Impact of the NaV1.8 variant, A1073V, on post-sigmoidectomy pain and electrophysiological function in rat sympathetic neurons.

NaV1.8 channels play a crucial role in regulating the action potential in nociceptive neurons. A single nucleotide polymorphism in the human NaV1.8 gene SCN10A, A1073V (rs6795970, G>A), has been linked to the diminution of mechanical pain sensation as well as cardiac conduction abnormalities. Furthermore, studies have suggested that this polymorphism may result in a "loss-of-function" phenotype. In the present study, we performed genomic analysis of A1073V polymorphism presence in a cohort of patients undergoing sigmoid colectomy who provided information regarding perioperative pain and analgesic use. Homozygous carriers reported significantly reduced severity in postoperative abdominal pain compared with heterozygous and wild-type carriers. Homozygotes also trended toward using less analgesic/opiates during the postoperative period. We also heterologously expressed the wild-type and A1073V variant in rat superior cervical ganglion neurons. Electrophysiological testing demonstrated that the mutant NaV1.8 channels activated at more depolarized potentials compared with wild-type channels. Our study revealed that postoperative abdominal pain is diminished in homozygous carriers of A1073V and that this is likely due to reduced transmission of action potentials in nociceptive neurons. Our findings reinforce the importance of NaV1.8 and the A1073V polymorphism to pain perception. This information could be used to develop new predictive tools to optimize patient pain experience and analgesic use in the perioperative setting.NEW & NOTEWORTHY We present evidence that in a cohort of patients undergoing sigmoid colectomy, those homozygous for the NaV1.8 polymorphism (rs6795970) reported significantly lower abdominal pain scores than individuals with the homozygous wild-type or heterozygous genotype. In vitro electrophysiological recordings also suggest that the mutant NaV1.8 channel activates at more depolarizing potentials than the wild-type Na+ channel, characteristic of hypoactivity. This is the first report linking the rs6795970 mutation with postoperative abdominal pain in humans.

Heterologous expression of the human wild-type and variant NaV 1.8 (A1073V) in rat sensory neurons.

BACKGROUND: Silent inflammatory bowel disease (IBD) is a condition in which individuals with the active disease experience minor to no pain. Voltage-gated Na+ (NaV ) channels expressed in sensory neurons play a major role in pain perception. Previously, we reported that a NaV 1.8 genetic polymorphism (A1073V, rs6795970) was more common in a cohort of silent IBD patients. The expression of this variant (1073V) in rat sympathetic neurons activated at more depolarized potentials when compared to the more common variant (1073A). In this study, we investigated whether expression of either NaV 1.8 variant in rat sensory neurons would exhibit different biophysical characteristics than previously observed in sympathetic neurons. METHODS: Endogenous NaV 1.8 channels were first silenced in DRG neurons and then either 1073A or 1073V human NaV 1.8 cDNA constructs were transfected. NaV 1.8 currents were recorded with the whole-cell patch-clamp technique. KEY RESULTS: The results indicate that 1073A and 1073V NaV 1.8 channels exhibited similar activation values. However, the slope factor (k) for activation determined for this same group of neurons decreased by 5 mV, suggesting an increase in voltage sensitivity. Comparison of inactivation parameters indicated that 1073V channels were shifted to more depolarized potentials than 1073A-expressing neurons, imparting a proexcitatory characteristic. CONCLUSIONS AND INFERENCES: These findings differ from previous observations in other expression models and underscore the challenges with heterologous expression systems. Therefore, the use of human sensory neurons derived from induced pluripotent stem cells may help address these inconsistencies and better determine the effect of the polymorphism present in IBD patients.

Effects of transient, persistent, and resurgent sodium currents on excitability and spike regularity in vestibular ganglion neurons.

Vestibular afferent neurons occur as two populations, regular and irregular, that provide distinct information about head motions. Differences in spike timing regularity are correlated with the different sensory responses important for vestibular processing. Relative to irregular afferents, regular afferents have more sustained firing patterns in response to depolarizing current steps, are more excitable, and have different complements of ion channels. Models of vestibular regularity and excitability emphasize the influence of increased expression of low-voltage-activated potassium currents in irregular neurons. We investigated the potential impact of different modes of voltage-gated sodium (NaV) current (transient, persistent, and resurgent) in cell bodies from vestibular ganglion neurons (VGNs), dissociated and cultured overnight. We hypothesized that regular VGNs would show the greatest impact of persistent (non-inactivating) NaV currents and of resurgent NaV currents, which flow when NaV channels are blocked and then unblocked. Whole-cell patch clamp experiments showed that much of the NaV current modes is carried by NaV1.6 channels. With simulations, we detected little substantial effect in any model VGN of persistent or resurgent modes on regularity of spike timing driven by postsynaptic current trains. For simulated irregular neurons, we also saw little effect on spike rate or firing pattern. For simulated regular VGNs, adding resurgent current changed the detailed timing of spikes during a current step, while the small persistent conductance (less than10% of transient NaV conductance density) strongly depolarized resting potential, altered spike waveform, and increased spike rate. These results suggest that persistent and resurgent NaV current can have a greater effect on the regular VGNs than on irregular VGNs, where low-voltage-activated K conductances dominate.