Activity and connectivity changes of central projection areas revealed by functional magnetic resonance imaging in NaV1.8-deficient mice upon cold signaling

Abstract

The voltage-gated sodium channel subtype NaV1.8 is expressed in the peripheral nervous system in primary afferent nociceptive C-fibers and is essential for noxious cold signaling. We utilized functional magnetic resonance imaging on NaV1.8-deficient (NaV1.8-/-) compared with wildtype (WT) mice to identify brain structures decoding noxious cold and/or heat signals. In NaV1.8-/- mice functional activity patterns, activated volumes and BOLD signal amplitudes are significantly reduced upon noxious cold stimulation whereas differences of noxious heat processing are less pronounced. Graph-theoretical analysis of the functional connectivity also shows dramatic alterations in noxious cold sensation in NaV1.8-/- mice and clearly reduced interactions between certain brain structures. In contrast, upon heat stimulation qualitatively quite the same functional connectivity pattern and consequently less prominent connectivity differences were observed between NaV1.8-/- and WT mice. Thus, the fact that NaV1.8-/- mice do not perceive nociceptive aspects of strong cooling in contrast to their WT littermates seems not only to be a pure peripheral phenomenon with diminished peripheral transmission, but also consists of upstream effects leading to altered subsequent nociceptive processing in the central nervous system and consequently altered connectivity between pain-relevant brain structures.