Chronic electrical stimulation reduces hyperalgesia and associated spinal changes induced by peripheral nerve injury.

OBJECTIVES: We aimed to investigate if different protocols of electrical stimulation following nerve injury might improve neuropathic pain outcomes and modify associated plastic changes at the spinal cord level. MATERIALS AND METHODS: Adult rats were subjected to sciatic nerve transection and repair, and distributed in four groups: untreated (SNTR, n = 12), repeated acute electrical stimulation (rAES, 50 Hz, one hour, n = 12), chronic electrical stimulation (CES, 50 Hz, one hour, n = 12), and increasing-frequency chronic electrical stimulation (iCES, one hour, n = 12) delivered during two weeks following the lesion. The threshold of nociceptive withdrawal to mechanical stimuli was evaluated by means of a Von Frey algesimeter during three weeks postlesion. Spinal cord samples were processed by immunohistochemistry for labeling glial cells, adrenergic receptors, K+ -Cl- cotransporter 2 (KCC2) and GABA. RESULTS: Acute electrical stimulation (50 Hz, one hour) delivered at 3, 7, and 14 days induced an immediate increase of mechanical pain threshold that disappeared after a few days. Chronic electrical stimulation given daily reduced mechanical hyperalgesia until the end of follow-up, being more sustained with the iCES than with constant 50 Hz stimulation (CES). Chronic stimulation protocols restored the expression of ß2 adrenergic receptor and of KCC2 in the dorsal horn, which were significantly reduced by nerve injury. These treatments decreased also the activation of microglia and astrocytes in the dorsal horn. CONCLUSION: Daily electrical stimulation, especially if frequency-patterned, was effective in ameliorating hyperalgesia after nerve injury, and partially preventing the proinflammatory and hyperalgesic changes in the dorsal horn associated to neuropathic pain.

NKCC1 Activation Is Required for Myelinated Sensory Neurons Regeneration through JNK-Dependent Pathway.

After peripheral nerve injury, axons are able to regenerate, although specific sensory reinnervation and functional recovery are usually worse for large myelinated than for small sensory axons. The mechanisms that mediate the regeneration of different sensory neuron subpopulations are poorly known. The Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) is particularly relevant in setting the intracellular chloride concentration. After axotomy, increased NKCC1 phosphorylation has been reported to be important for neurite outgrowth of sensory neurons; however, the mechanisms underlying its effects are still unknown. In the present study we used in vitro and in vivo models to assess the differential effects of blocking NKCC1 activity on the regeneration of different types of dorsal root ganglia (DRGs) neurons after sciatic nerve injury in the rat. We observed that blocking NKCC1 activity by bumetanide administration induces a selective effect on neurite outgrowth and regeneration of myelinated fibers without affecting unmyelinated DRG neurons. To further study the mechanism underlying NKCC1 effects, we also assessed the changes in mitogen-activated protein kinase (MAPK) signaling under NKCC1 modulation. The inhibition of NKCC1 activity in vitro and in vivo modified pJNK1/2/3 expression in DRG neurons. Together, our study identifies a mechanism selectively contributing to myelinated axon regeneration, and point out the role of Cl(-) modulation in DRG neuron regeneration and in the activation of MAPKs, particularly those belonging to the JNK family.

Role of JNK isoforms in the development of neuropathic pain following sciatic nerve transection in the mouse.

BACKGROUND: Current tools for analgesia are often only partially successful, thus investigations of new targets for pain therapy stimulate great interest. Consequent to peripheral nerve injury, c-Jun N-terminal kinase (JNK) activity in cells of the dorsal root ganglia (DRGs) and spinal cord is involved in triggering neuropathic pain. However, the relative contribution of distinct JNK isoforms is unclear. Using knockout mice for single isoforms, and blockade of JNK activity by a peptide inhibitor, we have used behavioral tests to analyze the contribution of JNK in the development of neuropathic pain after unilateral sciatic nerve transection. In addition, immunohistochemical labelling for the growth associated protein (GAP)-43 and Calcitonin Gene Related Peptide (CGRP) in DRGs was used to relate injury related compensatory growth to altered sensory function. RESULTS: Peripheral nerve injury produced pain-related behavior on the ipsilateral hindpaw, accompanied by an increase in the percentage of GAP43-immunoreactive (IR) neurons and a decrease in the percentage of CGRP-IR neurons in the lumbar DRGs. The JNK inhibitor, D-JNKI-1, successfully modulated the effects of the sciatic nerve transection. The onset of neuropathic pain was not prevented by the deletion of a single JNK isoform, leading us to conclude that all JNK isoforms collectively contribute to maintain neuropathy. Autotomy behavior, typically induced by sciatic nerve axotomy, was absent in both the JNK1 and JNK3 knockout mice. CONCLUSIONS: JNK signaling plays an important role in regulating pain threshold: the inhibition of all of the JNK isoforms prevents the onset of neuropathic pain, while the deletion of a single splice JNK isoform mitigates established sensory abnormalities. JNK inactivation also has an effect on axonal sprouting following peripheral nerve injury.

Reduced Anxiety Associated to Adaptive and Mindful Coping Strategies in General Practitioners Compared With Hospital Nurses in Response to COVID-19 Pandemic Primary Care Reorganization.

COVID-19 pandemic imposed psychosocial stress increasing in frontline healthcare workers, who managed by responding with different coping strategies. General practitioners were targeted by an extraordinary increase in the demand for reception, diagnosis and treatment from all patients even if working in solo. In Italy, the emergency changed risk assumption and roles in between primary care, unraveling the emotional distress of general practitioners, who suffered not only for isolation, but also emotional threatens. In this correlational study we wanted to evaluate trait anxiety and stress as perceived by general practitioners working in individual ambulatory practice room, and by hospital ward nurses working in group, during a chronic phase (February-May 2021) of COVID-19 pandemic. Our hypothesis is that a different work social organization in clinic contest as for general practitioners compared with nurses could induce adaptive or non-adaptive coping to stress under emergency and mindful attitude could be crucial. A number of 37 general practitioners, and 36 nurses were taken from the sanitary district of ASL1 Avezzano-Sulmona-L'Aquila in Italy. For our analyses we used the Health Professions Stress and Coping Scale to assess the risk of burn-out, and detect the coping strategies. We also used the Cognitive and Affective Mindfulness Scale-Revised, investigating whether clinicians used an eventual mindful attitude to prevent anxiety and responding with adaptive coping strategies. General practitioners reported high levels of anxiety, associated to an increased use of emotional distress. Mindful attitude was protective for anxiety in both general practitioners and nurses. As anxiety increased, it was coped by increasing the demand for social support. This coping strategy correlated with emotional distress and when enhanced, it corresponded to avoidance of the problem. Mindful attitude addressed general practitioners to adaptive coping strategies as the solution of the problem. On the other side, nurses accepted the problem but addressed it to others, by avoiding solving it themselves as beyond their role and organizational responsibility. In conclusion, mindful attitude can prevent dysfunctional reactive behaviors among clinicians at the forefront of emergency and reduce emotional distress for isolation as suffered by general practitioners.

Revealing the Therapeutic Potential of Botulinum Neurotoxin Type A in Counteracting Paralysis and Neuropathic Pain in Spinally Injured Mice.

Botulinum neurotoxin type A (BoNT/A) is a major therapeutic agent that has been proven to be a successful treatment for different neurological disorders, with emerging novel therapeutic indications each year. BoNT/A exerts its action by blocking SNARE complex formation and vesicle release through the specific cleavage of SNAP-25 protein; the toxin is able to block the release of pro-inflammatory molecules for months after its administration. Here we demonstrate the extraordinary capacity of BoNT/A to neutralize the complete paralysis and pain insensitivity induced in a murine model of severe spinal cord injury (SCI). We show that the toxin, spinally administered within one hour from spinal trauma, exerts a long-lasting proteolytic action, up to 60 days after its administration, and induces a complete recovery of muscle and motor function. BoNT/A modulates SCI-induced neuroglia hyperreactivity, facilitating axonal restoration, and preventing secondary cells death and damage. Moreover, we demonstrate that BoNT/A affects SCI-induced neuropathic pain after moderate spinal contusion, confirming its anti-nociceptive action in this kind of pain, as well. Our results provide the intriguing and real possibility to identify in BoNT/A a therapeutic tool in counteracting SCI-induced detrimental effects. Because of the well-documented BoNT/A pharmacology, safety, and toxicity, these findings strongly encourage clinical translation.

Monoaminergic descending pathways contribute to modulation of neuropathic pain by increasing-intensity treadmill exercise after peripheral nerve injury.

This study characterizes the impact of increasing-intensity treadmill exercise (iTR) on noradrenergic (NE) and serotonergic (5HT) modulation of neuropathic pain. Following sciatic nerve transection and repair (SNTR) rats developed significant mechanical and thermal hyperalgesia that was partially prevented by iTR performed during the first 2weeks after injury. Marked decrease in the expression of 5HT2A and α1A and ß-, but not α2A adrenergic receptors in the spinal cord dorsal horn was associated to SNTR and recovered by iTR, particularly in lamina II. iTR significantly increased 5HT2A in periaqueductal grey (PAG), raphe magnus (RM) and dorsal raphe nucleus (DRN), with a pattern suggesting reorganization of serotonergic excitatory interconnections between PAG and DRN. iTR also increased the expression of α1A in locus coeruleus (LC) and DRN, and ß2 in LC, indicating that exercise enhanced activity of NE neurons, likely by activating autologous projections from DRN and PAG. iTR hypoalgesia was antagonized by blockade of ß2 and 5HT2A receptors with administration of butoxamine and ketanserin. The neurotoxin DSP4 was injected to induce depletion of NE projections from LC before starting iTR. DSP4 treatment worsened mechanical hyperalgesia, but iTR hypoalgesia was similarly produced. Moreover, 5HT2A expression in LC further increased after DSP4 injection, all these results suggesting an intrinsic regulation of 5HT and NE activity between PAG, DRN and LC neurons activated by iTR. Finally, iTR significantly reduced microglial reactivity in LC and increased non-microglial BDNF expression, an effect that was reverted by butoxamine, implicating BDNF regulation in central 5HT/NE actions on neuropathic pain.

Neuroprotective Effects of Exercise Treatments After Injury: The Dual Role of Neurotrophic Factors.

BACKGROUND: Shared connections between physical activity and neuroprotection have been studied for decades, but the mechanisms underlying this effect of specific exercise were only recently brought to light. Several evidences suggest that physical activity may be a reasonable and beneficial method to improve functional recovery in both peripheral and central nerve injuries and to delay functional decay in neurodegenerative diseases. In addition to improving cardiac and immune functions, physical activity may represent a multifunctional approach not only to improve cardiocirculatory and immune functions, but potentially modulating trophic factors signaling and, in turn, neuronal function and structure at times that may be critical for neurodegeneration and regeneration. METHODS: Research content related to the effects of physical activity and specific exercise programs in normal and injured nervous system have been reviewed. RESULTS: Sustained exercise, particularly if applied at moderate intensity and early after injury, exerts anti-inflammatory and pro-regenerative effects, and may boost cognitive and motor functions in aging and neurological disorders. However, newest studies show that exercise modalities can differently affect the production and function of brain-derived neurotrophic factor and other neurotrophins involved in the generation of neuropathic conditions. These findings suggest the possibility that new exercise strategies can be directed to nerve injuries with therapeutical benefits. CONCLUSION: Considering the growing burden of illness worldwide, understanding of how modulation of neurotrophic factors contributes to exercise-induced neuroprotection and regeneration after peripheral nerve and spinal cord injuries is a relevant topic for research, and represents the beginning of a new non-pharmacological therapeutic approach for better rehabilitation of neural disorders.

Botulinum neurotoxin A promotes functional recovery after peripheral nerve injury by increasing regeneration of myelinated fibers.

The injection of safe doses of botulinum neurotoxin A (BoNT/A) have been reported to be useful for the treatment of neuropathic pain, but it is still unknown how functional recovery is induced after peripheral nerve injury. We evaluated the effects of intranerve application of BoNT/A, on regeneration and sensorimotor functional recovery in partial and complete peripheral nerve injuries in the mouse. After sciatic nerve crush (SNC) and intranerve delivery of BoNT/A (15pg), axonal regeneration was measured by nerve pinch test at different days. Regeneration of myelinated and unmyelinated fibers was assessed by immunohistochemical double labeling for NF200/GAP43 and CGRP/GAP43. S100 was used as Schwann cells marker. Medial footpad skin reinnervation was assessed by PGP staining. Motor functions were assessed by means of nerve conduction tests. In other mice groups, nerve conduction tests were performed also after chronic constriction injury (CCI) of the sciatic nerve and intraplantar injection of BoNT/A (15pg). In SNC mice, BoNT/A increased the rate of axonal regeneration. The advantage of regrowing myelinated axons after BoNT/A injection was evidenced by longer NF200+ nerve profiles and confirmed by nerve histology. We observed also a higher expression of S100 in the distal portion of BoNT/A-injected regenerated nerves. In CCI mice, BoNT/A induced an increase in reinnervation of gastrocnemius and plantar muscles. These results show that a low dose of BoNT/A, insufficient to produce muscular dysfunction, conversely speeds up sensorimotor recovery by stimulating myelinated axonal regeneration, and points out its application as a multipotent treatment for peripheral neuropathies.

Endogenous modulation of TrkB signaling by treadmill exercise after peripheral nerve injury.

After peripheral nerve injury, transected fibers distal to the lesion are disconnected from the neuronal body. This results in target denervation but also massive stripping of the central synapses of axotomized motoneurons, disrupting spinal circuits. Even when axonal regeneration is successful, the non-specific target reinnervation and the limited rebuilding of spinal circuits impair functional recovery. Therefore, strategies aimed to preserve spinal circuits after nerve lesions may improve the functional outcome. Activity-dependent therapy in the form of early treadmill running reduces synaptic stripping, mainly of excitatory synapses, and the disorganization of perineuronal nets (PNNs) on axotomized motoneurons. The mechanism underlying these effects remains unknown, although the benefits of exercise are often attributed to an increase in the neurotrophin brain-derived neurotrophic factor (BDNF). In this study, tropomyosin-related kinase (TrkB) agonist and antagonist were administered to rats subjected to sciatic nerve injury in order to shed light on the role of BDNF. The maintenance of synapses on axotomized motoneurons induced by treadmill running was partially dependent on TrkB activation. Treatment with the TrkB agonist at a low dose, but not at a high dose, prevented the decrease of excitatory glutamatergic synapses, and both doses increased the density of inhibitory synapses. TrkB inactivation counteracted only some of the positive effects exerted by exercise after nerve injury, such as maintenance of excitatory synapses surrounding motoneurons. Therefore, specific regimes of physical exercise are a better strategy to attenuate the alterations that motoneurons suffer after axotomy than pharmacological modulation of the TrkB pathway.

Stabilization, Rolling, and Addition of Other Extracellular Matrix Proteins to Collagen Hydrogels Improve Regeneration in Chitosan Guides for Long Peripheral Nerve Gaps in Rats.

Background: Autograft is still the gold standard technique for the repair of long peripheral nerve injuries. The addition of biologically active scaffolds into the lumen of conduits to mimic the endoneurium of peripheral nerves may increase the final outcome of artificial nerve devices. Furthermore, the control of the orientation of the collagen fibers may provide some longitudinal guidance architecture providing a higher level of mesoscale tissue structure. Objective: To evaluate the regenerative capabilities of chitosan conduits enriched with extracellular matrix-based scaffolds to bridge a critical gap of 15 mm in the rat sciatic nerve. Methods: The right sciatic nerve of female Wistar Hannover rats was repaired with chitosan tubes functionalized with extracellular matrix-based scaffolds fully hydrated or stabilized and rolled to bridge a 15 mm nerve gap. Recovery was evaluated by means of electrophysiology and algesimetry tests and histological analysis 4 months after injury. Results: Stabilized constructs enhanced the success of regeneration compared with fully hydrated scaffolds. Moreover, fibronectin-enriched scaffolds increased muscle reinnervation and number of myelinated fibers compared with laminin-enriched constructs. Conclusion: A mixed combination of collagen and fibronectin may be a promising internal filler for neural conduits for the repair of peripheral nerve injuries, and their stabilization may increase the quality of regeneration over long gaps.

Botulinum neurotoxins and formalin-induced pain: central vs. peripheral effects in mice.

Neurotoxins affecting neuroexocytosis can represent an innovative pharmacological approach to the investigation of neural mechanisms of pain. Our interest has been focused on the use of botulinum neurotoxins (BoNTs), whose peripheral effects are extensively documented, while the effects on the central nervous system are much less clear. We have investigated both peripheral (sc into the hindpaw) and central (icv) effects of two BoNTs isoforms, BoNT/A and BoNT/B, on inflammatory pain. BoNT/A (sc: 0.937-15; icv: 0.937-3.75 pgtox/mouse) and BoNT/B (sc: 3.75, 7.5; icv: 1.875, 3.75 pgtox/mouse) were injected in CD1 mice and tested in the formalin test 3 days later. Licking response, as index of pain, and behavioral parameters, such as general activity and grooming, were recorded for 40 min during the test. BoNT/A partially affects the licking response in the second phase of formalin test in a similar magnitude of attenuation whether peripherally or centrally administered. BoNT/A does not significantly affect licking behavior during the first phase of the test. Peripheral administration of BoNT/B attenuates the licking response during the first phase not modifying the second phase, while the icv administration has hyperalgesic effect on the interphase of the formalin test. General activity and grooming behavior are not affected either by peripheral or by central administration of BoNTs. Our results show for the first time a central effect of BoNTs that differently modulate inflammatory pain depending both on serotype and on route of administration. Such data suggest BoNTs as a useful tool in the studies aimed at the comprehension of the mechanisms of inflammatory pain.

Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury.

Activity treatments, such as treadmill exercise, are used to improve functional recovery after nerve injury, parallel to an increase in neurotrophin levels. However, despite their role in neuronal survival and regeneration, neurotrophins may cause neuronal hyperexcitability that triggers neuropathic pain. In this work, we demonstrate that an early increasing-intensity treadmill exercise (iTR), performed during the first week (iTR1) or during the first 2 weeks (iTR2) after section and suture repair of the rat sciatic nerve, significantly reduced the hyperalgesia developing rapidly in the saphenous nerve territory and later in the sciatic nerve territory after regeneration. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in sensory neurons and spinal cord was reduced in parallel. iTR prevented the extension of collateral sprouts of saphenous nociceptive calcitonin gene-related peptide fibers within the adjacent denervated skin and reduced NGF expression in the same skin and in the L3 dorsal root ganglia (DRG). Injury also induced Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1) upregulation in DRG, and K⁺-Cl⁻ cotransporter 2 (KCC2) downregulation in lumbar spinal cord dorsal horn. iTR normalized NKCC1 and boosted KCC2 expression, together with a significant reduction of microgliosis in L3-L5 dorsal horn, and a reduction of BDNF expression in microglia at 1 to 2 weeks postinjury. These data demonstrate that specific activity protocols, such as iTR, can modulate neurotrophins expression after peripheral nerve injury and prevent neuropathic pain by blocking early mechanisms of sensitization such as collateral sprouting and NKCC1/KCC2 disregulation.

Prevention of NKCC1 phosphorylation avoids downregulation of KCC2 in central sensory pathways and reduces neuropathic pain after peripheral nerve injury.

Neuropathic pain after peripheral nerve injury is characterized by loss of inhibition in both peripheral and central pain pathways. In the adult nervous system, the Na(+)-K(+)-2Cl(-) (NKCC1) and neuron-specific K(+)-Cl(-) (KCC2) cotransporters are involved in setting the strength and polarity of GABAergic/glycinergic transmission. After nerve injury, the balance between these cotransporters changes, leading to a decrease in the inhibitory tone. However, the role that NKCC1 and KCC2 play in pain-processing brain areas is unknown. Our goal was to study the effects of peripheral nerve injury on NKCC1 and KCC2 expression in dorsal root ganglia (DRG), spinal cord, ventral posterolateral (VPL) nucleus of the thalamus, and primary somatosensory (S1) cortex. After sciatic nerve section and suture in adult rats, assessment of mechanical and thermal pain thresholds showed evidence of hyperalgesia during the following 2 months. We also found an increase in NKCC1 expression in the DRG and a downregulation of KCC2 in spinal cord after injury, accompanied by later decrease of KCC2 levels in higher projection areas (VPL and S1) from 2 weeks postinjury, correlating with neuropathic pain signs. Administration of bumetanide (30 mg/kg) during 2 weeks following sciatic nerve lesion prevented the previously observed changes in the spinothalamic tract projecting areas and the appearance of hyperalgesia. In conclusion, the present results indicate that changes in NKCC1 and KCC2 in DRG, spinal cord, and central pain areas may contribute to development of neuropathic pain.

Assessment of sensory thresholds and nociceptive fiber growth after sciatic nerve injury reveals the differential contribution of collateral reinnervation and nerve regeneration to neuropathic pain.

Following traumatic peripheral nerve injury reinnervation of denervated targets may be achieved by regeneration of injured axons and by collateral sprouting of neighbor undamaged axons. Experimental models commonly use sciatic nerve injuries to assess nerve regeneration and neuropathic pain, but behavioral tests for evaluating sensory recovery often disregard the pattern of hindpaw innervation. This may lead to confounding attribution of recovery of sensory responses to improvement in sciatic nerve regeneration instead of collateral reinnervation by the undamaged saphenous nerve. We used a standardized methodology to assess the separate contribution of collateral and regenerative skin reinnervation on sensory responses. Section and suture of the sciatic nerve induced loss of sensibility in the lateral and central areas of the injured paw, but nociceptive responses rapidly recovered by expansion of the intact saphenous innervation territory. We used electronic Von Frey and Plantar test devices to measure mechanical and thermal withdrawal thresholds in specific sites of the injured paw: lateral site innervated by the sciatic nerve, medial site that remained innervated by the saphenous nerve, and central site originally innervated by the sciatic nerve but affected by saphenous sprouting. After sciatic section, signs of early hyperalgesia developed in medial and central paw areas due to saphenous sprouting and expansion. The regenerating sciatic nerve fibers reached the paw at 3-4weeks and a late mechanical hyperalgesia was observed at the lateral site. Immunohistochemical staining of sensory fibers innervating the medial and lateral areas revealed a different pattern of skin reinnervation. Hypersensitivity in the intact saphenous nerve area was paralleled by early fiber sprout growth in the subepidermal plexus, but not entering the epidermis. On the other side, late sciatic hyperalgesia was accompanied by gradual skin reinnervation after 4weeks. The standardization of algesimetry testing in sciatic nerve injury models, as proposed in this study, provides a suitable model for studying in parallel neuropathic pain and sensory nerve regeneration processes. Our results also indicate that collateral sprouting and axonal regeneration contribute differently in the initiation and maintenance of neuropathic pain.

Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury.

Activity treatments are useful strategies to increase axonal regeneration and functional recovery after nerve lesions. They are thought to benefit neuropathy by enhancing neurotrophic factor expression. Nevertheless the effects on sensory function are still unclear. Since neurotrophic factors also play a fundamental role in peripheral and central sensitization, we studied the effects of acute electrical stimulation and early treadmill exercise on nerve regeneration and on neuropathic pain, and the relation with the expression of neurotrophins. After sciatic nerve section and suture repair, rats were subjected to electrical stimulation (ES) for 4h after injury, forced treadmill running (TR) for 5 days, or both treatments combined. Sciatic nerve section induced hyperalgesia in the medial area of the plantar skin in the injured paw. TR and ES differently but positively reduced adjacent neuropathic pain before and after sciatic reinnervation. ES enhanced motor and sensory reinnervation, and combination with TR induced strong agonistic effects in relieving pain. The differential effects of these activity treatments were related to changes in neurotrophic factor mRNA levels in sensory and motor neurons. ES speeded up expression of BDNF and GDNF in DRG, and of BDNF and NT3 in the ventral horn. TR reduced the levels of pro-nociceptive factors such as BDNF, NGF and GDNF in DRG. Combination of ES and TR induced intermediate levels suggesting an optimal balancing of treatment effects.

Effects of activity-dependent strategies on regeneration and plasticity after peripheral nerve injuries.

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.