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.
Highlights
Evolutionary pressure requires nociceptive processing functions through the entire range of noxious temperatures from hot to cold to enable protection of the organism from hazardous tissue damage
We performed a second order group statistics of statistical parametric maps (SPMs) generated from the functional data set of NaV1.8−/− and WT mice to visualize the spatial pattern of significantly different voxels throughout the brain upon cold stimulation (5 °C) (Fig. 1)
Brain structures, which are important for processing of cold nociception, are the ones where the SPM values for NaV1.8−/− are significantly different and smaller compared to WT (n = 10 for WT and NaV1.8−/−, respectively; for further calculation of significance see methods section)
Summary
Evolutionary pressure requires nociceptive processing functions through the entire range of noxious temperatures from hot to cold to enable protection of the organism from hazardous tissue damage. A pattern of activated areas in the medial and lateral pain system was detected upon nociceptive processing[13, 14]. These findings demonstrate the potential of functional imaging for translation of findings from mice to humans. In this context we sought to utilize functional magnet resonance imaging (fMRI) in combination with genetically modified mice as a versatile combination to study functions of specific genes/proteins within central processing of noxious input information[15]. We focused on the impact of a lack of the voltage gated sodium channel NaV1.8 on the cerebral manifestation of noxious cold and heat temperatures to identify the related brain structures and their interactions contributing to the perception of cold and heat noxious input
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