Credit: Marc Phares / Science Source

High levels of neuronal activity in pain-sensing neurons can cause structural and functional changes in those neurons that lead to chronic pain. Now, Manuela Simonetti et al. report that calcium entry into the nucleus of neurons in the spinal cord leads to changes in gene expression that are responsible for inducing pain (Neuron 77, 43–57).

The research team used calcium sensors to show that intense stimulation of spinal cord neurons, which can lead to chronic hyperalgesia (hypersensitivity to touch or temperature stimuli), causes an influx in calcium into the nucleus of those neurons. When they blocked nuclear calcium signaling in spinal cord neurons of mice by nuclear overexpression of calmodulin-binding protein 4, a protein that buffers signaling downstream of calcium-dependent calmodulin, this reduced hyperalgesia after inflammation, probably owing to an inability to activate the transcription factor CREB.

Using gene profiling, the authors found that pain-dependent nuclear calcium signaling reduced expression of the complement pathway component C1q. When the researchers reduced expression of C1q in the spinal cord, they showed that this increased pain, whereas administering C1q protein induced pain. C1q seemed to act by reducing the density of dendritic spines on neurons, although how exactly these molecules affect this process remains to be determined.