Elsevier

Neuroscience

Volume 199, 29 December 2011, Pages 86-102
Neuroscience

Cellular and Molecular Neuroscience
Research Paper
Intermittent noxious stimulation following spinal cord contusion injury impairs locomotor recovery and reduces spinal brain-derived neurotrophic factor–tropomyosin-receptor kinase signaling in adult rats

https://doi.org/10.1016/j.neuroscience.2011.10.007Get rights and content

Abstract

Intermittent nociceptive stimulation following a complete transection or contused spinal cord injury (SCI) has been shown to exert several short- and long-lasting negative consequences. These include maladaptive spinal plasticity, enhanced mechanical allodynia, and impaired functional recovery of locomotor and bladder functions. The neurotrophin, brain-derived neurotrophic factor (BDNF) has been shown to play an important role in adaptive plasticity and also to restore functions following SCI. This suggests that the negative behavioral effects of shock are most likely related to corresponding changes in BDNF spinal levels. In this study, we investigated the cellular effects of nociceptive stimulation in contused adult rats focusing on BDNF, its receptor, tropomyosin-receptor kinase (TrkB), and the subsequent downstream signaling system. The goal was to determine whether the behavioral effect of stimulation is associated with concomitant cellular changes induced during the initial post-injury period. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to assess changes in the mRNA and/or protein levels of BDNF, TrkB, and the downstream signaling proteins calcium-calmodulin kinase II (CaMKII) and extracellular related kinase 1/2 (ERK1/2) at 1 h, 24 h, and 7 days following administration of intermittent noxious shock to the tail of contused subjects. In addition, recovery of locomotor function (Basso, Beattie, and Bresnahan [BBB] score) was assessed daily for the first week after injury. The results showed that, although nociceptive stimulation failed to induce any changes in gene expression at 1 h, it significantly reduced the expression of BDNF, TrkB, ERK2, and CaMKII at 24 h. In general, changes in gene expression were spatially localized to the dorsal spinal cord. In addition, locomotor recovery was impaired by shock. Evidence is also provided suggesting that shock engages a neuronal circuitry without having any negative effects on neuronal survival at 24 h. These results suggest that nociceptive activity following SCI decreases BDNF and TrkB levels, which may significantly contribute to diminished functional recovery.

Highlights

▶Noxious stimulation after SCI impairs the recovery of locomotor functions. ▶Spinal BDNF and TrkB levels are decreased by noxious stimulation following SCI. ▶Shock engages a neuronal circuitry in the dorsal spinal cord. ▶Impaired locomotor recovery is associated with decreased BDNF-TrkB levels.

Section snippets

Experimental procedures

Male Sprague–Dawley rats obtained from Harlan (Houston, TX, USA) served as subjects. Rats were approximately 90–110 days old and weighed between 350 and 400 g. They were housed individually and maintained on a 12-h light/dark cycle, with all behavioral testing performed during the light cycle. Food and water were available ad libitum. All experiments were carried out in accordance with NIH standards for the care and use of laboratory animals (NIH publications No. 80-23) and were approved by the

Results

Previously, we showed that in adult rats with a complete T2 transection, uncontrollable intermittent shock inhibits adaptive plasticity (Grau et al., 1998) and causes a down-regulation in BDNF mRNA expression within the lumbar spinal cord (Gómez-Pinilla et al., 2007). The same intermittent stimulation also impairs recovery after a contusion injury (Grau et al., 2004). Here, we investigated the cellular pathways that may mediate the detrimental effects of intermittent noxious shock in spinal

Discussion

In several previous studies, we have identified conditions that undermine plasticity or recovery of locomotor functions following SCI. For example, administration of intermittent stimulation to the leg or tail disrupts adaptive plasticity and induces a learning deficit, which lasts up to 48 h in completely transected rats (Crown et al., 2002a). This stimulation paradigm undermines the recovery of locomotor functions in spinal contused rats (Grau et al., 2004). In addition to electrical

Conclusion

This study identifies a potential mechanism for stimulation-induced maladaptive plasticity following SCI. Stimulation that produces a learning deficit significantly decreased components of the BDNF pathway at the lesion site. Although excess BDNF, indicative of peripheral injury or inflammation, can increase BDNF levels beyond normal and consequently lead to central sensitization or pain, following SCI, an increase in spinal BDNF levels can be restorative. On the other end of the spectrum,

Acknowledgments

This work was funded by National Institute of Neurological Disorders and Stroke (NS41548) and National Institute of Child Health and Human Development (HD058412). The authors wish to thank John Hartman for technical assistance and Dr. Kevin Hoy for reviewing an earlier version of this manuscript.

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    Present address: University of California, San Francisco, 1001 Potrero Avenue, Bldg. 1, Room 101, San Francisco, CA 94110, USA.

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