title: Expression and Regulation of Cav3.2 T-Type Calcium Channels during Inflammatory Hyperalgesia in Mouse Dorsal Root Ganglion Neurons.
abstract: The Cav3.2 isoform of the T-type calcium channel is expressed in primary sensory neurons of the dorsal root ganglion (DRG), and these channels contribute to nociceptive and neuropathic pain in rats. However, there are conflicting reports on the roles of these channels in pain processing in rats and mice. In addition, the function of T-type channels in persistent inflammatory hyperalgesia is poorly understood. We performed behavioral and comprehensive histochemical analyses to characterize Cav3.2-expressing DRG neurons and examined the regulation of T-type channels in DRGs from C57BL/6 mice with carrageenan-induced inflammatory hyperalgesia. We show that approximately 20% of mouse DRG neurons express Cav3.2 mRNA and protein. The size of the majority of Cav3.2-positive DRG neurons (69 ± 8%) ranged from 300 to 700 μm2 in cross-sectional area and 20 to 30 μm in estimated diameter. These channels co-localized with either neurofilament-H (NF-H) or peripherin. The peripherin-positive cells also overlapped with neurons that were positive for isolectin B4 (IB4) and calcitonin gene-related peptide (CGRP) but were distinct from transient receptor potential vanilloid 1 (TRPV1)-positive neurons during normal mouse states. In mice with carrageenan-induced inflammatory hyperalgesia, Cav3.2 channels, but not Cav3.1 or Cav3.3 channels, were upregulated in ipsilateral DRG neurons during the sub-acute phase. The increased Cav3.2 expression partially resulted from an increased number of Cav3.2-immunoreactive neurons; this increase in number was particularly significant for TRPV1-positive neurons. Finally, preceding and periodic intraplantar treatment with the T-type calcium channel blockers mibefradil and NNC 55-0396 markedly reduced and reversed mechanical hyperalgesia during the acute and sub-acute phases, respectively, in mice. These data suggest that Cav3.2 T-type channels participate in the development of inflammatory hyperalgesia, and this channel might play an even greater role in the sub-acute phase of inflammatory pain due to increased co-localization with TRPV1 receptors compared with that in the normal state.
authors.affiliation: Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueda
authors.affiliation: Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shibata
authors.affiliation: Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kumamoto
authors.affiliation: Department of Neuroscience and Cell Biology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Shimada
authors.affiliation: Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ugawa
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D020748:Mibefradil / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D009437:Neuralgia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000700:Analgesics; D001562:Benzimidazoles; C504883:Cacna1h protein, mouse; D020747:Calcium Channels, T-Type; D003521:Cyclopropanes; D009281:Naphthalenes; C484287:NNC 55-0396; D020748:Mibefradil