Mechanisms of Neuropathic Pain following Spinal Cord Injury

Neuropathic pain (NP) is a common and severe complication after spinal cord injury (SCI). It has been associated with a variety of pathophysiological processes along the entire nociceptive system. An underlying hyperresponsiveness of nociceptive neurons within the central nervous system is assumed in chronic pain sufferers. This enhanced excitability is likely attributed to a shift towards pro-nociceptive mechanisms which is based on increased facilitatory aspects and/or decreased inhibitory aspects within the nociceptive system. Thus, the understanding of the underlying mechanisms in central NP is necessary in order to provide mechanism-based treatment approaches. Therefore, this thesis aimed to improve the phenotyping of NP after SCI employing sophisticated pain drawings, neurophysiological methods, and experimental protocols assessing the balance between pro- and anti-nociceptive mechanisms. In the first study (Chapter 2), we aimed to establish the test-retest reliability of standardized quantitative pain drawings, and related the findings to NP characteristics in paraplegic subjects. The excellent reliability of pain extent and intensity was a cornerstone for employing these pain drawings in the following studies. Additionally, we observed a correlation between sensory loss and spatial extent of NP which may indicate that deafferentation is leading to supra-spinal maladaptive plasticity, e.g., cortical reorganization. These findings are in line with the concept of “pain centralization” which has previously been related to widespread pain extent. The improved assessment of the nociceptive neuraxis has been addressed in two studies. A recently developed electrode for intra-epidermal electrical stimulation (Chapter 3) was assumed to specifically activate free nerve endings in the epidermal layer in a receptor-unspecific fashion. We observed higher robustness and signal-to-noise ratio of pain-related evoked potentials after intra-epidermal electrical stimulation compared to contact heat stimulation that elicits similar pain intensity. Additionally, in a patient case of a spinal disorder, the electrical but not thermal stimulation elicited evoked potentials which is indicative of activating preserved nociceptive fibers, and highlights its added value for clinical neurophysiology. A further advancement in the investigation of nociceptive tract integrity (Chapter 4) was achieved by recording a pain-autonomic measure, i.e., sympathetic skin response, after contact heat stimulation. Preserved nociceptive function was recorded in subjects with clinically graded abolished function. The investigation of pro- and anti-nociceptive mechanisms was performed in the fourth and fifth study (Chapter 5 and 6). Enhanced temporal summation of pain for tonic heat stimulation, which is a facilitatory aspect within the central nervous system, has been revealed in SCI subjects with NP compared to those without and healthy controls. This finding highlights that the hyperexcitability of the nociceptive system in SCI subjects with NP is a factor contributing to their pain state. No group difference has been observed regarding habituation of pain-autonomic measures, endogenous inhibition during a sophisticated conditioned pain modulation paradigm, and temporal summation of repetitive heat stimuli. However, deficient habituation of sympathetic skin responses was associated with higher NP extent and deficient endogenous inhibition was associated with higher NP intensity. Taken together, this thesis highlights improvements in the assessment of the nociceptive nervous system in subjects with chronic NP after SCI. Overall, the findings provide insights into disentangling the mechanisms underlying the diverse pain phenotypes which ultimately provides important information for future personalized and mechanism-based pain treatment