Mutations affecting glycinergic neurotransmission in hyperekplexia increase pain sensitivity.

See Dickenson (doi:10.1093/brain/awx334) for a scientific commentary on this article.Inhibitory interneurons in the spinal cord use glycine and GABA for fast inhibitory neurotransmission. While there is abundant research on these inhibitory pain pathways in animal models, their relevance in humans remains unclear, largely due to the limited possibility to manipulate selectively these pathways in humans. Hyperekplexia is a rare human disease that is caused by loss-of-function mutations in genes encoding for glycine receptors and glycine transporters. In the present study, we tested whether hyperekplexia patients display altered pain perception or central pain modulation compared with healthy subjects. Seven patients with genetically and clinically confirmed hyperekplexia were compared to 14 healthy age- and sex-matched controls. The following quantitative sensory tests were performed: pressure pain detection threshold (primary outcome), ice water tolerance, single and repeated electrical pain detection thresholds, nociceptive withdrawal reflex threshold, and conditioned pain modulation. Statistical analysis was performed using linear mixed models. Hyperekplexia patients displayed lower pain thresholds than healthy controls for all of the quantitative sensory tests [mean (standard deviation)]: pressure pain detection threshold [273 (170) versus 475 (115) kPa, P = 0.003], ice water tolerance [49.2 (36.5) versus 85.7 (35.0) s, P = 0.015], electrical single pain detection threshold [5.42 (2.64) versus 7.47 (2.62) mA, P = 0.012], electrical repeated pain detection threshold [3.76 (1.41) versus 5.8 (1.73) mA, P = 0.003], and nociceptive withdrawal reflex [7.42 (3.63) versus 14.1 (6.9) mA, P = 0.015]. Conditioned pain modulation was significantly reduced in hyperekplexia [increase to baseline: 53.2 (63.7) versus 105 (57) kPa, P = 0.030]. Our data demonstrate increased pain sensitivity and impaired central pain modulation in hyperekplexia patients, supporting the importance of glycinergic neurotransmission for central pain modulation in humans.

Psychophysical and Electrophysiological Evidence for Enhanced Pain Facilitation and Unaltered Pain Inhibition in Acute Low Back Pain Patients.

The aim of this case-control study was to examine differences in neural correlates of pain facilitatory and inhibitory mechanisms between acute low back pain (LBP) patients and healthy individuals. Pressure pain tolerance, electrical pain detection thresholds, pain ratings to repetitive suprathreshold electrical stimulation (SES) and conditioned pain modulation (CPM) were assessed in 18 patients with acute LBP and 18 healthy control participants. Furthermore, event-related potentials (ERPs) in response to repetitive SES were obtained from high-density electroencephalography. Results showed that the LBP group presented lower pressure pain tolerance and higher pain ratings to SES compared with the control group. Both groups displayed effective CPM, with no differences in CPM magnitude between groups. Both groups presented similar reductions in ERP amplitudes during CPM, but ERP responses to repetitive SES were significantly larger in the LBP group. In conclusion, acute LBP patients presented enhanced pain facilitatory mechanisms, whereas no significant changes in pain inhibitory mechanisms were observed. These results provide new insight into the central mechanisms underlying acute LBP. PERSPECTIVE: This article present evidence that acute LBP patients show enhanced pain facilitation and unaltered pain inhibition compared with pain-free volunteers. These results provide new insight into the central mechanisms underlying acute LBP.