Regardless of the scale of peripheral nerve damage, human neonates usually suffer no chronic neuropathic pain. However, by early adulthood, this situation is starkly different, with rates of chronic pain related to the severity of nerve injury, genetic makeup and as yet undetermined risk factors. Rodents display similar age related traits in differential neuropathic hypersensitivity and we have used this phenomenon to perform a whole genome expression screen of the spinal dorsal horns ipsilateral to the injured sciatic nerve from neonates (with no hypersensitivity) and adults (with chronic pain-like symptoms). We found virtually all of the genes regulated in the adult, but not in the neonate were immune related, and within this group we found evidence for the presence of two cell types, microglia and T lymphocytes. As we had previously characterized the role of microglia, we further defined the role of T cells in this process. Preventing T cell function in adult animals resulted in marke decreases in pain-like behavior, suggesting that T cell migration into the nervous system was a crucial part of chronic neuropathic pain, a mechanism that has remained largely unrecognized to date. Here we wish to define this system further, by (1) blocking leukocyte action and infiltration in adult animals subject to peripheral nerve injury;(2) investigating the mechanisms f T cell recruitment to the sciatic nerve injury site (neuroma), the dorsal root ganglion, and the dorsal horn following nerve injury;(3) separating and defining the individual roles of the T helpe cell subtypes (Th1, Th2, Th17 and T regulatory) by gain and loss of function techniques.

Public Health Relevance

Neuropathic pain is a chronic disease with few effective therapies that destroys the lives of those that suffer its devastating consequences. Its treatment thus represents a major unmet clinical need. We have found that immune cells from the blood (T cells) infiltrate the peripheral nervous system and spinal cord following injury to peripheral sensory nerves and contribute to this pain. We believe we have found an important new mechanism of neuropathic pain, one with existing therapies designed for other conditions that may prove beneficial in reducing chronic pain symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS074430-03
Application #
8640215
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Babcock, Debra J
Project Start
2012-07-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$390,374
Indirect Cost
$156,811
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Sieberg, Christine B; Taras, Caitlin; Gomaa, Aya et al. (2018) Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients. Pain Rep 3:e651
Gonzalez-Cano, Rafael; Boivin, Bruno; Bullock, Daniel et al. (2018) Up-Down Reader: An Open Source Program for Efficiently Processing 50% von Frey Thresholds. Front Pharmacol 9:433
Latremoliere, Alban; Costigan, Michael (2018) Combining Human and Rodent Genetics to Identify New Analgesics. Neurosci Bull 34:143-155
Banno, Tomohiro; Omura, Takao; Masaki, Noritaka et al. (2017) Arachidonic acid containing phosphatidylcholine increases due to microglial activation in ipsilateral spinal dorsal horn following spared sciatic nerve injury. PLoS One 12:e0177595
Lisi, VĂ©ronique; Singh, Bhagat; Giroux, Michel et al. (2017) Enhanced Neuronal Regeneration in the CAST/Ei Mouse Strain Is Linked to Expression of Differentiation Markers after Injury. Cell Rep 20:1136-1147
Browne, Liam E; Latremoliere, Alban; Lehnert, Brendan P et al. (2017) Time-Resolved Fast Mammalian Behavior Reveals the Complexity of Protective Pain Responses. Cell Rep 20:89-98
Tedeschi, Andrea; Omura, Takao; Costigan, Michael (2017) CNS repair and axon regeneration: Using genetic variation to determine mechanisms. Exp Neurol 287:409-422
Chandran, Vijayendran; Coppola, Giovanni; Nawabi, Homaira et al. (2016) A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program. Neuron 89:956-70
Latremoliere, Alban; Latini, Alexandra; Andrews, Nick et al. (2015) Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway. Neuron 86:1393-406

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