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Biology subjects

Rance, M.

Publications and source records attributed to Rance, M..

2 recordsLinked to original sources

Phantom limb pain intensity is associated with generalized hyperalgesia

After limb amputation, most amputees suffer from phantom limb pain (PLP). The mechanisms underlying this condition are complex and insufficiently understood. Altered somatosensory sensitivity (either heightened or lowered) might contribute to PLP. Recent studies have tested this assumption but mainly focused on the residual limb. However, altered somatosensation in PLP might be generalized. In this study, we applied quantitative sensory testing to 37 unilateral upper-limb amputees (23 with PLP, 14 without PLP) and 19 healthy controls. We assessed thresholds to heat pain (HPT), pressure pain (PPT), warmth detection (WDT), and two-point discrimination (2PDT) at the residual limb, a homologous point and the thenar of the intact limb, and both corners of the mouth. We did not find significant differences in any of the thresholds between the groups. However, higher PLP intensity was significantly related to lower HPT at all measured body sites except for the residual limb. At the residual limb, lower HPT were observed in more distal amputations and in amputees showing a higher degree of prosthesis use. Although WDT did by itself not significantly correlate with PLP intensity at any of the body sites, multiple regression analysis showed the highest multiple correlations with PLP intensity for a combination of high WDT and low HPT at the corners of the mouth. In this model, the combination of HPT and WDT shared 58% of the variance with PLP intensity. Other factors of potential importance, especially residual limb pain, were not significantly associated to any sensory threshold. We conclude that the intensity, but not the presence of PLP is positively associated with higher heat pain sensitivity. Since this association was observed at various, distributed body sites, we suggest that central mechanisms might be underlying such generalized hyperalgesia.

neuroscience↗

Defining a canonical ligand-binding pocket in the orphan nuclear receptor Nurr1

Nuclear receptor related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor that is considered to function without a canonical ligand-binding pocket. A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other nuclear receptors with solvent accessible apo-protein ligand-binding pockets bind synthetic and natural ligands. Using solution NMR spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show here that the putative canonical ligand-binding pocket in the Nurr1 LBD is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystalized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinsons disease and schizophrenia.

biophysics↗