Cold avoidance and heat pain hypersensitivity in neuronal nucleoredoxin knockout mice

Nucleoredoxin is a thioredoxin-like oxidoreductase that mainly acts as oxidase and thereby regulates calcium calmodulin kinase Camk2a, an effector of nitric oxide mediated synaptic potentiation and nociceptive sensitization. We asked here if and how NXN affects thermal sensation and nociception in mice using pan-neuronal NXN deletion driven by Nestin-Cre, and sensory neuron specific deletion driven by Advillin-Cre. In a thermal gradient ring, where mice can freely choose the temperature of well-being, Nestin-NXN^-/- mice avoided unpleasant cold temperatures. In neuropathic and inflammatory nociceptive models, Nestin-NXN^-/- and Advillin-NXN^-/- mice displayed subtle phenotypes of heightened heat nociception. Abnormal thermal in vivo responses were associated with heightened calcium influx upon stimulation of transient receptor channels, with heightened oxygen consumption upon disruption of the mitochondrial membrane potential and with higher density of neurite trees of primary sensory neurons of the dorsal root ganglia in cultures. The data suggest that loss of NXN's balancing redox functions leads to maladaptive changes in sensory neurons that manifest in vivo as polyneuropathy-like abnormal cold sensitivity and heat "pain".