NaV1.7: stress-induced changes in immunoreactivity within magnocellular neurosecretory neurons of the supraoptic nucleus

Abstract

Background: NaV1.7 is preferentially expressed, at relatively high levels, in peripheral neurons, and is often referred to as a "peripheral" sodium channel, and NaV1.7-specific blockers are under study as potential pain therapeutics which might be expected to have minimal CNS side effects. However, occasional reports of patients with NaV1.7 gain-of-function mutations and apparent hypothalamic dysfunction have appeared. The two sodium channels previously studied within the rat hypothalamic supraoptic nucleus, NaV1.2 and NaV1.6, display up-regulated expression in response to osmotic stress.

Results: Here we show that NaV1.7 is present within vasopressin-producing neurons and oxytocin-producing neurons within the rat hypothalamus, and demonstrate that the level of Nav1.7 immunoreactivity is increased in these cells in response to osmotic stress.

Conclusions: NaV1.7 is present within neurosecretory neurons of rat supraoptic nucleus, where the level of immunoreactivity is dynamic, increasing in response to osmotic stress. Whether NaV1.7 levels are up-regulated within the human hypothalamus in response to environmental factors or stress, and whether NaV1.7 plays a functional role in human hypothalamus, is not yet known. Until these questions are resolved, the present findings suggest the need for careful assessment of hypothalamic function in patients with NaV1.7 mutations, especially when subjected to stress, and for monitoring of hypothalamic function as NaV1.7 blocking agents are studied.

Figure 1

Na_v1.7 expression in vasopressin- and oxytocin-producing magnocellular neurosecretory cells in supraoptic nucleus. Magnocellular neurosecretory neurons (MSN) of the supraoptic nucleus (SON) exhibit robust vasopressin and oxytocin immunolabeling (green). MSN of the SON display Na_v1.7 immunoreactivity (red). Double-immunocytochemical studies with antibodies to vasopressin or oxytocin and Na_v1.7 demonstrate that both peptide-producing cell-types exhibit co-localization (magenta) with Na_v1.7. Merged image of vasopressin or oxytocin with Na_v1.7 is presented as magenta to enhance visualization of co-localization.

Figure 2

Na_v1.7 is upregulated in magnocellular neurosecretory neurons of supraoptic nucleus following salt loading. (A) Magnocellular neurosecretory neurons (MSN) within supraoptic nucleus (SON) of control rats exhibit Na_v1.7 immunolabeling. Following salt-loading, MSN display more prominent Na_v1.7 immunoreactivity compared to control rats. (B) Quantification of Na_v1.7 immunosignal within the SON demonstrates an approximately two-fold increase in Na_v1.7 immunofluorescence in SON of salt-loaded rats compared to control rats.