HC and SCD iSNs are differentially sensitized to electrical and agonist stimulation. HC and SCD iSNs treated with plasma samples from healthy patients (HC), patients with SCD at baseline (SS BL), or patients with SCD experiencing an acute pain crisis (SS IP) show changes in functional response to agonists. No significant differences in response to KCl (A), glutamate (B), or ab-meATP (C) were found between HC and SCD iSNs after any plasma treatments (2-way ANOVA; ns, not significant). (D) Treatment of SCD iSNs with SS IP plasma did significantly increase response to 10 μM capsaicin compared with HC iSN response after SS IP plasma treatment (2-way ANOVA, ∗P < .05). (E) No differences found between HC and SCD iSN response to 50 μM capsaicin after plasma treatment (2-way ANOVA, ns). (F) Data from panels B through D represented to compare effects of plasma on iSN response. SS IP plasma significantly increased SCD iSN response to glutamate (F, left) and 10 μM capsaicin (F, right) compared with untreated (UTX) SCD iSNs but in HC iSNs significantly increased response to ab-meATP only (F, middle); 2-way ANOVA, ∗P < .05, ∗∗P < .005. (G) SCD iSNs show increased intrinsic membrane excitability. Relationship between action potential firing and injected current (2-way repeated-measures ANOVA, significant interaction between genotype and current injection F_(19,341) = 1.892, ∗P = .0139; Bonferroni multiple comparison at 190 pA HC vs SCD, ∗P = .0427); n = 2 independent differentiations. (H) Representative waveforms show current-evoked action potential firing from each treatment group. Calibration: 10 mV, 100 ms.