MaleHbSS mice exhibit marked hypersensitivity to mechanical, heat,and cold stimuli compared with control HbAA mice. (A) Male HbSS mice exhibited significantly reduced hind paw withdrawal thresholds compared with HbAA controls (***P < .0001, Mann Whitney U test; HbAA n = 20; HbSS n = 19). (B) Male HbSS mice had significantly shorter hind paw withdrawal latencies to radiant heat than controls (***P < .0001, t test; HbAA n = 20; HbSS n = 17). (C) Male HbSS mice had shorter latencies in response to a cold plate held at 20°C than HbAA controls (**P = .007, t test; HbAA n = 20; HbSS n = 18). (D) Exposure to hypoxia (10% F_iO₂, 2 hours) followed by reoxygenation (ambient air, tested at 1, 2, and 3 hours) further exacerbated mechanical hypersensitivity of male HbSS mice (P = .0005, Friedman repeated-measures test; ††P < .01, posthoc Dunn test comparing HbSS baseline with the 2- and 3-hour reoxygenation time points; HbSS n = 13), but not control HbAA mice (Friedman test, HbAA n = 15); HbSS mice exhibited significantly reduced hind paw withdrawal thresholds compared with HbAA mice at each time point (P < .0001 for all comparisons, Mann Whitney U test).