Abstract
The T-type calcium channel, Cav3.2, is necessary for acute pain perception, as well as mechanical and cold allodynia in mice. Being found throughout sensory pathways, from excitatory primary afferent neurons up to pain matrix structures, it is a promising target for analgesics. In our study, Cav3.2 was detected in ~60% of the lamina II (LII) neurons of the spinal cord, a site for integration of sensory processing. It was co-expressed with Tlx3 and Pax2, markers of excitatory and inhibitory interneurons, as well as nNOS, calretinin, calbindin, PKCγ and not parvalbumin. Non-selective T-type channel blockers slowed the inhibitory but not the excitatory transmission in LII neurons. Furthermore, T-type channel blockers modified the intrinsic properties of LII neurons, abolishing low-threshold activated currents, rebound depolarizations, and blunting excitability. The recording of Cav3.2-positive LII neurons, after intraspinal injection of AAV-DJ-Cav3.2-mcherry, showed that their intrinsic properties resembled those of the global population. However, Cav3.2 ablation in the dorsal horn of Cav3.2GFP-Flox KI mice after intraspinal injection of AAV-DJ-Cav3.2-Cre-IRES-mcherry, had drastic effects. Indeed, it (1) blunted the likelihood of transient firing patterns; (2) blunted the likelihood and the amplitude of rebound depolarizations, (3) eliminated action potential pairing, and (4) remodeled the kinetics of the action potentials. In contrast, the properties of Cav3.2-positive neurons were only marginally modified in Cav3.1 knockout mice. Overall, in addition to their previously established roles in the superficial spinal cord and in primary afferent neurons, Cav3.2 channel appear to be necessary for specific, significant and multiple controls of LII neuron excitability.
Highlights
Pain therapeutics act at various levels of the nociceptive pathway and of the pain matrix where they frequently target ion channels, or receptors
This mouse model was used as a genetic tool for identifying Cav3.2 expressing neurons and for ablating them in lamina II (LII) of the spinal cord where Cav3.2 was found to play an important, and specific role in the subthreshold and suprathreshold properties
There is a gap between these sets of data: the small population of projection neurons, which is rather homogenous[54], was examined after retrograde labeling[6,8,10], while the current data were obtained in unidentified LII neurons, that is, a heterogeneous population where some, rather than all, excitatory inputs might be Cav3.2-dependent[5,9,11]
Summary
Pain therapeutics act at various levels of the nociceptive pathway and of the pain matrix where they frequently target ion channels, or receptors. Pharmacological data support pre- and post-synaptic roles for T-type channels in the dorsal horn (DH) of the spinal cord where primary sensory inputs are first integrated and processed[5,6,7,8,9,10,11,12]. Post-synaptic Cav3.2 channels should be investigated within spinal cord networks as well, since Cav3.2 expression is found in lamina II-IV interneurons[13,14,15]. This region is well-known to receive descending nociceptive controls to gate sensory flow within the spinal cord, and to undergo disinhibition during allodynia[20,21,22,23,24,25,26]. Our findings reveal important functions for Cav3.2 in the processing of sensory information within the spinal cord
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