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Abstract

Chronic pain represents one major health problem of today’s global society. Some treatments fail and still many aspects of chronic pain development and maintenance are unknown. Here, we present new insights into the Ca2+ signalling behaviour of acute slices of murine spinal cord dorsal horn astrocytes and parvalbumin(PV)-positive neurons. To our knowledge we showed here for the first time that stimulation of preferred fibre classes from the dorsal root evokes Ca2+ signalling in the cytosol and nucleus of astrocytes and the cytosol of PV-neurons. In addition, we detected a decrease of these evoked Ca2+ signals under neuropathic pain conditions when stimulated with Aβ- or Aδ-fibre preferred frequencies. We did not observe differences under chronic inflammatory pain conditions, neither in astrocytes nor in PV-positive neurons. Further investigation showed that the Ca2+ signalling dependent immediate early gene Npas4 was reduced 3 days after neuropathic pain induction and that overexpression of NPAS4 in spinal dorsal horn neurons in vivo, leads to a rescue of mechanical but not thermal hypersensitivity. These findings suggest an important role of the Ca2+ signalling behaviour of astrocytes in response to Aβ- and Aδ-fibre stimulation under neuropathic pain under the tested conditions. Especially because of the occurrence of Ca2+ signalling in the astrocytic nucleus, we propose a similar gene regulation function as in neurons, which probably induce plasticity changes in astrocytes. This might be due to adaption to the neuronal activity required to transmit signals from the periphery to the brain, which is possibly disturbed under chronic pain conditions. Thus, the purpose of astrocytes to support those changes in pain conditions would also require changes in signalling behaviour. In addition we hypothesize an important role of NPAS4 regulation in the spinal cord dorsal horn under neuropathic pain conditions, primarily to control the inhibition of pain stimuli.