CHAPEL HILL, NC, United States
CHAPEL HILL, NC, United States
SEARCH FILTERS
Time filter
Source Type

Levitt R.C.,University of Miami | Levitt R.C.,Bruce W Carter Miami Veterans Healthcare System | Zhuang G.Y.,University of Miami | Kang Y.,University of Miami | And 10 more authors.
Mammalian Genome | Year: 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-Car8WT 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. © 2017 Springer Science+Business Media New York


Sorge R.E.,McGill University | Trang T.,Hospital for Sick Children | Dorfman R.,Hospital for Sick Children | Smith S.B.,University of North Carolina at Chapel Hill | And 29 more authors.
Nature Medicine | Year: 2012

Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da. Using genome-wide linkage analyses, we discovered an association between nerve-injury-induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain. © 2012 Nature America, Inc. All rights reserved.


Smith S.B.,Algynomics, Inc. | Smith S.B.,University of North Carolina at Chapel Hill | Maixner D.W.,University of North Carolina at Chapel Hill | Fillingim R.B.,University of Florida | And 14 more authors.
Arthritis and Rheumatism | Year: 2012

Objective Fibromyalgia (FM) represents a complex disorder that is characterized by widespread pain and tenderness and is frequently accompanied by additional somatic and cognitive/affective symptoms. Genetic risk factors are known to contribute to the etiology of the syndrome. The aim of this study was to examine >350 genes for association with FM, using a large-scale candidate gene approach. Methods The study group comprised 496 patients with FM (cases) and 348 individuals with no chronic pain (controls). Genotyping was performed using a dedicated gene array chip, the Pain Research Panel, which assays variants characterizing >350 genes known to be involved in the biologic pathways relevant to nociception, inflammation, and mood. Association testing was performed using logistic regression. Results Significant differences in allele frequencies between cases and controls were observed for 3 genes: GABRB3 (rs4906902; P = 3.65 à- 10-6), TAAR1 (rs8192619; P = 1.11 à- 10-5), and GBP1 (rs7911; P = 1.06 à- 10 -4). These 3 genes and 7 other genes with suggestive evidence for association were examined in a second, independent cohort of patients with FM and control subjects who were genotyped using the Perlegen 600K platform. Evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4. Conclusion Variation in these 4 replicated genes may serve as a basis for development of new diagnostic approaches, and the products of these genes may contribute to the pathophysiology of FM and represent potential targets for therapeutic action. © 2012 American College of Rheumatology.


A method of combating a somatosensory disorder in a subject, comprising administering to the subject an effective amount of a composition comprising bupranolol and/or pharmaceutically acceptable derivative(s) thereof. Compositions useful for such administration are described, including salts, esters, solvates, etc. of tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine, in which such salt, ester, solvate, etc. compound is in enantiomeric excess or homoenantiomeric in the R isomer thereof, or is formulated with racemic mixtures of the R and S stereoisomers of the salts, esters, solvates, etc. of tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine. Combination therapy compositions of opioid receptor agonists and such compounds are also described. A method is disclosed of referential genotypic screening of candidate subjects in connection with therapeutic intervention using the compositions of the disclosure to combat the somatosensory disorder.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 656.97K | Year: 2012

DESCRIPTION (provided by applicant): The mu-opioid receptor (MOR) is the primary target for opioid analgesics. While opioids are the most frequently used and effective analgesics for the treatment of moderate to severe clinical pain, their prolonged use leads to reduced efficacy and a number of adverse side effects, including post dosing-induced hyperalgesia and analgesic tolerance. MOR induces analgesia through several mechanisms including the inhibition of second messenger pathways and modulation of ion channel activity. Nevertheless, the opposite, opioid induced cellular excitation, has also been demonstrated and proposed to mediate reductions in efficacy, tolerance, and opioid-induced hyperalgesia following the exposure to opioids. While an array of mechanisms has been advanced that contribute to these use-dependence changes in MOR-mediated effects, we have recently identified a novel mechanism underlying the shift in MOR signaling: a MOR splice variant encoding a functional 6 transmembrane (6TM) receptor. This 6TM isoform was identified in a study designed to determine the genetic basis for variability in sensitivity to exogenous opiates. Importantly, morphine exposure to cells overexpressing the 6TM receptor isoform leads to excitatory cellular effects rather than the classic inhibitory effects that are produced by stimulating the canonical 7TM MOR isoform. The discovery of this new alternative 6TM isoform, which evokes responses that oppose the biological effects of the major 7TM isoform, provides a unique opportunity to identify pharmacological probes that will further our understanding of the mechanisms that mediate the pharmacodynamic effects of opioids and will enable the future development of new opioid compounds that show 7TM agonist and/or 6TM antagonist properties providing high analgesic efficacy with a diminished ability to produce post dosing-induced hyperalgesia, analgesic tolerance, and unwanted physiological side effects. To take maximal advantage of this opportunity, an interdisciplinary investigative team with unique, but complementary, areas of expertise has been assembled to develop, validate and characterize the in silico models of the major 7TM and alternative 6TM receptor isoforms can be used to identity putative isoform selective compounds. The long-term goal of this effort is to develop novel opioids that evoke high potency analgesia without deleterious short- or long-term consequences. PUBLIC HEALTH RELEVANCE: While opioids are the most frequently used and effective analgesicsfor the treatment of moderate to severe clinical pain, their prolonged use leads to a number of treatment limiting side-effects in a large percentage of patients. An experienced multidisciplinary investigative team proposes a set of studies that have derived from new data on the molecular and signaling basis of opioid receptor pharmacology and associated side-effects. These studies will build in silico models of the human 5-opioid receptor isoforms whose activities differentially contribute to the clinicalefficacy of opioids and allow identification of novel and potentially a new class of opioid compounds that will show high analgesic properties with a diminished ability to produce opioid-induced hyperalgesia, analgesic tolerance, and unwanted physiologicalside effects.


Algynomics, Inc. | Entity website

2012 Algynomics will sponsor the Satellite Symposium "SS 04: Current Concepts, Methods and Progress in Pain Genetics Research," supported by the SIG Genetics and Pain at the 14th World Congress on Pain, International Association for the Study of Pain. The meeting will take place on August 26, 2012 in Milan, Italy ...


PubMed | Algynomics, Inc.
Type: Journal Article | Journal: Arthritis and rheumatism | Year: 2012

Fibromyalgia (FM) represents a complex disorder that is characterized by widespread pain and tenderness and is frequently accompanied by additional somatic and cognitive/affective symptoms. Genetic risk factors are known to contribute to the etiology of the syndrome. The aim of this study was to examine >350 genes for association with FM, using a large-scale candidate gene approach.The study group comprised 496 patients with FM (cases) and 348 individuals with no chronic pain (controls). Genotyping was performed using a dedicated gene array chip, the Pain Research Panel, which assays variants characterizing >350 genes known to be involved in the biologic pathways relevant to nociception, inflammation, and mood. Association testing was performed using logistic regression.Significant differences in allele frequencies between cases and controls were observed for 3 genes: GABRB3 (rs4906902; P = 3.65 10(-6)), TAAR1 (rs8192619; P = 1.11 10(-5)), and GBP1 (rs7911; P = 1.06 10(-4)). These 3 genes and 7 other genes with suggestive evidence for association were examined in a second, independent cohort of patients with FM and control subjects who were genotyped using the Perlegen 600K platform. Evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4.Variation in these 4 replicated genes may serve as a basis for development of new diagnostic approaches, and the products of these genes may contribute to the pathophysiology of FM and represent potential targets for therapeutic action.


A method of combating a somatosensory disorder in a subject, comprising administering to the subject an effective amount of a composition comprising bupranolol and/or pharmaceutically acceptable derivative(s) thereof. Compositions useful for such administration are described, including salts, esters, solvates, etc. of tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine, in which such salt, ester, solvate, etc. compound is in enantiomeric excess or homoenantiomeric in the R isomer thereof, or is formulated with racemic mixtures of the R and S stereoisomers of the salts, esters, solvates, etc. of tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine. Combination therapy compositions of opioid receptor agonists and such compounds are also described. A method is disclosed of referential genotypic screening of candidate subjects in connection with therapeutic intervention using the compositions of the disclosure to combat the somatosensory disorder.


PubMed | Algynomics, Inc., University of Miami and University of North Carolina at Chapel Hill
Type: Journal Article | Journal: PloS one | Year: 2015

Calcium dysregulation is causally linked with various forms of neuropathology including seizure disorders, multiple sclerosis, Huntingtons disease, Alzheimers, 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.


Algynomics, Inc. | Entity website

The unique expertise of the Algynomics team in the fields of clinical pain and pain genetics provides the basis for both early and late stage clinical services to pharmaceutical companies. Algynomics currently has consulting contracts with Fortune 500 pharmaceutical companies providing these services ...

Loading Algynomics, Inc. collaborators
Loading Algynomics, Inc. collaborators