New research may have uncovered a 'master switch' protein for the development of a broad variety of pain-sensing neurons.

Nociception, the transmission of pain signals in response to potentially harmful stimuli, is under the control of a diverse array of neuron subtypes expressing receptors activated by a wide range of triggers, including temperature, noxious chemicals and mechanical injury. However, the developmental process by which this diversity is attained has remained largely unclear.

Dana-Farber Cancer Institute (Boston, MA) investigator Qiufu Ma and his colleagues were interested in identifying proteins that manage these processes; they began by investigating the importance of Runx1, a transcription factor gene for which expression is restricted to nociceptive neurons. They generated mice in which Runx1 expression had been inactivated in the peripheral nervous system, and they observed a number of clear deficits in nociceptor development (Neuron, 2 February).

The absence of Runx1 expression seems to block the development of at least one key population of nociceptor precursors in the dorsal root ganglia, the structure in which somatosensory neurons reside. This has apparently serious implications for downstream developmental steps, for Ma's team found that these mice showed eliminated or markedly reduced levels of a variety of nociceptive receptors, including a number of heat- and cold-responsive receptors. They also observed marked alterations in the targeting of afferent processes from Runx1−/− neurons to the spinal cord, where pain signals are processed before transmission to the brain.

The Runx1−/− mice showed significantly delayed responses to cold or heat stimuli relative to wild-type animals, as well as reduced sensitivity to the hot pepper-derived compound capsaicin. However, their responses to pinprick discomfort did not change, suggesting that not all modes of pain detection were impaired. Ma's team also tested the animals' response to neuropathic pain—the perception of typically nonpainful stimuli as painful, often a result of nerve damage. Unlike wild-type animals, nerve-damaged Runx1−/− mice showed no neuropathic pain response, suggesting an important role for the gene in this particular pathology.

The action of Runx1 seems to govern the development of a wide variety of classes of nociceptive neurons, and the authors conclude: “The identification of a core transcriptional control program for many of the ion channels and receptors known to transduce noxious stimuli has intriguing implications for the design of more effective pain therapies.”