mouse models of spinal cord injury

However, in experimental animals, these injuries are most frequently induced dorsally and in the thoracic spine, whereas most clinical injuries occur anteriorly and in the cervical region (Akhtar et al., 2008). Piao MS, Lee JK, Jang JW, Kim SH, Kim HS. B. Nielsen, Reduced reciprocal inhibition is seen only in spastic limbs in patients with neurolathyrism,, S. A. Edgley and N. C. Aggelopoulos, Short latency crossed inhibitory reflex actions evoked from cutaneous afferents,, A. D. Bennett, A. W. Everhart, and C. E. Hulsebosch, Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury,, M. D. Christensen, A. W. Everhart, J. T. Pickelman, and C. E. Hulsebosch, Mechanical and thermal allodynia in chronic central pain following spinal cord injury,, B. C. Hains, K. M. Chastain, A. W. Everhart, D. J. McAdoo, and C. E. Hulsebosch, Transplants of adrenal medullary chromaffin cells reduce forelimb and hindlimb allodynia in a rodent model of chronic central pain after spinal cord hemisection injury,, M. F. Coronel, F. Labombarda, M. J. Villar, A. F. De Nicola, and S. L. Gonzlez, Progesterone prevents allodynia after experimental spinal cord injury,, D. H. Roh, S. Y. Yoon, H. S. Seo et al., Intrathecal injection of carbenoxolone, a gap junction decoupler, attenuates the induction of below-level neuropathic pain after spinal cord injury in rats,, J. Kim, J. H. Kim, Y. Kim, H. Y. Cho, S. K. Hong, and Y. W. Yoon, Role of spinal cholecystokinin in neuropathic pain after spinal cord hemisection in rats,, Y. S. Gwak and C. E. Hulsebosch, Remote astrocytic and microglial activation modulates neuronal hyperexcitability and below-level neuropathic pain after spinal injury in rat,, F. Marchand, C. Tsantoulas, D. Singh et al., Effects of Etanercept and Minocycline in a rat model of spinal cord injury,, Y. Lu, J. Zheng, L. Xiong, M. Zimmermann, and J. Yang, Spinal cord injury-induced attenuation of GABAergic inhibition in spinal dorsal horn circuits is associated with down-regulation of the chloride transporter KCC2 in rat,, F. Labombarda, M. F. Coronel, M. J. Villar, A. F. D. Nicola, and S. L. Gonzlez, Neuropathic pain and temporal expression of preprodynorphin, protein kinase C and N-methyl-d-aspartate receptor subunits after spinal cord injury,, W. Liu, Z. Liu, LI. It is crucial for a pain clinician to distinguish between nociceptive or neuropathic pain, because the clinical approach for each is different. These include contusion impactors (Krishna et al., 2013) and clip compression (Alluin et al., 2011). Lumbar canal stenosis is due to entrapment of the cauda equine and/or lumber nerve roots by hypertrophy of osseous and soft tissue structures surrounding the lumbar spinal canal. Inflammation is known to be detrimental to the neurologic outcome during the acute phase after an injury, and therefore provides a potential target for preventive or therapeutic approaches for spinal cord ischemia-reperfusion injury (Li et al., 2014). This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Some studies have predominately used rodents for in vivo SCI modeling and experimentation (Gonzalez-Lara et al., 2009; Basoglu et al., 2013). Motoneuron and sensory neurons are often regulated by common mechanisms [127], and common molecular mechanisms could be responsible for below-level neuropathic pain and spasticity [18, 37]. Most SCI in humans affects the anterior spinal artery that supplies three quarters of cord tissue, in contrast to the dorsal arteries that are more commonly affected in experimental SCI (de la Torre, 1981). A. Acetone is applied 5 times to each paw at an interval of at least 5 minutes. According to the National Spinal Cord Injury Statistical Center, in 2005, 51% of SCI cases in the U.S. occurred in the cervical region (Akhtar et al., 2008). In chronic states, secondary overuse or abnormal use of structures, such as the arm and shoulder, occurs [17]. In addition, a multitude of behavioral outcome measures have become widely available. 2012;9:380392, 32. According to studies published in flagship journals, pain studies comprise approximately 25% of total studies, more than any other field of study [27]. A novel porcine model of traumatic thoracic spinal cord injury J Neurotrauma. Highlight selected keywords in the article text. In the future, several points should be addressed. SCI pain classification by Bryce and Ragnarsson. Aprikalim a potassium adenosine triphosphate channel opener reduces neurologic injury in a rabbit model of spinal cord ischemia Int J Surg. Gait (CatWalk) and ladder climbing have also been assessed (van Gorp et al., 2013). Lafci G, Gedik HS, Korkmaz K, Erdem H, Cicek OF, Nacar OA, Yildirim L, Kaya E, Ankarali H. Efficacy of iloprost and montelukast combination on spinal cord ischemia/reperfusion injury in a rat model J Cardiothorac Surg. However, it is likely that too many genes are involved [26]. Up to 80% of patients experience clinically significant pain, which is described as burning, stabbing, and/or electric-like [9, 10]. Yu CG, Singh R, Crowdus C, Raza K, Kincer J, Geddes JW. (1991) developed a rat model of photochemical-induced SCI, in which female rats were intravenously injected with Erythrosin B and the T10 vertebra was irradiated with a laser beam for 1, 5 or 10 minutes. By continuing to use this website you are giving consent to cookies being used. The unique features of controlled displacement and monitoring of biomechanical parameters at the time of impact help to reduce outcome variability [105]. Limited success in the pain field during the past few decades has resulted in a plethora of basic scientific data. 2009;46:479483, 33. Battistuzzo CR, Callister RJ, Callister R, Galea MP. Following injury, motor function analysis is needed to exclude unilateral paralysis and the possibility of unilateral contusion. Recently, these various SCI animal models have been utilized for pain studies [5]. Observation and establishment of an animal model of tractive spinal cord injury in rats Chin J Traumatol. Several major problems still exist in understanding SCI in animal models and humans: (1) the lack of anatomical and pathophysiological correlation between experimental SCI and clinical SCI; (2) lack of congruent SCI pathology between different species and strains; (3) difficulties in interpreting outcomes measured in animals. Overall, we can conclude that accurate measurement of fine motor and sensory function in animals, especially in rodents, is quite difficult. 2000;17:317324, 39. A cost-effective approach for an experimental SCI rat model has been to create a customized impact device (Vijayaprakash and Sridharan, 2013), which is a customized blunt-force impact device designed to induce a standard animal model of contusive SCI at the thoracic level. Liu L, Chi LT, Tu ZQ, Sheng B, Zhou ZK, Pei FX. Aya Nakae, Kunihiro Nakai, Kenji Yano, Ko Hosokawa, Masahiko Shibata, Takashi Mashimo, "The Animal Model of Spinal Cord Injury as an Experimental Pain Model", BioMed Research International, vol. Locomotor function is observed and recorded using the Basso, Beattie, and Bresnahan (BBB) Locomotor Rating Scale [95]. For example, some animal studies benefit from the treatment of acute SCI. It is important to understand the pathologies in each model. Possible mechanisms for observed pathophysiological variability in experimental spinal cord injury by the method of Allen J Neurosurg. All authors approved the final version of this manuscript. Spinal cord injury leads to immediate impaired motor and sensory functions, which are also manifested over time. The development of reliable neurotrauma mouse models provides great promise for evaluating overexpression or inactivation of certain genes on lesion pathophysiology and functional outcome. Wolters Kluwer Health However, the direct translation of the results from rodents to clinical cases is difficult because of neurofunctional and anatomic differences between the two species. These endpoint measurements produce interpretable and comparable results between studies. However, clinical trials have, thus far, been uniformly disappointing. Both the Tarlov and inclined plane tests assess general locomotor ability and do not reflect specific changes in motor or sensory function (Kunkel-Bagden et al., 1993). Fan L, Wang K, Shi Z, Die J, Wang C, Dang X. Tetramethylpyrazine protects spinal cord and reduces inflammation in a rat model of spinal cord ischemia-reperfusion injury J Vasc Surg. However, more attention should be focused on motor recovery while evaluating pain behavior, because of the delayed motor recovery in mice compared with rats [32, 33]. Akhtar AZ, Pippin JJ, Sandusky CB. Either clip is dorsoventrally closed over the entire cord for 1min and then subsequently removed [58, 100102]. Animal models of neurologic disorders: a nonhuman primate model of spinal cord injury Neurotherapeutics. However, when SCI animal models are used for pain research, special attention should be paid to the concomitant conditions. Canal stenosis can also be termed a spinal cord injury model, in which square-shaped pieces of silicon are placed into the epidural space in the rat [106, 107]. Kunkel-Bagden E, Dai HN, Bregman BS. 2011;54:192200. Many spinal cord injury models exist for pain research. The forelimb asymmetry, or paw preference test, is sensitive to asymmetries produced by a variety of CNS insults [117]. This results in gradual increases in the degree of histopathological injury leading to decreased Tarlov and BBB scores for the behavioral test and increased Ashworth scores for the hind limb. Several models of neuropathic pain due to spinal cord injury have been simulated in rats. 2006;59:957982, 41. The pathology of human SCI is not greatly different from that of experimental animals, although important specific differences exist. 2014;7:28, 27. These patients typically cannot only walk, but also lose bowel, bladder, and sexual functions. Because there is no curative treatment for spinal cord injury, establishing an ideal animal model is important to identify injury mechanisms and develop therapies for individuals suffering from spinal cord injuries. For more information, please refer to our Privacy Policy. Kwon BK, Okon EB, Tsai E, Beattie MS, Bresnahan JC, Magnuson DK, Reier PJ, McTigue DM, Popovich PG, Blight AR, Oudega M, Guest JD, Weaver LC, Fehlings MG, Tetzlaff W. A grading system to evaluate objectively the strength of pre-clinical data of acute neuroprotective therapies for clinical translation in spinal cord injury J Neurotrauma. Koozekanani SH, Vise WM, Hashemi RM, McGhee RB. Therefore, this model could provide useful and novel insights into the underlying biological mechanisms of spinal cord injury [108]. 2011;197:97103, 36. In excitotoxic animal models, nearly 100% animals develop varying degrees of hypersensitivity to mechanical and thermal stimuli [98]. With the exposed spinal column intact, 560 nm light irradiation of the dorsal surface induces excitation of the systemically injected dye, rose bengal, in the spinal cord microvasculature (Watson et al., 1986). The promotion of, 15. Future studies should extend the scope of inquiry to include the psychosocial aspects of chronic pain and spinal cord injury. Watson BD, Prado R, Dietrich WD, Ginsberg MD, Green BA. Pathology in visceral structures, such as urinary tract infection, bowel impaction, and renal calculi, generally results in nociceptive pain. This model is designed to lesion only the spinothalamic tract area using a tungsten microelectrode. Differences in injury exist between experimental and clinical SCI. In human SCI, trauma severity is not proportional to pain severity, because the method of injury varies. Motor and sensory dysfunction has been periodically assessed using open field locomotion scoring, thermal/tactile pain/escape thresholds, and myogenic motor evoked potentials. Experimental SCI is induced by dropping calibrated weights through a vented tube onto a small impounder resting on the surgically exposed cord (Koozekanani et al., 1976). Following cervical spinal cord injury, recovery of forelimb function can be measured [114] by indicators such as the grooming test and forelimb asymmetry test [115]. 2011;25:705710, 48. These models have also been adapted for mice [2831]. This results in an intense platelet response, as well as subsequent vessel occlusion and parenchymal tissue infarction [83]; the pathology is of a purely ischemic origin. Awad H, Ankeny DP, Guan Z, Wei P, McTigue DM, Popovich PG. Lozos VA, Toumpoulis IK, Agrogiannis G, Giamarellos-Bourboulis EJ, Chamogeorgakis TP, Rizos IK, Patsouris ES, Anagnostopoulos CE, Rokkas CK. The tractive SCI rat models can also be successfully established with a spinal impactor, and monitoring the somatosensory evoked potential for several minutes is more suitable for studying tractive SCI (Wang et al., 2011). 2013;4:57, 44. However, SCI caused by impact and compression is more common in clinical patients. In response to noxious stimuli, behaviors can be reliably and objectively scored, although these simple reflexes or innate responses (such as licking an inflamed paw) seem to lack clinical validity. The primary mechanisms hypothesized to be responsible for spasticity are increased motoneuron excitability [122, 123] and increased synaptic input, as a result of muscle stretch and reduced inhibitory mechanisms (presynaptic [124] and reciprocal inhibitions [125]). Stereotactic radiosurgery improves locomotor recovery after spinal cord injury in rats Neurosurgery. Pain behavior should not be measured in injured animals during maximal motor dysfunction. Lee JH, Tigchelaar S, Liu J, Stammers AM, Streijger F, Tetzlaff W, Kwon BK. Kwon BK, Okon EB, Plunet W, Baptiste D, Fouad K, Hillyer J, Weaver LC, Fehlings MG, Tetzlaff W. A systematic review of directly applied biologic therapies for acute spinal cord injury J Neurotrauma. Rivlin AS, Tator CH. Intraspinal or intrathecally injection of some excitotoxins, such as quisqualic acid or other excitatory amino acids (glutamate, N-methylasparate, and kainic acid), produces long-lasting spontaneous pain, mechanical allodynia, and thermal hyperalgesia in rats and mice [97, 98]. Scores from 0 to 7 rank early phase of recovery, with return of isolated movements from three joints (hip, knee, and ankle); scores from 8 to 13 describe the intermediate recovery phase with, return of paw placement, stepping, and forelimb-hindlimb coordination; and scores from 14 to 21 represent late phase of recovery, with return of toe clearance during the step phase, predominant paw position, trunk stability, and tail position. A. Ricci, E. Chee, D. Morganstein, and R. Lipton, Lost productive time and cost due to common pain conditions in the US workforce,, J. S. Richards, R. L. Meredith, C. Nepomuceno, P. R. Fine, and G. Bennett, Psycho-social aspects of chronic pain in spinal cord injury,, N. B. Finnerup, I. L. Johannesen, S. H. Sindrup, F. W. Bach, and T. S. Jensen, Pain and dysesthesia in patients with spinal cord injury: a postal survey,, P. J. Siddall, J. M. McClelland, S. B. Rutkowski, and M. J. Cousins, A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury,, D. H. Rintala, P. G. Loubser, J. Castro, K. A. Hart, and M. J. Fuhrer, Chronic pain in a community-based sample of men with spinal cord injury: prevalence, severity, and relationship with impairment, disability, handicap, and subjective well-being,, T. E. Balazy, Clinical management of chronic pain in spinal cord injury,, J. Blight AR. [. Thoracic or thoracoabdominal aortic aneurysm surgery may cause spinal cord ischemia. Implantation of scaffolding biomaterials is applicable to this kind of SCI model, and these biomaterials provide effective bridging and stimulating effects on neural regeneration and prevent the formation of glial scars in the completely transected SCI rat models (Han et al., 2010). Alluin O, Karimi-Abdolrezaee S, Delivet-Mongrain H, Leblond H, Fehlings MG, Rossignol S. Kinematic study of locomotor recovery after spinal cord clip compression injury in rats J Neurotrauma. Min SH, Lee SH, Shim H, Park JS, Lee YI, Kim HW, Hyun JK. Li XQ, Wang J, Fang B, Tan WF, Ma H. Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood-spinal cord barrier following ischemia/reperfusion injury in rats Mol Brain. A long-term epidemiological survey from Denmark Spinal Cord. Sroga JM, Jones TB, Kigerl KA, McGaughy VM, Popovich PG. Treatment effectiveness in animals with SCI is often measured simply by whether or not independent ambulation has occurred. Possible explanations for the discrepancy may be due to the heterogeneity of human SCI and the challenging nature of measuring neurological function in clinical trial settings (Kwon et al., 2011). Like contusion injury in humans, rat contusion injury leads to the formation of both small and large cavities and fluid-filled cysts (Sroga et al., 2003; Norenberg et al., 2004). A summary of results from 10 studies indicates that an average of 69% of the patients experienced pain, and nearly one-third of patients in pain rated their pain as severe [6]. Lozos et al. The number of brisk foot withdrawals is recorded. Therefore, motor deficit scores, such as BBB [95] and CBS [96], have been widely utilized [86, 90]. For SCI research, it is essential to establish an ideal animal model of SCI. The von Frey hair can also be used to determine vocalization threshold to graded mechanical allodynia as a means to evaluate at-level neuropathic pain in the trunk [92]. Ackery A, Tator C, Krassioukov A. Sun T, Schlag MG, Hopf R, Shen Q, Redl H. Brainstem-evoked muscle potentials: their prognostic value in experimental spinal cord injury in the rat Somatosens Mot Res. Liu et al., A novel human foamy virus mediated gene transfer of GAD67 reduces neuropathic pain following spinal cord injury,, N. E. Saad, H. A. Amin, S. Chalouhi, S. A. Baki, S. J. Jabbur, and S. F. Atweh, Spinal pathways involved in supraspinal modulation of neuropathic manifestations in rats,, X. M. Peng, Z. G. Zhou, J. C. Glorioso, D. J. Fink, and M. Mata, Tumor necrosis factor-, J. Kim, Y. W. Yoon, S. K. Hong, and H. S. Na, Cold and mechanical allodynia in both hindpaws and tail following thoracic spinal cord hemisection in rats: time courses and their correlates,, B. C. Hains, K. M. Johnson, M. J. Eaton, W. D. Willis, and C. E. Hulsebosch, Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitability of dorsal horn neurons after spinal hemisection in rat,, Y. S. Gwak, B. C. Hains, K. M. Johnson, and C. E. Hulsebosch, Effect of age at time of spinal cord injury on behavioral outcomes in rat,, C. D. Mills, B. C. Hains, K. M. Johnson, and C. E. Hulsebosch, Strain and model differences in behavioral outcomes after spinal cord injury in rat,, J. H.T. Tractive SCI model: To establish an animal model of tractive SCI in rats, Liu et al. Your message has been successfully sent to your colleague. These procedures initiated an intravascular photochemical reaction, resulting in ischemic SCI. Nout YS, Rosenzweig ES, Brock JH, Strand SC, Moseanko R, Hawbecker S, Zdunowski S, Nielson JL, Roy RR, Courtine G, Ferguson AR, Edgerton VR, Beattie MS, Bresnahan JC, Tuszynski MH. 1977;47:577581, 35. Cervical contusion is rarely reported, because life-threatening adverse effects could occur. Following excitotoxin injections, neuronal loss, cavity formation, astrocytic scaring, and prominent inflammation occur. Epidemiology demographics and pathophysiology of acute spinal cord injury Spine (Phila Pa 1976). 2010;34:184192 192, 43. van Gorp S, Leerink M, Kakinohana O, Platoshyn O, Santucci C, Galik J, Joosten EA, Hruska-Plochan M, Goldberg D, Marsala S, Johe K, Ciacci JD, Marsala M. Amelioration of motor/sensory dysfunction and spasticity in a rat model of acute lumbar spinal cord injury by human neural stem cell transplantation Stem Cell Res Ther. The spinal cord displacement model attempts to regulate trauma impact by controlling displacement length of the spinal cord. The spinal cord injury model, in particular the spinal transaction model, is considered useful for spasticity research. Experimental failures with novel drugs are associated with adverse side effects and the lack of efficacy in humans. Hoque MF, Grangeon C, Reed K. Spinal cord lesions in Bangladesh: an epidemiological study 1994 - 1995 Spinal Cord. [96] and termed the Combined Behavioral Score (CBS) (Table 4), has been used to measure locomotor function. In terms of animal behavior, this classification helps to provide a better understanding of pain pathology. Zurita M, Aguayo C, Bonilla C, Otero L, Rico M, Rodriguez A, Vaquero J. Methods for reproducible and controlled SCI models have been well described. A similar contusion injury in mice results in the development of a dense connective tissue matrix that more closely resembles the long-term effects of some laceration and massive compression injuries in humans (Sroga et al., 2003; Norenberg et al., 2004). The animal skin is briskly stroked with a pencil point in a rostral to caudal direction. 1954;71:271290, 40. Three to five minutes are allowed between each trial, and three trials are averaged for each limb. Bryce et al. Animal models cannot self-report. Pathological reactions between the von Frey probe and pencil point vary due to reactions to the von Frey hair (caused by A-delta-fiber and C-fiber) or the pencil (A-beta fiber). Du, H. Y. Tan et al., Peripheral and central sensitization in remote spinal cord regions contribute to central neuropathic pain after spinal cord injury,, T. Furuya, M. Hashimoto, M. Koda et al., Treatment of rat spinal cord injury with a Rho-kinase inhibitor and bone marrow stromal cell transplantation,, I. D. Hentall and S. B. Burns, Restorative effects of stimulating medullary raphe after spinal cord injury,, M. A. Hook, G. Moreno, S. Woller et al., Intrathecal morphine attenuates recovery of function after a spinal cord injury,, S. Lord-Fontaine, F. Yang, Q. Diep et al., Local inhibition of Rho signaling by cell-permeable recombinant protein BA-210 prevents secondary damage and promotes functional recovery following acute spinal cord injury,, A. M. Tan, S. Stamboulian, Y. W. Chang et al., Neuropathic pain memory is maintained by Rac1-regulated dendritic spine remodeling after spinal cord injury,, F. Knerlich-Lukoschus, M. Juraschek, U. Blmer, R. Lucius, H. M. Mehdorn, and J. Held-Feindt, Force-dependent development of neuropathic central pain and time-related CCL2/CCR2 expression after graded spinal cord contusion injuries of the rat,, Y. Berrocal, D. D. Pearse, A. Singh et al., Social and environmental enrichment improves sensory and motor recovery after severe contusive spinal cord injury in the rat,, J. Biernaskie, J. S. Sparling, J. Liu et al., Skin-derived precursors generate myelinating Schwann cells that promote remyelination and functional recovery after contusion spinal cord injury,, M. G. Dombourian, N. A. Turner, T. A. Gerovac et al., B1 and TRPV-1 receptor genes and their relationship to hyperalgesia following spinal cord injury,, C. D. Mills, J. J. Grady, and C. E. Hulsebosch, Changes in exploratory behavior as a measure of chronic central pain following spinal cord injury,, C. H. Hubscher, J. D. Fell, and D. S. Gupta, Sex and hormonal variations in the development of at-level allodynia in a rat chronic spinal cord injury model,, C. H. Hubscher, E. G. Kaddumi, and R. D. Johnson, Segmental neuropathic pain does not develop in male rats with complete spinal transections,, J. Voda, A. Hama, and J. Sagen, FK506 reduces the severity of cutaneous hypersensitivity in rats with a spinal cord contusion,, B. C. Hains, J. P. Klein, C. Y. Saab, M. J. Craner, J.

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