Inherited propensity for neuropathic pain is mediated by sensitivity to injury discharge.

We reported previously that injury discharge (ID), a burst of impulses fired following nerve injury, plays a role in triggering autotomy, a neuropathic pain-related behavior in rats. Here we affirm this link using two lines of rats, derived by selective breeding from the Sabra strain to express high (HA) or low (LA) levels of autotomy following hindpaw denervation. Blocking ID in HA rats before injury suppressed autotomy. Correspondingly, artificial prolongation of ID in LA rats just prior to neurectomy, increased autotomy. The autotomy in these HA and LA rats was like that of their Sabra ancestors. This suggests that the underlying basis for selection of these lines was differential sensitivity of the CNS to the effects of ID.     

Heat hyperalgesia following partial sciatic ligation in rats: interacting nature and nurture

As in humans, levels of neuropathic pain produced by nerve injury are highly variable among animals. This variability was attributed to genetic and environmental factors. For example, we reported that chronic neuropathic sensory disorders developing following total (autotomy) or partial nerve injury (allodynia and hyperalgesia) depended on the diet rats consumed. Here we investigated the interaction between genetic and dietary factors in the development of heat hyperalgesia in rats following partial sciatic ligation (the PSL model). We show that heat sensitivity of intact rats and levels of heat hyperalgesia of PSL-injured rats were highly variable across eight different rat strains and seven different diets. Thus, genetic and environmental variables interact in determination of levels of chronic neuropathic sensory disorders in rats.     

Central noradrenergic blockade prevents autotomy in rat: implication for pharmacological prevention of postdenervation pain syndrome

Following transection of peripheral nerve, rats exhibit autotomy, which is considered to be the animal model of postdenervation pain syndrome. It has been suggested that phantom limb pain is a result of peripheral denervation leading to reorganization of somatosensory pathways, particularly in the cerebral cortex, which is shown to depend upon central noradrenergic activity. In this study, sciatic and saphenous nerves were sectioned in the left hindpaw of 30 adult rats resulting in complete loss of pain sensation in the hindpaw. A group of rats received normal saline, compared to another group which received N-(2-) Chloroethyl-N-ethyl-2-bromobenzylamine (DSP4) injection 24 h prior to transection. The latter group was also compared to a third group whose central noradrenergic system were also blocked by bilateral injection of 6-OHDA into the ascending noradrenergic bundle 1 week prior to transection. A fourth group received contralateral cortical ablation in addition to peripheral nerve transection and was compared to the first group whose cortex remained intact. The animals were observed daily for 60 days and autotomy was scored in accordance to the system of Wall et al. After 1 week, control animals began to exhibit autotomy. In contrast, autotomy was absent in rats treated with DSP4, similar to rats which received 6-OHDA. Rats which had contralateral cortical ablation showed a considerably delayed onset of autotomy and a reduction in final autotomy scores. We conclude that autotomy, as a model of postdenervation pain syndrome, can be prevented by blockade of noradrenergically mediated cortical reorganization. The clinical implications of this finding are discussed.     

Procedures which increase acute pain sensitivity also increase autotomy

Rats typically display self-mutilation (autotomy) of a paw that has been denervated by transection of the sciatic and saphenous nerves. The cause of autotomy, however, is not known. It may be due to hyperesthesia (comparable to that seen in humans after peripheral nerve injury) or anesthesia (as an attempt to shed an insensate appendage). The present study tested the assumption that if autotomy is produced by pain, then procedures that normally augment the expression of pain should enhance autotomy after transection of peripheral nerves. Groups of rats were subjected to procedures known to produce an increase in pain sensitivity: (i) prior heat injury of either the ipsilateral or contralateral paw; (ii) systemic injection of noradrenaline and the monoamine oxidase inhibitor, pargyline; and (iii) intrathecal administration of substance P. The results showed that each of these procedures produced an increase in the level of autotomy. These results strongly suggest that autotomy is due to a sensory phenomenon which, in terms of human experience, would be described as pain or dysesthesia.     

Autotomy following sciatic and saphenous nerve sections: sparing of the medial toes after treatment of the sciatic nerve with capsaicin

Autotomy, or self-mutilation of the foot following sciatic and saphenous nerve lesions, was examined in rats after pretreatment of the sciatic nerve with capsaicin. This pretreatment produced an alteration in autotomy behavior which resulted in the sparing of the medial side of the foot. The effect occurred following a long (12-week) pretreatment-test interval, but not after shorter (1- and 4-week) intervals. The effect also depended on the successive transecting of the saphenous and sciatic nerves. Sparing of the medial side of the foot occurred only when the saphenous nerve was transected at the time of the sciatic nerve treatment with capsaicin. Because the side of the foot innervated by the saphenous nerve was spared by treating the sciatic nerve with capsaicin, we suggest that capsaicin alters the course of autotomy by preventing collateral innervation of the saphenous region by the intact sciatic nerve during the pretreatment-test interval. The fact that this occurs only after a 12-week interval suggests that capsaicin's effect on collateral innervation is a gradual process that requires a long time to develop.     

Explosive Autotomy Induced by Simultaneous Dorsal Column Lesion and Limb Denervation: A Possible Model for Acute Deafferentation Pain

We report on a new "explosive" form of self-mutilation behavior (autotomy) characterized by rapid onset (1-2 days), short duration (1-2 days), and unpredictable progression. The possible neural mechanism(s) underlying this novel behavior were examined in rats by combining at varying time intervals one leg denervation with a lesion to the dorsal columns (DC lesion) or to a dorsolateral funiculus (DLF lesion). DC lesion, followed immediately by leg denervation, resulted in explosive autotomy in 62% of the rats and regular autotomy in 25% of the rats. Regular autotomy was characterized by slow onset (2-3 weeks), prolonged duration (2-3 weeks), and stereotyped progression from distal to proximal parts of the leg. DC lesion, followed 1 week later by leg denervation, resulted in regular autotomy in 71% of the rats which was not different from autotomy resulting from denervation alone. DC lesion preceded 1 week earlier by leg denervation resulted in slightly accelerated regular autotomy in 77% of the rats. Simultaneous DC lesion and leg denervation immediately preceded by application of a local anesthetic (4% procaine) for 30 or 60 min to the exposed lumbar spinal cord resulted in regular autotomy in all rats. All rats in a sham group, in which the procaine was replaced by normal saline, exhibited explosive autotomy. DLF lesion, followed immediately by leg denervation, resulted in accelerated regular autotomy. Our results support the hypothesis that explosive autotomy, following simultaneous DC lesion and leg denervation, could be due to the simultaneous injury to the peripheral and central ends of the primary afferent neurons that are involved in either nociceptive transmission or modulation, combined with injury to other afferent fibers involved in nociceptive transmission. It is felt that explosive autotomy could serve as an animal model for acute deafferentation pain exhibited by patients following acute neural trauma.     

Spontaneous pain following spinal nerve injury in mice

Autotomy behavior is frequently observed in rats and mice in which the nerves of the hindlimb are severed, denervating the paw. This is the neuroma model of neuropathic pain. A large body of evidence suggests that this behavior reflects the presence of spontaneous dysesthesia and pain. In contrast, autotomy typically does not develop in partial nerve injury pain models, leading to the belief that these animals develop hypersensibility to applied stimuli (allodynia and hyperalgesia), but not spontaneous pain. We have modified the widely used Chung (spinal nerve ligation [SNL]) model of neuropathic pain in a way that retains the fundamental neural lesion, but eliminates nociceptive sensory cover of the paw. These animals performed autotomy. Moreover, the heritable across strains predisposition to spontaneous pain behavior in this new proximal denervation model (SNN) was highly correlated with pain phenotype in the neuroma model suggesting that the pain mechanism in the two models is the same. Relative reproducibility of strain predispositions across laboratories was verified. These data indicate that the neural substrate for spontaneous pain is present in the Chung-SNL model, and perhaps in the other partial nerve injury models as well, but that spontaneous pain is not expressed as autotomy in these models because there is protective nociceptive sensory cover.     

A simple method for reducing autotomy in rats after peripheral nerve lesions

Experiments using peripheral nerve lesions (crush or transection) in rats to study repair processes are hampered by the tendency for the animals to attack the limb in which the peripheral nerves are damaged (autotomy). In this paper we describe a simple method which significantly reduces the incidence of autotomy after peripheral nerve lesions. The method consists of painting the hind paws of operated rats with a commercially available non-toxic lotion, which is used to discourage nail-biting and thumb-sucking in humans. Although the method is not absolute, it was extremely beneficial in our experiments, since the number of animals that had to be taken out of the experiment due to severe autotomy was greatly reduced. We believe that this method may prove to be as beneficial to other investigators who are using experimental peripheral nerve lesions to study the regenerative aspects of the nervous system.     

Spontaneous pain in partial nerve injury models of neuropathy and the role of nociceptive sensory cover

Spontaneous pain is difficult to measure in animals. One proposed biomarker of spontaneous pain is autotomy, a behavior frequently observed in rats with complete hindpaw denervation (the neuroma model of neuropathic pain). A large body of evidence suggests that this behavior reflects spontaneous dysesthesic sensations akin to phantom limb pain or anesthesia dolorosa. After partial paw denervation, such as in the spared nerve injury (SNI) model of neuropathic pain, autotomy is rare. Does this mean that spontaneous pain is absent? We denervated hindpaws in two stages: SNI surgery completed 7 or 28 days later by transection of the saphenous and sural nerves (SaSu). Minimal autotomy was evoked by the first stage. But it started rapidly after SaSu surgery rendered the limb numb, much more rapidly than after denervation in a single stage (neuroma model). The acceleration was proportional to the delay between the two surgeries. This “priming” effect of the first surgery indicates that the neural substrate of autotomy, spontaneous neuropathic pain, was not initiated by the onset of numbness, but rather by the first, SNI surgery. But the animal's pain experience was occult. The saphenous and sural nerves provided nociceptive sensory cover for the paw, preventing the behavioral expression of the spontaneous pain in the form of autotomy. The results support prior observations suggesting that partial nerve injury triggers spontaneous pain as well as allodynia, and illustrate the importance of nociceptive sensory cover in the prevention of self-inflicted limb injury.     

Cutaneous hyperalgesia: contributions of the peripheral and central nervous systems to the increase in pain sensitivity after injury

This study assesses the contributions of the peripheral and central nervous systems in the development of hyperalgesia (increased pain sensitivity) after an injury. Experiments were carried out to examine the role of C-fiber afferents, the spinal cord and sympathetic efferents on inflammation, primary hyperalgesia and referred hyperalgesia produced in rats by a heat injury. A peripheral mechanism was indicated since both primary hyperalgesia and inflammation after a heat injury were significantly attenuated by blocking C-fiber afferents with local capsaicin. In addition, a central mechanism was indicated since the spread of hyperalgesia to the paw contralateral to a heat injury was prevented by either spinal anesthesia or the blocking of sympathetic efferents by guanethidine. A further role for central mechanisms was indicated since referred hyperalgesia--the enhancement of self-mutilation (autotomy) of a denervated limb which had previously sustained a heat injury--was reduced by spinal anesthesia or a combined blocking of C-fiber afferents and sympathetic efferents with intrathecal capsaicin + guanethidine. The results strongly suggest that referred hyperalgesia after a heat injury is dependent on increased spinal cord activity. However, autotomy in rats that did not undergo a previous injury was unaffected by either spinal anesthesia or intrathecal capsaicin. This suggests that spinal cord hyperactivity, although it plays a role in hyperalgesia following a heat injury, is not a crucial factor in producing pain and hyperalgesia after a nerve injury.     

Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA receptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral and neurochemical consequences of multiple MDMA administrations in the rat: role of individual differences in anxiety-related behavior

Using the elevated plus-maze (EPM), Wistar rats can be distinguished into high (HA) or low anxiety (LA) subjects. These differences seem to reflect traits, since HA and LA rats vary also in other anxiety-dependent tasks, neurochemical mechanisms, and psychopharmacological reactivity, including lasting consequences after single treatment with 3,4-methylenedioxymethamphetamine (MDMA). Here, we tested whether multiple MDMA treatments also have subject-dependent effects. Based on routine EPM screening, male Wistar rats were divided into HA and LA sub-groups, which received five (i.e. multiple) daily injections of MDMA (5 mg/kg) or saline, followed by a test battery, including a challenge test with MDMA, a retest in the EPM, a novel-object test, and a final neurochemical analysis. Acutely, MDMA led to comparable hyperactivity in HA and LA rats. After multiple MDMA, behavioral sensitization was observed, especially in LA rats. Open arm time during the EPM retest (min 0-5) correlated with that of the initial one only in those rats, which had received a single injection of MDMA. Rats with multiple MDMA, especially LA-rats, showed more open-arm time and locomotion during the subsequent 5-10 min of the retest. In a novel-object test, rats with multiple MDMA, again especially LA subjects, showed more exploratory bouts towards the novel object. Neurochemically, multiple MDMA led to moderately lower serotonin in the ventral striatum, and higher dopamine levels in the frontal cortex as compared to single MDMA; these effects were also moderated by subject-dependent factors. Our data show that low-dosed multiple MDMA can lead to behavioral sensitization and outlasting consequences, which affect behavior in the EPM and a novel object task. Detecting such sequels partly requires consideration of individual differences.     

Individual differences in behavior of inbred Lewis rats are associated with severity of joint destruction in adjuvant-induced arthritis

The aim of our study was to test the hypothesis that differences in behavioral characteristics are linked to severity of arthritis in association with neuro-endocrine and immune reactivity in an inbred strain of rats. Lewis rats were selected as high-active (HA) and low-active (LA) animals based on their exploratory activity in the open field. Subsequently, adjuvant-arthritis (AA) was induced in both groups. We observed no differences in the severity of inflammation as determined by paw swelling and redness. However, LA and HA animals differed in the severity of bone destruction as determined on radiographs taken on day 30 after induction of AA. LA rats had more osteoporosis, periostal new bone formation, and bone destruction than HA rats. There were no differences between HA and LA rats in corticosterone response after acute or chronic immune challenge. Splenocytes of LA rats had a lower mitogen-induced IL-10 and IFNgamma production during AA. Histological examination revealed more intense factor VIII staining in arthritic joints of LA animals, indicating more pronounced synovial angiogenesis. In addition, LA rats had higher plasma VEGF, an important angiogenic factor. Expression of RANKL, a crucial factor promoting bone resorption, was also higher in joints of LA animals. Our data demonstrate that activity in the open field, a behavioral trait, is associated with the severity of bone destruction in AA. Lower production of bone-protective cytokines and a higher rate of angiogenesis leading to more synovial proliferation may be responsible for the more severe joint destruction in LA animals.     

Spinal cord injury triggers sensitization of wide dynamic range dorsal horn neurons in segments rostral to the injury

A spinal cord injury (SCI) was produced in adult rats by complete spinal cord transection at L6-S1. Neuropathic pain behaviors similar to the chronic central pain (CCP) syndrome in human, such as thermal hyperalgesia, mechanical allodynia and autotomy, were present in these rats after spinal cord injury. Meanwhile, wide dynamic range (WDR) neurons recorded in the spinal dorsal horn rostral to the lesion responded as high frequency of spontaneous activities, long duration of after-discharges to noxious electrical stimuli and an augmented wind-up to 0.5 Hz stimuli. By using bupivacaine powder, a sodium channel blocker, at the locus of transection immediate after nerve injury, the chronic pain behaviors were prevented; the hyperexcitability of WDR neurons was also substantially reduced. It is suggested that spinal cord transection induces the CCP syndromes, which may be evoked and maintained by the hyperexcitability in WDR neurons rostrally. Reducing the neuronal activity at the site of lesion following injury may prevent the development of CCP after SCI.     

Repair of peripheral nerve transections with fibrin sealant containing neurotrophic factors

Peripheral nerve injury is often followed by incomplete recovery of function and sometimes associated with neuropathic pain. There is, therefore, need for therapies which improve the speed of recovery and the final functional outcome after peripheral nerve injuries. In addition, neuropathic pain is not easily dealt with clinically and should preferably be eliminated. Neurotrophic factors have well-documented abilities to support neuron survival and stimulate neurite outgrowth, making them excellent candidates for use in repairing injured nerves. We investigated the possible beneficial effects of repairing the transected rat sciatic nerve by local application of a fibrin sealant containing nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), or acidic fibroblast growth factor (aFGF). Fibrin sealant was used in conjunction with sutures. Evaluation of motor and sensory function, autotomy, and histological parameters was carried out from 1 to 12 weeks after injury. We demonstrate that NGF cotreatment decreased the occurance of autotomy, suggesting a reduction of neuropathic pain, and improved the performance in motor and sensory tests. In addition, the number of regenerating motoneurons was significantly increased after NGF administration. GDNF increased the speed of sensory recovery, but also markedly increased autotomy, indicating an increased degree of neuropathic pain. aFGF did not alter the outcome of the motor or sensory tests. Fibrin sealant could easily be used in conjunction with sutures to deliver neurotrophic substances locally to the damaged nerve and to enhance recovery of nerve function.     

Behavioral effects of d-cycloserine in rats: the role of anxiety level

It has been reported that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in stress responses and that anxiety is the primary response to stress. Although individual differences in anxiety levels of rats have been demonstrated by using the elevated plus-maze (PM) test, the role of NMDA receptor activity in such individuality of anxiety is not clear. Here, we examined whether low (LA) and high (HA) anxiety rats might respond differently to treatment with d-cycloserine (DCS), a partial agonist of the glycine binding site located on NMDA receptors. Male Wistar rats were screened by using the PM and divided into LA and HA subgroups. On the next day, these rats were again tested in the PM, 30 min after the treatment with DCS (5, 10, or 30 mg/kg ip). Five days later, the rats were subjected to a 2-day forced swim (FS) test, receiving the DCS treatment again 30 min before the second day session. The PM data showed that DCS had anxiogenic effects in LA but not HA rats. The immobility of LA or HA rats in the FS test was not affected by DCS. The results indicate that the behavioral effects of DCS depend on the anxiety level of rats and have task-dependent behavioral consequences, suggesting that glycine binding sites on NMDA receptors are involved in individual differences of anxiety level.     

Alpha-lipoic acid provides neuroprotection from ischemia-reperfusion injury of peripheral nerve

BACKGROUND: Reperfusion aggravates nerve ischemic fiber degeneration, likely by the generation of reduced oxygen species. We therefore evaluated if racemic alpha-lipoic acid (LA), a potent antioxidant, will protect peripheral nerve from reperfusion injury, using our established model of ischemia-reperfusion injury. METHODS: We used male SD rats, 300+/-5 g. Ischemia was produced by the ligature of each of the supplying arteries to the sciatic-tibial nerve of the right hind-limb for predetermined periods of time (either 3 or 5 h), followed by the release of the ligatures, resulting in reperfusion. LA was given intraperitoneally daily for 3 days for both pre- and post-surgery. Animals received either LA, 100 mg/kg/day, or the same volume of saline intraperitoneally. Clinical behavioral score and electrophysiology of motor and sensory nerves were obtained at 1 week after ischemia-reperfusion. After electrophysiological examination, the sciatic-tibial nerve was fixed in situ and embedded in epon. We evaluated for ischemic fiber degeneration (IFD) and edema, as we described previously. RESULTS: Distal sensory conduction (amplitude of sensory action potential and sensory conduction velocity (SCV) of digital nerve) was significantly improved in the 3-h ischemia group, treated with LA (P<0.05). LA also improved IFD of the mid tibial nerve (P=0.0522). LA failed to show favorable effects if the duration of ischemia was longer (5-h ischemia). CONCLUSION: These results suggest that alpha-lipoic acid is efficacious for moderate ischemia-reperfusion, especially on distal sensory nerves.     

APP overexpression prevents neuropathic pain and motoneuron death after peripheral nerve injury in mice

Despite general capacity of peripheral nervous system to regenerate, peripheral nerve injury is often followed by incomplete recovery of function and sometimes burdened by neuropathic pain. Amyloid precursor protein (APP) was suggested to play a role in neuronal growth, however, its role in peripheral nerve repair was not studied. The aim of this study was to examine the role of APP overexpression in peripheral nerve regeneration and neuropathic pain-related behavior in mice. Sciatic nerves of APP overexpressing and FVB/N wild-type mice were transected and immediately resutured. Evaluation of motor and sensory function and autotomy was carried out during 4-week follow up. We found no autotomy behavior as well as less significant atrophy of denervated muscles in APP overexpressing animals when compared to wild-type ones. Sciatic nerve function index outcome did not differ between groups. Histological evaluation revealed that the intensity of regeneration features, including GAP-43-positive growth cones and Schwann cells number in the distal stump of the transected nerve, was also similar in both groups. However, the regenerating fibers were organized more chaotically in wild-type mice and neuromas were much more often seen in this group. The number of macrophages infiltrating the injury site was significantly higher in control group. The number of surviving motoneurons was higher in transgenic mice than in control animals. Taken together, our findings suggest that APP overexpression is beneficial for nerve regeneration processes due to better organization of regenerating fibers, increased survival of motoneurons after autotomy and prevention of neuropathic pain.     

Acute and long-term consequences of single MDMA administration in relation to individual anxiety levels in the rat

Our previous work has shown that normal male Wistar rats can differ systematically in their behavioral response to the elevated plus-maze (EPM), where animals with high (HA) or low anxiety (LA) levels can be identified based on the percentage of time spent in the open arms. These animals also differ in other behavioral tests (e.g. active avoidance), and in their serotonin levels in the ventral striatum. Here, we tested whether such HA and LA rats might respond differently to the amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). This drug can affect psychomotor activation and anxiety; effects which are probably due to its pronounced serotonergic and dopaminergic impacts in the rat brain. Based on a routine screening procedure in the plus-maze, male Wistar rats were divided into HA and LA sub-groups, in which rectal temperature was measured. Thirty minutes after the i.p. injection of MDMA (7.5 or 15 mg/kg) or vehicle, they were again tested in the plus-maze. During the next 3 weeks, the animals underwent further behavioral tests (plus-maze, open field, active avoidance, forced swimming) to test for possible long-term consequences of MDMA. Rectal temperature was found to be higher in LA than HA rats and was especially increased with the higher dose of MDMA (15 mg/kg). In the acute plus-maze test, the lower dose of MDMA led to an anxiogenic-like profile, whereas the higher dose led to an anxiolytic-like profile, both in HA and LA rats. Possible long-term consequences of MDMA were only tested with 7.5 mg/kg MDMA, since the 15 mg/kg dose led to a high level of lethality. The analysis of open field, plus-maze (performed after 9-12 days), and forced swimming behavior (performed after 20-21 days) did not provide indications for lasting effects of MDMA. In contrast, active avoidance learning was impaired in LA- but not HA-rats treated with MDMA. A single injection of MDMA does not only have acute effects on anxiety and psychomotor activation, but can also have some prolonged or delayed task-dependent behavioral consequences. The detection of such sequels can require that individual differences are taken into account and here, determining anxiety levels in the EPM seems to serve as a useful approach.     

APP/SOD1 overexpressing mice present reduced neuropathic pain sensitivity

There are controversies regarding pain expression in mentally disabled people, including Down syndrome patients. The aim of this study was to examine neuropathic pain-related behavior and peripheral nerve regeneration in mouse model of Down syndrome. Sciatic nerves of double transgenic mice, overexpressing both amyloid precursor protein (APP) and Cu/Zn superoxide dismutase (SOD1) genes, and FVB/N wild type mice were transected and immediately resutured. Evaluation of autotomy and functional recovery was carried out during 4-week follow-up. We found markedly less severe autotomy in transgenic animals, although the onset of autotomy was significantly delayed in control mice. Interestingly, neuroma formation at the injury site was significantly more prominent in transgenic animals. Sciatic function index outcome was better in transgenic mice than in wild-type group. Histological evaluation revealed no statistically significant differences in the number of GAP-43-positive growth cones and macrophages in the distal stump of the transected nerve between groups. However, in transgenic animals, the regenerating axons were arranged more chaotically. The number of Schwann cells in the distal stump of the transected nerves was significantly lower in transgenic mice. The number of surviving motoneurons was markedly decreased in transgenic group. We measured also the atrophy of denervated muscles and found it decreased in APP/SOD1 overexpressing mice. Taken together, in this model of Down syndrome, we observed increased neuroma formation and decreased autotomy after peripheral nerve injury. Our findings suggest that APP/SOD1 overexpressing mice are less sensitive for neuropathic pain associated with neuroma.