Over $150 billion is spent annually on over 30 million Americans suffering with unrelieved pain. Inadequate persistent pain treatments lead to poor quality of life, and social and emotional dysfunctioning. It is now generally accepted that susceptibility to persistent pain is a complex heritable trait influenced by multiple genes. Recently, common inherited genetic polymorphisms have been shown to cause individual differences in pain perception, and may underlie the transition from acute to persistent pain. However, these variants explain very little of the underlying genetic effect and most of the functional genetic variants are unknown. Pinpointing genes and associated variants that better define the variable biologic pathways underlying the transition from acute to persistent pain can yield a mechanistic understanding of how some forms of persistent pain develop facilitating more effective interventions greatly impacting these patients and this field. We have recently shown that variation in neuronal carbonic anhydrase 8 (CA8) is associated with variable nociception and persistent pain in mice. Additionally, biologic variability in human CA8 is associated with multiple prevalent persistent pain syndromes, suggesting biologic variability at the CA8 locus could play an important pleiotropic role in predisposing to these difficult to treat syndromes. CA8 is an allosteric inhibitor of neuronal inositol triphosphate receptor-1 (IP3R1) that is an intracellular IP3-gated Ca2+ channel. CA8 regulates diverse calcium-dependent neuronal activities such as cellular secretion, contraction, synaptic functioning, and membrane excitability. In this project, we will identify and validate functional CA8 variants that underlie susceptibility to one or more common persistent pain syndromes including temporomandibular disease (TMD), TMD with widespread pain, sciatica, post-herpetic neuralgia (PHN), neuropathic pain after spinal cord injury (SCI), and osteoarthritis (OA). We will use state-of-the-art exome arrays comprising exonic single nucleotide polymorphisms (SNPs) in annotated genes (including CA8 pathway genes) to identify SNPs associated with persistent pain, stiffness and emotional and social functioning in a large OA cohort. This will be followed by the selection of putative functional variants using the latest bioinformatics techniques. Presumed functional SNPs associated with the OA phenotype will then be genotyped in our replication cohorts including TMD, sciatica, PHN, and SCI to test for association with the persistent pain. The biologic role of SNPs meeting our replication criteria in the other persistent pain syndromes will then be established using functional genomics in vitro. We have assembled an outstanding collaborative team with great expertise in basic and clinical pain research and the genetic dissection of complex traits, with the ability to pursue this innovative and highly relevant state-f-the-art scientific plan related to the identification and functional validation of CA8 pathway variants in persistent pain. The results of this Collaborative Research on Transitions From Acute to Chronic Pain will lead to improved biomarkers of susceptibility and therapeutic response, and better interventions for persistent pain syndromes.

Public Health Relevance

The transition from acute to persistent pain is increasingly common leading to considerable morbidity and cost due to inadequate treatments. Recently, we identified biologic variation in neuronal CA8 (carbonic anhydrase 8) that is associated with multiple common persistent pain syndromes;our outstanding collaborative team will pursue this innovative and highly relevant state-of-the-art scientific plan to identify DNA variants and their functional impact on the CA8 pathway leading to persistent pain. The results of this program are designed to contribute to improved biomarkers of susceptibility and therapeutic response, resulting in better interventions for persistent pain sufferers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE022903-01
Application #
8368134
Study Section
Special Emphasis Panel (ZDE1-VH (09))
Program Officer
Kusiak, John W
Project Start
2012-08-13
Project End
2017-07-31
Budget Start
2012-08-13
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$541,227
Indirect Cost
$166,880
Name
University of Miami School of Medicine
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Sivanesan, Eellan; Levitt, Roy C; Sarantopoulos, Constantine D et al. (2018) Noninvasive Electrical Stimulation for the Treatment of Chronic Ocular Pain and Photophobia. Neuromodulation 21:727-734
Zhuang, Gerald Z; Upadhyay, Udita; Tong, Xiaoying et al. (2018) Human carbonic anhydrase-8 AAV8 gene therapy inhibits nerve growth factor signaling producing prolonged analgesia and anti-hyperalgesia in mice. Gene Ther 25:297-311
Galor, Anat; Seiden, Benjamin E; Park, Jasmine J et al. (2018) The Association of Dry Eye Symptom Severity and Comorbid Insomnia in US Veterans. Eye Contact Lens 44 Suppl 1:S118-S124
Crane, Ashley M; Levitt, Roy C; Felix, Elizabeth R et al. (2017) Patients with more severe symptoms of neuropathic ocular pain report more frequent and severe chronic overlapping pain conditions and psychiatric disease. Br J Ophthalmol 101:227-231
Fu, Eugene S; Erasso, Diana M; Zhuang, Gerald Z et al. (2017) Impact of human CA8 on thermal antinociception in relation to morphine equivalence in mice. Neuroreport 28:1215-1220
Crane, Ashley M; Feuer, William; Felix, Elizabeth R et al. (2017) Evidence of central sensitisation in those with dry eye symptoms and neuropathic-like ocular pain complaints: incomplete response to topical anaesthesia and generalised heightened sensitivity to evoked pain. Br J Ophthalmol 101:1238-1243
Levitt, Roy C; Zhuang, Gerald Y; Kang, Yuan et al. (2017) Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice. Mamm Genome 28:407-415
Kalangara, Jerry P; Galor, Anat; Levitt, Roy C et al. (2017) Characteristics of Ocular Pain Complaints in Patients With Idiopathic Dry Eye Symptoms. Eye Contact Lens 43:192-198
Chen, Wan; Batawi, Hatim Ismail M; Alava, Jimmy R et al. (2017) Bulbar conjunctival microvascular responses in dry eye. Ocul Surf 15:193-201
Lee, Charity J; Levitt, Roy C; Felix, Elizabeth R et al. (2017) Evidence that dry eye is a comorbid pain condition in a U.S. veteran population. Pain Rep 2:e629

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