Sensory afferents regenerated into dorsal columns after spinal cord injury remain in a chronic pathophysiological state

Object Central neuropathic pain is a frequent challenging complication after spinal cord injury (SCI), and specific therapeutic approaches remain elusive. The purpose of the present investigations was to identify potential key mediators of these pain syndromes by analyzing detailed expression profiles of important chemokines in an experimental SCI paradigm of posttraumatic neuropathic pain in rats. Methods Expression of CCR1, CCL3(MIP-1α), CXCR4, and CXCL12(SDF-1α) was investigated in parallel with behavioral testing for mechanical and thermal nociceptive thresholds after standardized SCI; 100-kdyn (moderate injury) and 200-kdyn (severe injury) force-defined thoracic spinal cord contusion lesions were applied via an Infinite Horizon Impactor at the T-9 level. Sham controls received laminectomies. Hindlimb locomotor function as well as mechanical and thermal sensitivities were monitored weekly by standardized behavioral testing after SCI. Chemokine expression was analyzed by real-time reverse transcriptase polymerase chain reaction in the early (7 days postoperatively) and late (42 days postoperatively) time courses after SCI, and immunohistochemical analysis (anatomical and quantitative) was performed 2, 7, 14, and 42 days after lesioning. Double staining with cellular markers and pain-related peptides (substance P and CGRP) or receptors (TRPV-1, TRPV-2, VRL-1, and TLR-4) was performed. Based on data obtained from behavioral testing, quantified immunohistochemical chemokine expressions in individual animals were correlated with the respective mechanical and thermal sensitivity thresholds 6 weeks after SCI. Results After 200-kdyn lesions, the animals exhibited prolonged reduction in their nociceptive thresholds, while 100-kdyn groups showed pain-related behaviors only in the early time course after SCI. Investigated chemokines were widely induced after SCI, involving cervical, thoracic, and lumbar spinal cord levels far beyond the lesion core. CCR1 and CCL3 were induced significantly in the dorsal horns 2 days after lesioning and remained at high levels after SCI with significantly higher intensities after 200-kdyn than 100-kdyn contusions. CXCR4 and CXCL12 levels continuously increased from 2 to 42 days after moderate and severe lesions. Additionally, chemokines were induced significantly in dorsal columns, with highest density levels 42 days after 200-kdyn lesions. In dorsal horns, CCR1 was coexpressed with TRPV-1 while CXCR4 and CXCL12 were partially coexpressed with substance P and CGRP. In dorsal columns, CCL3/CCR1 colabeled with GFAP, TRPV-2, TRPV-1, TLR-4; CXCR4/CXCL12 coexpressed with GFAP, CD68/ED1, and TLR4. Chemokine immunoreactivity density levels, especially CCL3 and its receptor, correlated in part significantly with nociceptive thresholds. Conclusions The authors report lesion grade–dependent upregulation of different chemokines/chemokine receptors after spinal cord contusion lesions in pain-processing spinal cord regions in a clinically relevant model of traumatic SCI in rats. Prolonged chemokine induction further correlated with below-level pain development in the delayed time course after severe SCI and was coexpressed with pain-associated peptides and receptors, suggesting that chemokines play a crucial role in chronic central pain mechanisms after SCI.

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Effects of Acute and Chronic Midthoracic Spinal Cord Injury on Neural Circuits for Male Sexual Function. I. Ascending Pathways

Journal of Neurophysiology ◽

10.1152/jn.1999.82.3.1381 ◽

1999 ◽

Vol 82 (3) ◽

pp. 1381-1389 ◽

Cited By ~ 39

Author(s):

Charles H. Hubscher ◽

Richard D. Johnson

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Sensory Input ◽

The Body ◽

Urogenital Tract ◽

High Threshold ◽

Cord Injury ◽

Nociceptive Information ◽

Ascending Pathways ◽

Dorsal Columns

Normal male reproductive function, particularly ejaculation, requires the integrity of urogenital sensory input and its ascending spinal projections. After midthoracic chronic spinal cord injury, sexual dysfunction occurs in both rats and humans. Neurons in the medullary reticular formation (MRF) are involved in the processing of bilaterally convergent sensory inputs from multiple cutaneous, mucocutaneous, and visceral regions of the body, including the penis and male urogenital tract. A variety of acute and chronic lesions were used to determine the midthoracic location of ascending spinal pathways conveying sensory input from the penis and male urogenital tract to MRF. A total of 371 single neurons were recorded in the MRF of 34 urethan-anesthetized mature male rats. Twenty-seven rats received a chronic T8dorsal (DHx) or lateral (LHx) hemisection or contusion (Cx) injury 30 days before the terminal electrophysiological experiments. In addition, nine dorsal nerve of the penis (DNP)-responsive MRF neurons in seven intact control animals were tested completely both before and after various select acute spinal cord lesions. The chronic lesion data indicate that low and high threshold input from the penis (mucocutaneous) and male urogenital tract (visceral) ascend bilaterally within the dorsal quadrant at T8 as opposed to high threshold input from the hindpaws (cutaneous), which ascends unilaterally in the ventrolateral quadrant (VLQ). The acute lesion data indicate that the low-threshold information conveyed from the penis and male urogenital tract ascends in the dorsal columns, as opposed to the high-threshold nociceptive inputs that ascend bilaterally in the dorsolateral quadrant (DLQ). These results, as well as previous data on ascending projections from female reproductive organs within the dorsal columns and DLQ to other caudal brain stem nuclei, provide evidence for ascending pathways conveying nociceptive information centrally via the DLQ. This spinal gray-DLQ pathway(s) conveying information from mucocutaneous/pelvic/visceral territories therefore differs from the traditionally recognized spinal gray-VLQ pathway(s), which is known to convey nociceptive information from cutaneous regions of the body.

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Motor improvements enabled by spinal cord stimulation combined with physical training after spinal cord injury: review of experimental evidence in animals and humans

Bioelectronic Medicine ◽

10.1186/s42234-021-00077-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Ismael Seáñez ◽

Marco Capogrosso

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Animal Models ◽

Motor Function ◽

Physical Training ◽

Spinal Cord Stimulation ◽

Task Complexity ◽

Sensory Afferents ◽

Cord Injury ◽

Complex Motor

AbstractElectrical spinal cord stimulation (SCS) has been gaining momentum as a potential therapy for motor paralysis in consequence of spinal cord injury (SCI). Specifically, recent studies combining SCS with activity-based training have reported unprecedented improvements in motor function in people with chronic SCI that persist even without stimulation. In this work, we first provide an overview of the critical scientific advancements that have led to the current uses of SCS in neurorehabilitation: e.g. the understanding that SCS activates dormant spinal circuits below the lesion by recruiting large-to-medium diameter sensory afferents within the posterior roots. We discuss how this led to the standardization of implant position which resulted in consistent observations by independent clinical studies that SCS in combination with physical training promotes improvements in motor performance and neurorecovery. While all reported participants were able to move previously paralyzed limbs from day 1, recovery of more complex motor functions was gradual, and the timeframe for first observations was proportional to the task complexity. Interestingly, individuals with SCI classified as AIS B and C regained motor function in paralyzed joints even without stimulation, but not individuals with motor and sensory complete SCI (AIS A). Experiments in animal models of SCI investigating the potential mechanisms underpinning this neurorecovery suggest a synaptic reorganization of cortico-reticulo-spinal circuits that correlate with improvements in voluntary motor control. Future experiments in humans and animal models of paralysis will be critical to understand the potential and limits for functional improvements in people with different types, levels, timeframes, and severities of SCI.

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