The major focus of Dr. Fletcher A. White’s laboratory is to understand, at the molecular/cellular level, the processes involved in inflammatory and chronic pain states. The main approaches utilized in the laboratory include biochemistry, molecular biology, electrophysiology, mouse genetics, and imaging. Projects in our laboratory involve the development of drugs that act on inflammatory mediators/receptors as well as the molecular basis for pain in bone fracture and mild traumatic brain injury.
The laboratory was the first to report that peripheral nerve injury results in the upregulation of both the chemokine, monocyte chemoattractant protein-1 (MCP1/CCL2) and its cognate receptor, CCR2. More importantly, that the use of a receptor antagonist, CCR2 RA [R], could elicit the reversal of neuropathic pain behavior. The White Lab also reported that other chemokine/receptor interactions could modulate chronic pain states in demyelinating peripheral neuropathy, painful neuropathy due to therapeutic drugs for HIV and bone cancer. More recent studies have examined the role that TRPV1, TRPA1, TRPC6, voltage-gated ion channels (NaV1.6/1.7, CaV2.2) toll-like receptor 4 (TLR4) and receptor of advanced glycation end-products (RAGE) play in the persistence of chronic pain states due to bone fracture, peripheral nerve injury, mild traumatic brain injury and opioid-induced hyperalgesia.
Cryo-EM structure of the open capsaicin-bound rat TRPV1 channel at 48 °C. (A) shows the side view of the TRPV1 channel, and (B) shows the bird’s eye view of the channel. (C,D) show the magnified views of the capsaicin binding site from the side and from the top, respectively. The key residues that are important for coordinating capsaicin are shown in blue. S3 and S5 transmembrane domains are colored in orange, and capsaicin molecules are shown as red sticks. (Munjuluri et al., Cells 2021 Dec 22;11(1):18 PMID: 35011580)
Expression pattern of TRPV1. TRPV1 channels are expressed in nociceptive, sensory nerve fibers innervating the skin and visceral sensory nerve fiber endings, smooth muscle, and endothelial cells within the vascular wall. TRPV1 activation in visceral sensory nerve endings leads to calcitonin gene related peptide (CGRP) release. CGRP then acts on vascular smooth muscle cells, causing vasodilation. Activation of postganglionic sympathetic nerve fibers results in noradrenaline (NA) release, which results in vasoconstriction. (Munjuluri et al., Cells 2021 Dec 22;11(1):18 PMID: 35011580)
Several of our pre-clinical studies have also translated into clinical observational and interventional studies. These projects include biomarkers of (i) subjects with mild traumatic brain injury who develop chronic headache; (ii) subjects with polytrauma alone or in combination with mild to moderate traumatic brain injury and (iii) subjects with spinal cord injury suffering with neuropathic pain. Additionally, an FDA-approved drug identified from one of the preclinical studies is now in a NIH RO1-sponsored phase I clinical trial for a novel use in patients suffering from pain due to chronic pancreatitis. These outcomes, achieved through extensive collaboration with clinical and basic scientists, demonstrate the translational nature of our research.
Current Research Funding
NIH/NINDS R01NS102415 (White, PI)
The Role of Cell-Specific TLR-4 Signaling in Oxaliplatin-induced Peripheral Neuropath
NIH/NIDDK R01DK132709 (Fogel and White, MPI)
Safety, tolerability, and dose limiting toxicity of lacosamide in patients with painful chronic pancreatitis
Department of Veterans Affairs I01BX12983911 (Kacena, PI; White Co-I)
Novel therapeutic approaches to improve fracture healing while reducing pain behavior
Department of Defense W81XWH-18-1-0433 (White and Naugle, MPI)
Chronic headache due to mild traumatic brain injury in adults: Alterations of brain function, central sensitization and inflammatory processes.
Naugle KM, Corrona S, Smith JA, Nguyen T, Saxe J, White FA. Physical activity behavior in the first month following mild traumatic brain injury is associated with physiological and psychological risk factors for chronic pain. Pain Reports, Oct 29;6(4):e969. 2021 PMID: 34765852
Ping X, Chai Z, Wang WM, Cungen M, White FA, Jin X. Blocking receptor for advanced glycation end-products (RAGE) or toll like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice. Epilepsia, Sep 18. doi: 10.1111/epi.17069, 2021 PMID: 34535891
Niculescu AB, Le-Niculescu H, Levey DF, Soe KC, Roseberry K, Khan F, Jones TJ, Judd S, McCormick MA, Williams A, Kurian S, White FA. Towards Precision Medicine for Pain: Diagnostic Biomarkers, Pharmacogenomics, and Repurposed Drugs. Molecular Psychiatry Apr;24(4):501-522, 2019. PMID:30755720
Chen X, Liu D, Zhou D, Si Y, Xu D, Stamatkin CW, Ghozayel M, Ripsch MS, Obukhov AG*, Meroueh SO* and White FA*. A Small-Molecule CaVα1•CaVβ Protein-Protein Interaction Antagonist Suppresses Neuronal Voltage-Gated Calcium Channel Trafficking. Proceedings of the National Academy of Science, USA Nov 6;115(45), E10566-E10575. 2018. PMID: 30355767
Allette YM, Kim Y, Smith JA, Randolph AL, Ripsch MS, White FA. Decoy peptide targeted to Toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons. Scientific Reports, Jun 16;7(1):3741, 2017. PMID: 28623271
Jared A. Smith
MD/PhD Graduate Student
Tyler Nguyen, PhD
Geunjoo Choi, MD, PhD
Visiting Associate Professor in Anesthesia
Mohammed Juboori, MS
Natalie Taylor, MS