Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity
Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) synd...
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| Published in | Pain (Amsterdam) Vol. 160; no. 5; pp. 1070 - 1081 |
|---|---|
| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Wolters Kluwer
01.05.2019
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (
BDNF
) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the
BDNF
gene. Corresponding behavioral assessments were made in heterozygous
Bdnf
knockout rats to examine the specific role of
Bdnf
. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the
BDNF
gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity. |
|---|---|
| AbstractList | Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity. Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity. Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor ( BDNF ) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf . These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity. Rare pain insensitive individuals offer unique insights into how pain circuits function, and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, range of intellectual disabilities) syndrome, who have variably-sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor ( BDNF ) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing (QST), demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf . These analogous experiments revealed impairment of Aδ and C-fiber mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber mediated cold responses and cold avoidance on a cold plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that heterozygous deletion of the BDNF gene reduces pain sensitivity, and establish BDNF as a determinant of nociceptive sensitivity. Haploinsufficiency of BDNF in humans with WAGR syndrome, and in rats with a specific disruption of Bdnf on a single allele have reduced sensitivity to pain. |
| Author | Fuhr, Shannon R. Huey, Amanda E. Han, Joan C. Sapio, Matthew R. Lehky, Tanya LaPaglia, Danielle M. Lee, Mark D. Mannes, Andrew J. Sharp, Stephen J. Danley, Kristen M. Yanovski, Jack A. Tsao, Jack W. Thurm, Audrey E. Iadarola, Michael J. |
| AuthorAffiliation | Section on Growth and Obesity, NICHD, NIH, Bethesda, MD, United States Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health (NIH), Bethesda, MD, United States Department of Perioperative Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, United States Departent of Neurology, Uniformed Services University, Bethesda, MD, United States Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, United States Electromyography Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, United States |
| AuthorAffiliation_xml | – name: Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health (NIH), Bethesda, MD, United States – name: Department of Perioperative Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, United States – name: Electromyography Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, United States – name: Departent of Neurology, Uniformed Services University, Bethesda, MD, United States – name: Section on Growth and Obesity, NICHD, NIH, Bethesda, MD, United States – name: Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, United States – name: 6 Department of Neurology, University of Tennessee Health Science Center, Memphis, TN – name: 10 Departments of Pediatrics and Physiology, University of Tennessee Health Science Center – name: 4 Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD – name: 2 Electromyography Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD – name: 9 Section on Growth and Obesity, NICHD, NIH, Bethesda, MD – name: 7 Department of Neurology, Memphis Veterans Affairs Medical Center, Memphis, TN – name: 5 Departent of Neurology, Uniformed Services University, Bethesda, MD – name: 8 Children’s Foundation Research Institute, Le Bonheur Children’s Hospital, Memphis, TN – name: 1 Department of Perioperative Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD – name: 3 Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, NIH, Bethesda, MD |
| Author_xml | – sequence: 1 givenname: Matthew R. surname: Sapio fullname: Sapio, Matthew R. organization: Department of Perioperative Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, United States – sequence: 2 givenname: Michael J. surname: Iadarola fullname: Iadarola, Michael J. organization: Department of Perioperative Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, United States – sequence: 3 givenname: Danielle M. surname: LaPaglia fullname: LaPaglia, Danielle M. organization: Department of Perioperative Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, United States – sequence: 4 givenname: Tanya surname: Lehky fullname: Lehky, Tanya organization: Electromyography Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, United States – sequence: 5 givenname: Audrey E. surname: Thurm fullname: Thurm, Audrey E. organization: Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health (NIH), Bethesda, MD, United States – sequence: 6 givenname: Kristen M. surname: Danley fullname: Danley, Kristen M. organization: Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, United States – sequence: 7 givenname: Shannon R. surname: Fuhr fullname: Fuhr, Shannon R. organization: Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, United States – sequence: 8 givenname: Mark D. surname: Lee fullname: Lee, Mark D. organization: Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, United States – sequence: 9 givenname: Amanda E. surname: Huey fullname: Huey, Amanda E. organization: Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, United States – sequence: 10 givenname: Stephen J. surname: Sharp fullname: Sharp, Stephen J. organization: Departent of Neurology, Uniformed Services University, Bethesda, MD, United States – sequence: 11 givenname: Jack W. surname: Tsao fullname: Tsao, Jack W. organization: Departent of Neurology, Uniformed Services University, Bethesda, MD, United States – sequence: 12 givenname: Jack A. surname: Yanovski fullname: Yanovski, Jack A. organization: Section on Growth and Obesity, NICHD, NIH, Bethesda, MD, United States – sequence: 13 givenname: Andrew J. surname: Mannes fullname: Mannes, Andrew J. organization: Department of Perioperative Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, United States – sequence: 14 givenname: Joan C. surname: Han fullname: Han, Joan C. organization: Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health (NIH), Bethesda, MD, United States |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30855519$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this manuscript Author Contributions M.R.S. designed experiments, performed behavioral testing and RNA-Seq analyses on animals, performed statistics, constructed figures, and analyzed and interpreted the data. D.M.L. analyzed the data, constructed figures, and extracted RNA. T.L. performed and interpreted nerve conduction measurements for human subjects. A.E.T. performed and interpreted cognitive testing in human subjects, and assisted in designing and interpreting the pain assessments for human subjects. K.M.D. S.R.F. M.D.L. A.E.H. directly performed or supervised research assistants in pain testing of human subject. S.J.S. and J.W.T. performed and interpreted neurological examinations on human subjects. M.J.I. analyzed the data, supervised behavioral assessments. J.C.H. designed human pain testing methods adapted for visual impairment, performed statistics, and analyzed the human subject data. M.J.I., J.A.Y., A.J.M., and J.C.H supervised the overall project and management. M.J.I., J.A.Y., and J.C.H. conceived the project. M.R.S., M.J.I., and J.C.H. prepared the manuscript. |
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| Snippet | Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We... Rare pain insensitive individuals offer unique insights into how pain circuits function, and have led to the development of new strategies for pain control. We... |
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| SubjectTerms | Adolescent Adult Animals Brain-Derived Neurotrophic Factor - genetics Brain-Derived Neurotrophic Factor - metabolism Child Female Ganglia, Spinal - metabolism Ganglia, Spinal - pathology Gene Expression Profiling Humans Hyperalgesia - genetics Hyperalgesia - physiopathology Lasers - adverse effects Male Mutation - genetics Pain - etiology Pain - genetics Pain Measurement Pain Threshold - physiology Physical Stimulation - adverse effects Rats Rats, Transgenic Spinal Cord - metabolism Spinal Cord - pathology WAGR Syndrome - complications WAGR Syndrome - genetics Young Adult |
| Title | Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity |
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