Skip to main content
Journal cover image

Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice.

Publication ,  Journal Article
Levitt, RC; Zhuang, GY; Kang, Y; Erasso, DM; Upadhyay, U; Ozdemir, M; Fu, ES; Sarantopoulos, KD; Smith, SB; Maixner, W; Diatchenko, L ...
Published in: Mamm Genome
October 2017

Carbonic anhydrase-8 (Car8 mouse gene symbol) is devoid of enzymatic activity, but instead functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) to regulate this intracellular calcium release channel important in synaptic functions and neuronal excitability. Causative mutations in ITPR1 and carbonic anhydrase-8 in mice and humans are associated with certain subtypes of spinal cerebellar ataxia (SCA). SCA mice are genetically deficient in dorsal root ganglia (DRG) Car8 expression and display mechanical and thermal hypersensitivity and susceptibility to subacute and chronic inflammatory pain behaviors. In this report, we show that DRG Car8 expression is variable across 25 naïve-inbred strains of mice, and this cis-regulated eQTL (association between rs27660559, rs27706398, and rs27688767 and DRG Car8 expression; P < 1 × 10-11) is correlated with nociceptive responses in mice. Next, we hypothesized that increasing DRG Car8 gene expression would inhibit intracellular calcium release required for morphine antinociception and might correlate with antinociceptive sensitivity of morphine and perhaps other analgesic agents. We show that mean DRG Car8 gene expression is directly related to the dose of morphine or clonidine needed to provide a half-maximal analgesic response (r = 0.93, P < 0.00002; r = 0.83, P < 0.0008, respectively), suggesting that greater DRG Car8 expression increases analgesic requirements. Finally, we show that morphine induces intracellular free calcium release using Fura 2 calcium imaging in a dose-dependent manner; V5-Car8 WT overexpression in NBL cells inhibits morphine-induced calcium increase. These findings highlight the 'morphine paradox' whereby morphine provides antinociception by increasing intracellular free calcium, while Car8 and other antinociceptive agents work by decreasing intracellular free calcium. This is the first study demonstrating that biologic variability associated with this cis-eQTL may contribute to differing analgesic responses through altered regulation of ITPR1-dependent calcium release in mice.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Mamm Genome

DOI

EISSN

1432-1777

Publication Date

October 2017

Volume

28

Issue

9-10

Start / End Page

407 / 415

Location

United States

Related Subject Headings

  • Regulatory Sequences, Nucleic Acid
  • Quantitative Trait Loci
  • Pharmacogenomic Variants
  • Pain Measurement
  • Nerve Tissue Proteins
  • Morphine
  • Mice
  • Male
  • Genome-Wide Association Study
  • Genetics & Heredity
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Levitt, R. C., Zhuang, G. Y., Kang, Y., Erasso, D. M., Upadhyay, U., Ozdemir, M., … Wiltshire, T. (2017). Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice. Mamm Genome, 28(9–10), 407–415. https://doi.org/10.1007/s00335-017-9694-7
Levitt, Roy C., Gerald Y. Zhuang, Yuan Kang, Diana M. Erasso, Udita Upadhyay, Mehtap Ozdemir, Eugene S. Fu, et al. “Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice.Mamm Genome 28, no. 9–10 (October 2017): 407–15. https://doi.org/10.1007/s00335-017-9694-7.
Levitt RC, Zhuang GY, Kang Y, Erasso DM, Upadhyay U, Ozdemir M, et al. Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice. Mamm Genome. 2017 Oct;28(9–10):407–15.
Levitt, Roy C., et al. “Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice.Mamm Genome, vol. 28, no. 9–10, Oct. 2017, pp. 407–15. Pubmed, doi:10.1007/s00335-017-9694-7.
Levitt RC, Zhuang GY, Kang Y, Erasso DM, Upadhyay U, Ozdemir M, Fu ES, Sarantopoulos KD, Smith SB, Maixner W, Diatchenko L, Martin ER, Wiltshire T. Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice. Mamm Genome. 2017 Oct;28(9–10):407–415.
Journal cover image

Published In

Mamm Genome

DOI

EISSN

1432-1777

Publication Date

October 2017

Volume

28

Issue

9-10

Start / End Page

407 / 415

Location

United States

Related Subject Headings

  • Regulatory Sequences, Nucleic Acid
  • Quantitative Trait Loci
  • Pharmacogenomic Variants
  • Pain Measurement
  • Nerve Tissue Proteins
  • Morphine
  • Mice
  • Male
  • Genome-Wide Association Study
  • Genetics & Heredity