ABOUT THE RESEARCHER

OVERVIEW

I am principally interested in the reaction of the peripheral nervous system, and second order neurons of the spinal dorsal horn to axonal damage, whether these changes result in maladaptive phenotypes (chronic pain) (Costigan et al., 2009a)or adaptive ones (regeneration) (Richardson et al., 2009). My focus is developing and using truly unbiased genetic research tools to obtain an unprecedented view of these mechanisms. 

From these data we wish to glean key genes and functional cascades, in order that these mechanisms can be proven in the laboratory, always with a view to translate such knowledge into future therapies. To do this I use whole genome expression microarrays in rodents with Dr Griffin (MGH), Dr’s Moss & Fitzgerald (London, UK), and Dr’s Coppola & Geschwind (UCLA). I use genome wide SNP arrays in humans, in collaboration with Dr’s Belfer & Lariviere (Pittsburgh), as well as Dr Diatchenko (UNC). I work with Dr’s Neely & Penninger (Vienna, Austria) to search drosophila genetics for relevant phenotypes (Neely et al., 2010). 

All of these data are combined to produce strong leads which are analyzed by multiple molecular methods prior to target development in humans. Examples of such work include, 1.The identification and subsequent characterization of GTP Cyclohydrolase 1 (GCH1) as a determinant of pain sensitivity in rodents (Tegeder et al., 2006). 

Current work develops cutting edge transgenic animals to further investigate the tetrahydrobiopterin pathway in sensory neurons as well as defining other human pain targets (Costigan et al., 2010). 2.The identification and characterization of the role of the innate (Griffin et al., 2007)and the adaptive immune system (Costigan et al., 2009b)in neuropathic pain. Current work develops an understanding of how T-lymphocytes and myeloid cells interact to create neuropathic pain. 3. I am actively exploring the mechanisms of regeneration within peripheral nervous system (Mills et al., 2007) and am currently working up multiple exciting new genetic leads in this area.

PUBLICATIONS

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  1. Intracolonic Mustard Oil Induces Visceral Pain in Mice by TRPA1-Dependent and -Independent Mechanisms: Role of Tissue Injury and P2X Receptors. Front Pharmacol. 2020; 11:613068. View abstract
  2. Cytotoxic Immunity in Peripheral Nerve Injury and Pain. Front Neurosci. 2020; 14:142. View abstract
  3. Human induced pluripotent stem cell-derived GABAergic interneuron transplants attenuate neuropathic pain. Pain. 2020 02; 161(2):379-387. View abstract
  4. Sepiapterin Reductase Inhibition Leading to Selective Reduction of Inflammatory Joint Pain in Mice and Increased Urinary Sepiapterin Levels in Humans and Mice. Arthritis Rheumatol. 2020 01; 72(1):57-66. View abstract
  5. The Genetics of Neuropathic Pain from Model Organisms to Clinical Application. Neuron. 2019 11 20; 104(4):637-653. View abstract
  6. Reading and writing: the evolution of molecular pain genetics. Pain. 2019 10; 160(10):2177-2185. View abstract
  7. Publisher Correction: The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature. 2019 Aug; 572(7769):E18. View abstract
  8. Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury. Cell. 2019 02 07; 176(4):716-728.e18. View abstract
  9. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature. 2018 11; 563(7732):564-568. View abstract
  10. Diltiazem Promotes Regenerative Axon Growth. Mol Neurobiol. 2019 Jun; 56(6):3948-3957. View abstract
  11. Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients. Pain Rep. 2018 May; 3(3):e651. View abstract
  12. Up-Down Reader: An Open Source Program for Efficiently Processing 50% von Frey Thresholds. Front Pharmacol. 2018; 9:433. View abstract
  13. Mechanistic Differences in Neuropathic Pain Modalities Revealed by Correlating Behavior with Global Expression Profiling. Cell Rep. 2018 01 30; 22(5):1301-1312. View abstract
  14. Enhanced Neuronal Regeneration in the CAST/Ei Mouse Strain Is Linked to Expression of Differentiation Markers after Injury. Cell Rep. 2017 08 01; 20(5):1136-1147. View abstract
  15. Time-Resolved Fast Mammalian Behavior Reveals the Complexity of Protective Pain Responses. Cell Rep. 2017 07 05; 20(1):89-98. View abstract
  16. Combining Human and Rodent Genetics to Identify New Analgesics. Neurosci Bull. 2018 Feb; 34(1):143-155. View abstract
  17. Arachidonic acid containing phosphatidylcholine increases due to microglial activation in ipsilateral spinal dorsal horn following spared sciatic nerve injury. PLoS One. 2017; 12(5):e0177595. View abstract
  18. CNS repair and axon regeneration: Using genetic variation to determine mechanisms. Exp Neurol. 2017 Jan; 287(Pt 3):409-422. View abstract
  19. Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS. Neuron. 2016 May 04; 90(3):662. View abstract
  20. A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program. Neuron. 2016 Mar 02; 89(5):956-70. View abstract
  21. Transcriptomic Approaches to Neural Repair. J Neurosci. 2015 Oct 14; 35(41):13860-7. View abstract
  22. Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway. Neuron. 2015 Jun 17; 86(6):1393-406. View abstract
  23. Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS. Neuron. 2015 Jun 03; 86(5):1215-27. View abstract
  24. The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. Nat Med. 2015 May; 21(5):518-23. View abstract
  25. Post-stroke pain hypersensitivity induced by experimental thalamic hemorrhage in rats is region-specific and demonstrates limited efficacy of gabapentin. Neurosci Bull. 2014 Dec; 30(6):887-902. View abstract
  26. Heritability of nociception IV: neuropathic pain assays are genetically distinct across methods of peripheral nerve injury. Pain. 2014 May; 155(5):868-880. View abstract
  27. High energy diets-induced metabolic and prediabetic painful polyneuropathy in rats. PLoS One. 2013; 8(2):e57427. View abstract
  28. Nuclear calcium signaling in spinal neurons drives a genomic program required for persistent inflammatory pain. Neuron. 2013 Jan 09; 77(1):43-57. View abstract
  29. Construction of a global pain systems network highlights phospholipid signaling as a regulator of heat nociception. PLoS Genet. 2012; 8(12):e1003071. View abstract
  30. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med. 2012 Mar 25; 18(4):595-9. View abstract
  31. Pain's peptide signature. Pain. 2012 Mar; 153(3):509-510. View abstract
  32. Analgesia by inhibiting tetrahydrobiopterin synthesis. Curr Opin Pharmacol. 2012 Feb; 12(1):92-9. View abstract
  33. The BMP coreceptor RGMb promotes while the endogenous BMP antagonist noggin reduces neurite outgrowth and peripheral nerve regeneration by modulating BMP signaling. J Neurosci. 2011 Dec 14; 31(50):18391-400. View abstract
  34. Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice. J Clin Invest. 2011 Nov; 121(11):4332-47. View abstract
  35. GCH1, BH4 and pain. Curr Pharm Biotechnol. 2011 Oct; 12(10):1728-41. View abstract
  36. TrpA1 regulates thermal nociception in Drosophila. PLoS One. 2011; 6(8):e24343. View abstract
  37. A genome-wide Drosophila screen for heat nociception identifies a2d3 as an evolutionarily conserved pain gene. Cell. 2010 Nov 12; 143(4):628-38. View abstract
  38. TRPA1 contributes to cold hypersensitivity. J Neurosci. 2010 Nov 10; 30(45):15165-74. View abstract
  39. Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain. 2010 Sep; 133(9):2519-27. View abstract
  40. R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids. PLoS One. 2010 May 13; 5(5):e10628. View abstract
  41. T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci. 2009 Nov 18; 29(46):14415-22. View abstract
  42. COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice. J Clin Invest. 2009 Feb; 119(2):287-94. View abstract
  43. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009; 32:1-32. View abstract
  44. Origins, actions and dynamic expression patterns of the neuropeptide VGF in rat peripheral and central sensory neurones following peripheral nerve injury. Mol Pain. 2008 Dec 10; 4:62. View abstract
  45. GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function. J Am Coll Cardiol. 2008 Jul 08; 52(2):158-65. View abstract
  46. Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats. Eur J Neurosci. 2008 Feb; 27(4):937-46. View abstract
  47. Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity. J Neurosci. 2007 Aug 08; 27(32):8699-708. View abstract
  48. GDNF selectively promotes regeneration of injury-primed sensory neurons in the lesioned spinal cord. Mol Cell Neurosci. 2007 Oct; 36(2):185-94. View abstract
  49. Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms. Clin Chem. 2007 Jun; 53(6):1010-5. View abstract
  50. The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity. J Neurosci. 2006 Dec 13; 26(50):12852-60. View abstract
  51. Spinal microglia and neuropathic pain in young rats. Pain. 2007 Apr; 128(3):215-224. View abstract
  52. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006 Nov; 12(11):1269-77. View abstract
  53. High basal expression and injury-induced down regulation of two regulator of G-protein signaling transcripts, RGS3 and RGS4 in primary sensory neurons. Mol Cell Neurosci. 2003 Sep; 24(1):106-16. View abstract
  54. Exploiting microarrays to reveal differential gene expression in the nervous system. Genome Biol. 2003; 4(2):105. View abstract
  55. Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC Neurosci. 2002 Oct 25; 3:16. View abstract
  56. No DREAM, No pain. Closing the spinal gate. Cell. 2002 Feb 08; 108(3):297-300. View abstract
  57. Developmental expression of the TTX-resistant voltage-gated sodium channels Nav1.8 (SNS) and Nav1.9 (SNS2) in primary sensory neurons. J Neurosci. 2001 Aug 15; 21(16):6077-85. View abstract
  58. Differential gene expression--how to find new analgesic targets. Curr Opin Investig Drugs. 2001 Mar; 2(3):396-8. View abstract
  59. Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2. Physiol Genomics. 2001 Jan 19; 4(3):165-74. View abstract
  60. Pain: molecular mechanisms. J Pain. 2000 Sep; 1(3 Suppl):35-44. View abstract
  61. Diversity of expression of the sensory neuron-specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2. Mol Cell Neurosci. 2000 Apr; 15(4):331-42. View abstract
  62. A role for HSP27 in sensory neuron survival. J Neurosci. 1999 Oct 15; 19(20):8945-53. View abstract
  63. Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A. 1999 Aug 03; 96(16):9385-90. View abstract
  64. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A. 1999 Jul 06; 96(14):7723-30. View abstract
  65. Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons. Nat Neurosci. 1998 Dec; 1(8):653-5. View abstract
  66. Heat shock protein 27: developmental regulation and expression after peripheral nerve injury. J Neurosci. 1998 Aug 01; 18(15):5891-900. View abstract
  67. Collagen turnover in renal disease. Exp Nephrol. 1995 Mar-Apr; 3(2):114-21. View abstract