title: Chelating luminal zinc mimics hydrogen sulfide-evoked colonic pain in mice: possible involvement of T-type calcium channels.
abstract: Luminal hydrogen sulfide (H(2)S) causes colonic pain and referred hyperalgesia in mice through activation of T-type Ca(2+) channels. To test a hypothesis that H(2)S might chelate and remove endogenous Zn(2+) that inhibits the Ca(v)3.2 isoform of T-type Ca(2+) channels, facilitating visceral nociception, we asked if intracolonic (i.col.) administration of Zn(2+) chelators mimics H(2)S-induced visceral nociception. Visceral nociceptive behavior and referred abdominal allodynia/hyperalgesia were determined after i.col. administration of NaHS, a donor for H(2)S, or Zn(2+) chelators in mice. Phospholylation of extracellular signal-regulated protein kinase (ERK) in the spinal cord was analyzed by immunohistochemistry. The visceral nociceptive behavior and referred abdominal allodynia/hyperalgesia caused by i.col. NaHS in mice were abolished by i.col. preadministration of zinc chloride (ZnCl(2)), known to selectively inhibit Ca(v)3.2, but not Ca(v)3.1 or Ca(v)3.3, isoforms of T-type Ca(2+) channels, and by i.p. preadministration of mibefradil, a pan-T-type Ca(2+) channel blocker. Two distinct Zn(2+) chelators, N,N,N',N'-tetrakis(2-pyridylmethyl)ehylenediamine (TPEN) and dipicolinic acid, when administered i.col., mimicked the NaHS-evoked visceral nociceptive behavior and referred abdominal allodynia/hyperalgesia, which were inhibited by mibefradil and by NNC 55-0396, another T-type Ca(2+) channel blocker. Like i.col. NaHS, i.col. TPEN caused prompt phosphorylation of ERK in the spinal dorsal horn, an effect blocked by mibefradil. Removal of luminal Zn(2+) by H(2)S and other Zn(2+) chelators thus produces colonic pain through activation of T-type Ca(2+) channels, most probably of the Ca(v)3.2 isoform. Hence, endogenous Zn(2+) is considered to play a critical role in modulating visceral pain.
authors.affiliation: Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Matsunami
authors.forename: S
authors.initials: S
authors.lastname: Kirishi
authors.forename: T
authors.initials: T
authors.lastname: Okui
authors.forename: A
authors.initials: A
authors.lastname: Kawabata
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D000818:Animals; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000502:physiology; D002614:Chelating Agents / Q000633:toxicity*; D003106:Colon / Q000187:drug effects* / Q000294:innervation / Q000503:physiopathology; D004195:Disease Models, Animal; D006862:Hydrogen Sulfide / Q000633:toxicity*; D008297:Male; D051379:Mice; D018716:Molecular Mimicry / Q000502:physiology; D015032:Zinc / Q000172:deficiency*
chemical_list: D020747:Calcium Channels, T-Type; D002614:Chelating Agents; D015032:Zinc; D006862:Hydrogen Sulfide