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Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity

Sapio, Matthew R.a; Iadarola, Michael J.a,*; LaPaglia, Danielle M.a; Lehky, Tanyab; Thurm, Audrey E.c; Danley, Kristen M.d; Fuhr, Shannon R.d; Lee, Mark D.d; Huey, Amanda E.d; Sharp, Stephen J.e; Tsao, Jack W.e,f,g,h; Yanovski, Jack A.i; Mannes, Andrew J.a; Han, Joan C.c,d,h,i,j,k

doi: 10.1097/j.pain.0000000000001485
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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.

Haploinsufficiency of BDNF in humans with WAGR syndrome and in rats with a specific heterozygous Bdnf disruption has reduced sensitivity to pain.

aDepartment of Perioperative Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, United States

bElectromyography Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, United States

cPediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health (NIH), Bethesda, MD, United States

dUnit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, United States

eDepartent of Neurology, Uniformed Services University, Bethesda, MD, United States

fDepartment of Neurology, University of Tennessee Health Science Center, Memphis, TN, United States

gDepartment of Neurology, Memphis Veterans Affairs Medical Center, Memphis, TN, United States

hChildren's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN, United States

iSection on Growth and Obesity, NICHD, NIH, Bethesda, MD, United States

Departments of jPediatrics and

kPhysiology, University of Tennessee Health Science Center, Memphis, TN, United States

Corresponding author. Address: Department of Perioperative Medicine, Clinical Center Building 10, Room 2C401, 10 Center Dr, MSC 1510, National Institutes of Health, Bethesda, MD 20892-1510, United States. Tel.: 301-496-2758. E-mail address: miadarol@cc.nih.gov (M.J. Iadarola).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

M.R. Sapio and M.J. Iadarola contributed equally to this manuscript.

Received October 01, 2018

Received in revised form December 04, 2018

Accepted December 09, 2018

© 2019 International Association for the Study of Pain
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