Involvement of Voltage-Gated Calcium Channels in Inflammation and Inflammatory Pain

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Voltage-gated calcium channels (VGCCs) are classified into high-voltage-activated (HVA) channels and low-voltage-activated channels consisting of Ca_v3.1–3.3, known as T (“transient”)-type VGCC. There is evidence that certain types of HVA channels are involved in neurogenic inflammation and inflammatory pain, in agreement with reports indicating the therapeutic effectiveness of gabapentinoids, ligands for the α₂δ subunit of HVA, in treating not only neuropathic, but also inflammatory, pain. Among the Ca_v3 family members, Ca_v3.2 is abundantly expressed in the primary afferents, regulating both neuronal excitability at the peripheral terminals and spontaneous neurotransmitter release at the spinal terminals. The function and expression of Ca_v3.2 are modulated by a variety of inflammatory mediators including prostanoids and hydrogen sulfide (H₂S), a gasotransmitter. The increased activity of Ca_v3.2 by H₂S participates in colonic, bladder and pancreatic pain, and regulates visceral inflammation. Together, VGCCs are involved in inflammation and inflammatory pain, and Ca_v3.2 T-type VGCC is especially a promising therapeutic target for the treatment of visceral inflammatory pain in patients with irritable bowel syndrome, interstitial cystitis/bladder pain syndrome, pancreatitis, etc., in addition to neuropathic pain.