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PLoS One. 2015 Mar 3;10(3):e0118273. doi: 10.1371/journal.pone.0118273. eCollection 2015.

Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway.

Author information

1
Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
2
Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
3
Department of Pharmacology and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
4
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
5
Algynomics Inc., Chapel Hill, North Carolina, United States of America.
6
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America; John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
7
Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida, United States of America; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America; John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Bruce W. Carter Miami Veterans Healthcare System, Miami, Florida, United States of America.

Abstract

Calcium dysregulation is causally linked with various forms of neuropathology including seizure disorders, multiple sclerosis, Huntington's disease, Alzheimer's, spinal cerebellar ataxia (SCA) and chronic pain. Carbonic anhydrase-8 (Car8) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates intracellular calcium release fundamental to critical cellular functions including neuronal excitability, neurite outgrowth, neurotransmitter release, mitochondrial energy production and cell fate. In this report we test the hypothesis that Car8 regulation of ITPR1 and cytoplasmic free calcium release is critical to nociception and pain behaviors. We show Car8 null mutant mice (MT) exhibit mechanical allodynia and thermal hyperalgesia. Dorsal root ganglia (DRG) from MT also demonstrate increased steady-state ITPR1 phosphorylation (pITPR1) and cytoplasmic free calcium release. Overexpression of Car8 wildtype protein in MT nociceptors complements Car8 deficiency, down regulates pITPR1 and abolishes thermal and mechanical hypersensitivity. We also show that Car8 nociceptor overexpression alleviates chronic inflammatory pain. Finally, inflammation results in downregulation of DRG Car8 that is associated with increased pITPR1 expression relative to ITPR1, suggesting a possible mechanism of acute hypersensitivity. Our findings indicate Car8 regulates the ITPR1-cytosolic free calcium pathway that is critical to nociception, inflammatory pain and possibly other neuropathological states. Car8 and ITPR1 represent new therapeutic targets for chronic pain.

PMID:
25734498
PMCID:
PMC4347988
DOI:
10.1371/journal.pone.0118273
[Indexed for MEDLINE]
Free PMC Article

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