The role of α2δ-3, a subunit of voltage gated calcium channels, in somatosensation and chronic pain

Abstract

The α2δ-3 subunit was first discovered as an auxiliary subunit of voltage gated calcium channels. Recently it has been shown that a deficit in the Cacna2d3-gene leads to a reduction in heat pain sensitivity in drosophila, mice and humans [Neely et al. Cell 2010]. The mechanism underlying this phenomenon, however, is not clear yet. Here we describe that the deficit in heat sensitivity is caused by alterations in the peripheral and central part of the somatosensory system. Mice deficient in α2δ-3 show a reduced sensitivity in the hot plate test. With X-gal staining we show that the subunit is expressed in most large cells (Aβ-fibers) and a subpopulation of small cells (C- and Aδ-fibers) in the dorsal root ganglion (DRG). In the spinal cord (SC), staining was found in the dorsal and the ventral horn. We further confirmed expression in DRG and SC with qRT-PCR. With ex-vivo skin-nerve recordings we were able to show deficits in signal transduction in the periphery. C-fibers of deficient mice show a reduction in spike frequency after thermal stimulation and an increased heat-threshold. The population of Aδ-fibers responding to heat is diminished in these animals. In calcium imaging experiments a reduced calcium influx upon heat stimulation was found. Interestingly, the data from whole cell patch experiments show that the voltage gated calcium currents are not affected in the deficient mice. However, the inward current, respectively the sodium current, is reduced in cells from deficient mice. Further the heat and capsaicin induced currents are smaller. This shows clearly that the loss of α2δ-3 leads to deficits in heat-pain transduction at the periphery, namely that less input from the periphery reaches the spinal cord. Surprisingly, the deficient animals show a second phenotype. In the Hargreaves test the animals show a higher sensitivity compared to wild type (WT) littermates. Same was found for the mechanical von Frey test. We further found an increased sensitivity after induction of chronic pain, like neuropathic or chronic inflammatory pain. Under chronic pain condition the increased sensitivity is not restricted to thermal stimulation and occurs for tactile as well. The subunit is down-regulated in neuropathic pain but recovers, same as the behavioral phenotype. Therefore this phenotype quite likely is a result of a reduced input onto inhibitory interneurons that in the end leads to a faster reflex. This input is mainly carried by Aβ-fibers, which are highly positive for α2δ-3. Altogether these data show a contribution of the α2δ-3 subunit of voltage gated calcium channels in the somatosensory system, in acute and chronic pain. Heat-pain or better burning pain can be a tough burden to suffer of, especially for chronic pain patients. The knowledge acquired here might help to improve the understanding of heat-pain perception mechanisms and might lead to new strategies for therapy and treatment, maybe even serve as a new target for pharmaceutical investigations.