers fail to produce
functionally effective collateral reinnervation of adjacent denervated skin (Jackson and Diamond, 1984). Diamond and coworkers
reported that collateral reinnervation of dorsal cutaneous “islands”
of the rat skin was accelerated by repeated mechanical stimulation
of the skin within the innervated regions, as well as by electrical
stimulation of the uninjured nerves (Doucette and Diamond, 1987;
Nixon et al., 1984). Activity-induced neurotrophic factor release
351
promotes neuronal growth and plasticity, and may partially antagonize the restrictions for axonal sprouting by changing the intrinsic
growth state of neurons. Indeed, administration of NGF and other
neurotrophins in vivo potentiates collateral sprouting in the denervated skin (Diamond et al., 1992). In sciatic nerve injury models,
collateral reinnervation of denervated skin territories by nociceptors may be related to the underlying hyperalgesia (Casals-Diaz
et al., 2009). Thus, inhibition or modulation of collateral sprouting
may be of interest for antinociceptive effects.
6. Effects of exercise on neuropathic pain
Peripheral nerve injuries often result in development of neuropathic pain symptoms, including spontaneous pain sensation,
hyperalgesia and allodynia (painful perception caused by a normally non-painful stimulus). Neuropathic pain symptoms are also
related to axonal regeneration mechanisms and functional recovery. After injury, mechanical allodynia affects the use of the injured
paw and compromises successful rehabilitation (Vogelaar et al.,
2004). However, only a few studies have investigated the effects
of activity treatments on neuropathic pain after nerve injuries.
Cobianchi et al. (2010) found that, after chronic constriction of
the sciatic nerve in mice, early short-lasting treadmill running was
able to reduce mechanical allodynia and to normalize the walking
pattern of the injured hindpaw. Interestingly, the reduction of allodynia was maintained for 2 months, even when treadmill running
was interrupted at day 7. Reduction of allodynia after early shortlasting exercise correlated with reduced microglia and astroglia
reactivity in the dorsal horn, but astrocytosis was not prevented
by long-lasting treadmill running. Other studies also suggest that
microglia activation can be related to the hyperalgesia observed
after peripheral nerve injuries, and astrocytes may be involved in
its maintenance (Cao and Zhang, 2008). These findings suggest
that the effectiveness of activity-dependent treatments on neuropathic lesions are related to specific time windows after nerve
injury when increased activity may stimulate or inhibit regeneration of injured axons. In line with this view, acute brief electrical
stimulation for 1 or 4 h after lesion to the injured nerve enhanced
axonal regeneration and muscle reinnervation, whereas chronic
daily electrical stimulation was detrimental for nerve regeneration (Asensio-Pinilla et al., 2009). Activity treatments can enhance
the plasticity of intact axonal projections to compensate the loss of
sensibility provoked by the disruption of neighboring axons. Since
synaptic plasticity and sprouting of sensory fibers enhance pain
perception during the denervation and reinnervation phases, different activity protocols could differently act on neuropathic pain
compared to effects on recovery of motor function.
The effects of treadmill running on pain symptoms may be
attributable to its modulation on central and/or peripheral neurotrophin release like in nerve regeneration. Neurotrophins, such
as BDNF, are up-regulated in several models of inflammatory and
neuropathic pain (Ha et al., 2001; Pezet et al., 2002), and physical exercise is an important modulator of neurotrophin release
in regenerating neurons (Molteni et al., 2004; Ying et al., 2005).
There is evidence that BDNF may serve both pro- and antinociceptive roles in different contexts (Pezet and McMahon, 2006). After
exercise, peripheral and/or central expression and delivery of BDNF
depend on the site and model of injury (Vanelderen et al., 2010).
BDNF redistribution between DRG neurons has been related to neuropathic pain; after nerve injury, BDNF is upregulated in smalland medium-sized neurons in rats with signs of neuropathic pain,
whereas its expression was increased in large sensory neurons in
rats without pain (Tender et al., 2010). The antinociceptive effects
of central BDNF are thought to arise from its ability to increase
the synthesis and release of serotonin in descending pathways,
352
E. Udina et al. / Annals of Anatomy 193 (2011) 347–353
or by rescuing GABAergic neurons and stimulating GABA release,
both providing inhibitory modulation at the dorsal horn (Pezet
et al., 2002; Vanelderen et al., 2010). Interestingly, treadmill exercise increases serotonergic immunoreactivity in medullary raphe
nuclei and spinal cord of rats submitted to sciatic nerve section. The increased serotonergic nerve activity is parallel to the
improvement in nociceptive responses and functional recovery. An
alternative mechanism of action to explain the hypoalgesia induced
by exercise could be the activation of endogenous opioids, specifically ␤-endorphins (Goldfarb and Jamurtas, 1997; Koltyn, 2000).
Otherwise, resistance exercise induced an antinociceptive effect
mediated by ␤-endorphin immediately after training, although it
lasted only a few minutes (Galdino et al., 2010).
Acknowledgments
This research was supported by grant CP-FP-INFSO 224012
(TIME project) from the EU, grant SAF2009-12495 from the Ministerio de Ciencia e Innovacion of Spain, grant PI080598 and CIBERNED
and TERCEL funds from the Fondo de Investigación Sanitaria of
Spain, and FEDER funds.
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