Centrally expressed Cav3.2 T-type calcium channel is critical for the initiation and maintenance of neuropathic pain

Abstract

Cav3.2 T-type calcium channel is a major molecular actor of neuropathic pain in peripheral sensory neurons, but its involvement at the supra-spinal level is almost unknown. In the Anterior Pretectum (APT), a hub of connectivity of the somatosensory system involved in pain perception, we show that Cav3.2 channels are expressed in a sub-population of GABAergic neurons co-expressing parvalbumin (PV). In these PV-expressing neurons, Cav3.2 channels contribute to a high frequency bursting activity, which is increased in the spared nerve injury model of neuropathy. Specific deletion of Cav3.2 channels in APT neurons reduced both the initiation and maintenance of mechanical and cold allodynia. These data are a direct demonstration that centrally expressed Cav3.2 channels also play a fundamental role in pain pathophysiology.

Activation of GABAergic neurons in anterior cingulate cortex and their impacts on pulpitis-induced pain

“…It is widely acknowledged that PV neurons play a dominating role in pain regulation [53][54] . However, the results of the present study suggested that SST neurons, rather than PV neurons, in the ACC are the major players in pulpitis pain regulation.…”

Ion channels in cancer-induced bone pain: from molecular mechanisms to clinical applications

“…Increased voltage-gated sodium channel 1.7 (NaV1.7) expression leads to increased neuronal excitability and ultimately causes neuropathic pain in animal models ( Li et al, 2018 ). In the early stage of nerve injury, the expression of the Cav3.2 channel and functional enhancement of damaged neurons lead to an increase in ectopic discharge frequency ( Fayad et al, 2022 ). Transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential melastatin 8 (TRPM8) knockout mice demonstrated relief of pain sensitization in neuropathic models ( Trevisan et al, 2016 ; de Caro et al, 2018 ).…”

Analgesic Buxus alkaloids with Enhanced Selectivity for the Low‐Voltage‐Gated Calcium Channel Cav3.2 over Cav3.1 through a New Binding Mode

“…[2,9,10] Moreover, within the nociceptive circuitry encompassing dorsal root ganglion (DRG) neurons, the superficial dorsal horn, and anterior pretectum, Ca v 3.2 is the predominant isoform implicated in numerous intractable painful symptoms. [11][12][13] LVGCCs are attractive drug targets for several serious neurological disorders, such as epilepsy, pain, and essential tremor. [2,14,15] At least eight classes of selective triple LVGCCs blockers (STLBs) have been synthesized, and several candidates, such as CX8998, Z944, and ACT-709478 are currently in phase I or II clinical trials.…”

“…[20][21][22][23][24][25] Cyclovirobuxine D (CVBÀ D), a representative alkaloid of the traditional Chinese medicine B. microphylla and also an in-use cardiovascular drug in China, was initially identified as a potent analgesic agent mainly through inhibition of Ca v 3.2. [22] In this study, we further investigated the Ca v 3.2 inhibition of 23 natural Buxus alkaloids (1-23) with 9,19cyclo-artane-type (1-7), 9(10/19)abeo-artane-type (8)(9)(10)(11)(12)(13)(14)(15)(16), and 17(13/18)abeo-artane-type (17)(18)(19)(20)(21)(22)(23) chemical scaffolds (Figure 1A). Compounds 1-5 and 7 were isolated from B. rugulosa, [26] 6, 8-16, and 23 were purified from B. sempervirens, [27] and 17-22 were identified from B. austroyunnanensis.…”

“…For instance, Ca v 3.1 in thalamocortical neurons is involved in slow‐wave sleep oscillations and absence seizures [2,9,10] . Moreover, within the nociceptive circuitry encompassing dorsal root ganglion (DRG) neurons, the superficial dorsal horn, and anterior pretectum, Ca v 3.2 is the predominant isoform implicated in numerous intractable painful symptoms [11–13] . LVGCCs are attractive drug targets for several serious neurological disorders, such as epilepsy, pain, and essential tremor [2,14,15] …”