Motor activity affects dopaminergic and noradrenergic systems of the dorsal horn of the rat lumbar spinal cord.

Dopamine (DA) and noradrenaline (NA) modulate responses to nociceptive stimuli, within the dorsal horn of the spinal cord. Both neurotransmitters may play a role in supraspinal regulation in response to proprioceptive afferences to the dorsal horn. However, direct evidence of changes in neurotransmitter release within the dorsal horn due to non-noxious stimuli is lacking. The present study was designed to determine, whether non-nociceptive exercise produces changes in release of DA and NA within the dorsal horn, and whether these changes are associated with long-lasting inhibition after the exercise stops. Microdialysis probes, implanted in layers 2-5 of Rexed, in combination with high-performance liquid chromatography coupled to electrochemical detection (HPLC-EC) were used to measure concentrations of DA and NA metabolite (MHPG) in lumbar spinal cords of rats. Microdialysate was sampled before, during, and after a treadmill exercise of one hour. Results indicate that DA and NA releases are inhibited during non-nociceptive motor activity. At rest, DA concentration was 204 ± 10.5 pg/10 µl and was significantly decreased during exercise to -11.4% (P ≤ 0.05). Greater decrease occurred after 30 min of exercise and was of -31.4% (P ≤ 0.05). Similarly, MHPG was significantly decreased of -18% during exercise (P ≤ 0.05). When exercise stopped, both systems showed long-lasting inhibition. Exercise post-release lasted 30 min for DA and 90 min for MHPG. MHPG greatest decrease of -47.8% occurred 30 min after stopping the exercise (P ≤ 0.001). Thus, DA and NA systems seem to respond to exercise-induced proprioceptive afferent stimuli to the dorsal horn.

Combination strategies for repair, plasticity, and regeneration using regulation of gene expression during the chronic phase after spinal cord injury.

Although recovery after spinal cord injury (SCI) is rare in humans, recent literature indicates that some patients do recover sensorimotor function years after the trauma. This study seeks to elucidate the genetic underpinnings of SCI repair through the investigation of neurodegenerative and regenerative associated genes involved in the response to SCI during the chronic phase in adult rats. Intervention on the level of gene regulation focused on enhancing naturally attempting SCI regenerative genes has the potential to promote SCI repair. Our aim was to analyze gene expression characteristics of candidate genes involved in the neuro-degenerative and -regenerative processes following various animal models of SCI. We compiled data showing gene expression changes after SCI in adult rats and created a chronological time-line of candidate genes differentially expressed during the chronic phase of SCI. Compiled data showed that SCI induced a transient upregulation of endogenous neuro-regenerative genes not only within a few hours but also within a few days, weeks, and months after SCI. For example, gene controlling growth-associated protein-43 (GAP-43), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and others, showed significant changes in mRNA accumulation in SCI animals, from 48 hours to 12 weeks after SCI. Similarly, inhibitory genes, such as RhoA, LINGO-1, and others, were upregulated as late as 4 to 14 days after injury. This indicates that gene specific regulation changes, corresponding to repair and regenerative attempts, are naturally orchestrated over time after injury. These delayed changes after SCI give ample time for therapeutic gene modulation through upregulation or silencing of specific genes responsible for the synthesis of the corresponding biogenic proteins. By following the examination of differential gene regulation during the chronic phase, we have determined times, successions, co-activations, interferences, and dosages for potential therapeutic synchronized interventions. Finally, local cellular specificities and their neuropathophysiologies have been taken into account in the elaboration of the combination treatment strategy we propose. The interventions we propose suggest the delivery of exogenous therapeutic agents to upregulate or downregulate chosen genes or the expression of the downstream proteins to revert the post-traumatic stage of SCI during the chronic phase. The proposed combination and schedule of local cell-specific treatment should enhance intrinsic regenerative machinery and provide a promising strategy for treating patients sustaining chronic SCI.

Serotonin release variations during recovery of motor function after a spinal cord injury in rats.

Current literature suggests that serotonin (5-HT) release within the ventral horn of the spinal cord plays a role in motor function. We hypothesized that endogenous 5-HT release is involved in the recovery of motor function after spinal cord injury. To appreciate the functional parameters of regenerating serotonergic fibers, a microdialysis probe was stereotactically implanted in the ventral horn of subhemi-lesioned rats. Microdialysis in combination with HPLC was used to measure concentrations of 5-HT in the lumbar ventral horn during periods of rest (90 min), treadmill run (60 min) and postexercise rest (90 min) for a 1-month time period of recovery following the surgical lesion. Within the same period of time, 5-HT levels varied significantly. A significant (202%) increase was observed at day 18 postlesion relative to day 8, and a 16.4% decrease was observed at day 34 relative to day 18. Treadmill exercise challenge induced a 10% decrease of 5-HT release relative to rest at days 18 and 34. In conclusion, overtime treadmill locomotor recovery is parallel to amounts (rest basal levels) and patterns (exercise and postexercise levels) of 5-HT release suggesting that changes in serotonergic system occurred within the same time frame than locomotor recovery using treadmill challenge.