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B.M. Lutz et al.
(Figure 7C). These data further indicate that the increase in Nav1.8 current from HbSS DRG neurons is ETA receptor- dependent. We also examined the gating properties of Nav1.8 in HbSS DRG neurons. HbSS DRG neurons showed a hyperpolarizing potential shift compared to HbAA DRG neurons under the conditions of either activa- tion or inactivation of Nav1.8 (Figure 7 D, E). The half- maximal activation voltage (V1/2) was -20.35 ± 1.16 mV in the HbAA mice and -24.79 ± 0.93 mV in the HbSS mice (Figure 7D), whereas the half-maximal inactivation volt- age (V1/2) was -37.56 ± 1.32 mV in the HbAA mice and - 45.80 ± 1.80 mV in the HbSS mice (Figure 7E). In vivo
administration of ABT-627 as described above did not lead to changes in the gating properties of Nav1.8 in HbAA or HbSS mice. HbSS DRG neurons likely display ETA recep- tor-independent changes in the gating properties of Nav1.8 channels.
NF-κ B-triggered Nav1.8 expression in HbSS DRG neurons
How does ETA receptor activation mediate an increase in Nav1.8 expression and activity in SCD (HbSS) DRG neurons? The transcription factor, NF-κB, may be upstream of Nav1.8 upregulation in DRG neurons and is
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Figure 3. Hindpaw administration of ABT-627 can alleviate pain hypersensitivity and spontaneous ongoing pain under normoxic and hypoxic conditions in male HbSS mice. (A-D) Effect of hindpaw injection of ABT-627 on paw withdrawal frequencies (PWF) to a 0.16 g low force (A) and a 0.4g medium force (B) and paw with- drawal latencies (PWL) to heat (C) and cold (D) stimuli on the ipsilateral side of HbAA mice and HbSS mice under normoxic and hypoxic conditions. Veh: vehicle. ABT: ABT-627. n=6 mice/genotype/treatment. *P<0.05, **P<0.01 vs. the corresponding HbAA group. ##P<0.01 vs. the HbSS baseline value. $P<0.05 vs. the correspon- ding vehicle-treated HbSS group. (E and F) Effect of hindpaw injection of ABT-627 (ABT) on ongoing pain as assessed by the conditioned place preference paradigm. n=6-8 mice/group. **P<0.01 vs. the corresponding pre-conditioning (E) or the HbAA plus vehicle (Vel) group (F). ##P<0.01 vs. the corresponding post-conditioning (post) from the HbSS plus vehicle group or the HbSS plus vehicle group (F).
haematologica | 2018; 103(7)