Sodium-Calcium Exchanger-3 Regulates Pain ‘Wind-Up’: From Human Psychophysics to Spinal Mechanisms

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is “wind-up”, in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding Sodium-Calcium exchanger type-3 (NCX3). NCX3 was found to be expressed in mouse dorsal horn neurons and mice lacking NCX3 showed normal, acute pain but enhanced second phase of the formalin response, suggesting increased central sensitisation. Dorsal horn neurons lacking NCX3 showed increased intra-cellular calcium following repetitive stimulation, slowed calcium clearance and increased wind-up. Moreover, virally-mediated enhanced spinal expression of NCX3 reduced central sensitisation. Our study highlights Ca2+ efflux as a pathway underlying temporal summation and persistent pain which may be amenable to therapeutic targeting.