The Increased Activity of CaV3.2 Channels Contributes to Nociceptors’ Hyperexcitability and Chronic Neuropathic Pain Following Spinal Cord Injury in Mice

Abstract

Following spinal cord injury (SCI), up to 60–70% of patients develop chronic neuropathic pain. SCI-induced neuropathic pain (SCI-NP) is often lifelong and therapeutically intractable, leading to a severe decline in quality of life and increased risk for depression, anxiety, and addiction. Studies in preclinical rat models of SCI support the contribution of nociceptors’ hyperexcitability and their spontaneous activity (SA) in driving the development/maintenance of SCI-NP and suggest that reducing nociceptors’ hyperexcitability could provide a therapeutic strategy to treat SCI-NP. Previous data from our laboratory collected from SCI rats showed that the increased activity of T-type calcium channels induced by SCI contributes to drive nociceptors’ hyperexcitability and their SA in vitro and pain hypersensitivity in vivo, supporting a contribution of T-type calcium channels in driving nociceptors’ hyperexcitability and the development/maintenance of SCI-NP. The data presented here in a mouse model of SCI confirm a similar increase in nociceptors’ excitability, supporting a conserved mechanism(s) between species. Data collected in SCI CaV3.2−/− mice showed reduced nociceptors’ excitability in vitro and reduced mechanical hypersensitivity and spontaneous pain in vivo as compared with SCI wild-type mice, consistent with a contribution of CaV3.2 channels in driving nociceptors’ hyperexcitability and SCI-NP. Data with behavioral pharmacology in vivo showed that TTA-P2 (a blocker of T-type calcium channels) and gabapentin (inhibitor of trafficking of high voltage-activated calcium channels) reduced mechanical hypersensitivity in male and female SCI mice, while only a TTA-P2–sensitive component of spontaneous pain was observed.