Chelating luminal zinc mimics hydrogen sulfide-evoked colonic pain in mice: possible involvement of T-type calcium channels

• Published in: Neuroscience 2011-05, Vol.181, p.257-264
• Main Authors: Matsunami, M, Kirishi, S, Okui, T, Kawabata, A
• Format: Article
• Language: English
• Subjects: Abdominal Pain - chemically induced; Abdominal Pain - enzymology; Abdominal Pain - physiopathology; allodynia; Animals; Biological and medical sciences; Calcium Channels, T-Type - drug effects; Calcium Channels, T-Type - physiology; Chelating Agents - toxicity; Colon - drug effects; Colon - innervation; Colon - physiopathology; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; gasotransmitter; Hydrogen Sulfide - toxicity; hyperalgesia; ion channels; Male; Medical sciences; Mice; Molecular Mimicry - physiology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Vertebrates: nervous system and sense organs; visceral nociception; Zinc - deficiency; zinc chelator
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2011.02.044

Abstract Luminal hydrogen sulfide (H2 S) causes colonic pain and referred hyperalgesia in mice through activation of T-type Ca2+ channels. To test a hypothesis that H2 S might chelate and remove endogenous Zn2+ that inhibits the Cav 3.2 isoform of T-type Ca2+ channels, facilitating visceral nociception, we asked if intracolonic (i.col.) administration of Zn2+ chelators mimics H2 S-induced visceral nociception. Visceral nociceptive behavior and referred abdominal allodynia/hyperalgesia were determined after i.col. administration of NaHS, a donor for H2 S, or Zn2+ 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 (ZnCl2 ), known to selectively inhibit Cav 3.2, but not Cav 3.1 or Cav 3.3, isoforms of T-type Ca2+ channels, and by i.p. preadministration of mibefradil, a pan-T-type Ca2+ channel blocker. Two distinct Zn2+ 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 Ca2+ 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 Zn2+ by H2 S and other Zn2+ chelators thus produces colonic pain through activation of T-type Ca2+ channels, most probably of the Cav 3.2 isoform. Hence, endogenous Zn2+ is considered to play a critical role in modulating visceral pain.