Department of
Anesthesiology and Perioperative Medicine

Bradley K. Taylor, PhD

  • Professor

Education & Training

  • Postdoctoral fellowship, University of California, San Francisco
  • PhD, University of California, San Diego
  • BS, University of California, Davis

Representative Publications

Dr. Taylor's publications can be viewed through NCBI.

Research, clinical, and/or academic interests

Dr. Taylor's laboratory investigates the mechanisms through which inflammation or injury produces changes in the peripheral nerves, spinal cord, and brain, leading to a transition from acute pain to chronic pain. He has authored one book (as Senior Co-editor) and over 85 peer-reviewed research and review articles (most as first or senior author), including high profile senior-author publications in Science and PNAS. His current annual NIH funding portfolio includes three R01s continuing through 2020, 2021, and 2022. These grants allow Dr. Taylor's laboratory to explore innovative ideas using state-of-the art techniques so as to better understand the molecular neurobiology of pain sensitization and opioid dependence, and thus contribute to new pharmacotherapeutic approaches to the development of analgesic drugs. 

Research Grants

PI, NIH/NIDA RO1 DA037621-01A1, 08/15/15-05/31/20: "Long-term activation of spinal opioid analgesia after inflammation." Mu opioid receptor constitutive activity. This large R01 in collaboration with Suzanne Doolen studies clinical pain patients and mouse models of latent sensitization (LS). It is based on Dr. Taylor's work showing that tissue inflammation produces an LS that is masked by spinal mu opioid receptor (MOR) signaling for months, even after complete recovery from injury and re-establishment of normal pain thresholds. Disruption with MOR inverse agonists reinstates pain and precipitates cellular, somatic and aversive signs of physical withdrawal; this phenomenon requires N-methyl-D-aspartate receptor-mediated activation of calcium-sensitive adenylyl cyclase type 1 (AC1). His grant tests a new conceptual model of the transition from acute to chronic pain, based on the delicate balance between LS and endogenous analgesia that develops after painful tissue injury (Taylor and Corder, 2014). First, injury activates pain pathways. Second, the spinal cord establishes MOR constitutive activity (MORCA) as it attempts to control pain. Third, over time, the body becomes dependent on MORCA, which paradoxically sensitizes pain pathways. Stress or injury escalates opposing inhibitory and excitatory influences on nociceptive processing as a pathological consequence of increased endogenous opioid receptor tone. Pain begets MORCA begets pain vulnerability in a vicious cycle. The final result is a silent insidious state characterized by the escalation of two opposing excitatory and inhibitory influences on pain transmission: LS mediated by AC1 (which maintains the accelerator), and pain inhibition mediated by MORCA (which maintains the brake). This raises the prospect that opposing homeostatic interactions between MORCA analgesia and latent NMDAR–AC1-mediated pain sensitization create a lasting vulnerability to develop chronic pain. Thus, chronic pain syndromes may result from a failure in constitutive signaling of spinal MORs and a loss of endogenous analgesic control. Dr. Taylor's paper underlying this working hypothesis (Corder et al, 2013) was featured on the cover of the September 20, 2013 issue of Science, was accompanied by an Editor’s cover story, was the focus of several news stories (e.g. The Scientist, Businessweek, Nature Medicine, Pain Research Forum), and was later announced in 2014 as the annual “Top Science Advance in Pain Research” by the NIH Interagency Pain Research Coordinating Committee.

Clinical Studies. Aim 1: The first experiments conducted in human volunteers (NCT02684669) has already demonstrated that naloxone reinstates secondary hyperalgesia after mild heat injury – a direct translation of Dr. Taylor's animal studies published in Science. This data was highlighted in the translational symposium which Dr. Taylor developed and chaired at the 2017 American Pain Society meeting in Pittsburgh. To extend his studies to postoperative pain, Dr. Taylor's lab is now close to completing recruitment of postoperative patients following third molar extraction (NCT02976337) and groin hernia repair (NCT01992146). They are also setting up analogous studies in other forms of post-operative pain. Positive results would indicate that surgery sets up a long-lasting, compensatory increase in endogenous opioid receptor analgesia that prevents the transition from acute to chronic postoperative pain. If true, then it could be predicted that anything that causes this pain inhibitory system to fail, such as stress, would be associated with the development of chronic postoperative pain.

Basic science studies, Aims 2-4 use patch clamp electrophysiology of adult spinal neurons and behavioral pharmacology to understand the neurobiological mechanisms of latent sensitization (including pre and post-synaptic plasticity at multiple NMDA receptor subtypes) and its inhibition by tonic inhibitory GPCR activity (including MOR, kappa opioid, and cannabinoid CB1 and CB2 receptors). Because of the close interplay between stress, chronic pain relapse, and addiction, Dr. Taylor is launching a new project to test the hypothesis that stress will reduce MORCA, thus unleashing a pain episode. With this work, Dr. Taylor's lab hopes to ultimately generate clinical trials to either: a) facilitate endogenous opioid receptor analgesia, thus restricting chronic pain within a state of remission; or b) extinguish chronic pain altogether. 

PI, NIH/NINOS 2 R01 NS45954-11, 12/15/16-11/30/21: “Neuropeptidergic Inhibition of Spinal Pain Transmission.” Dorsal horn microcircuity. This R01 was just renewed for a third five-year period to study the spinal neuropeptide Y Y1 receptor as a novel pharmacotherapeutic target for chronic pain. They Taylor lab's initial work indicated that intrathecal administration of NPY acts in a dose- and receptor-dependent manner to reduce behavioral signs of inflammatory pain and peripheral neuropathic pain (Taiwo et al, 2002; Intondi et al, 2008). They then discovered that an injury-induced enhancement of endogenous NPY-Y1 receptor GPCR signaling could be maintained long enough to confine chronic inflammatory and neuropathic pain within a state of remission (Solway et al, PNAS, 2011). The objective of the current renewal is to determine whether injury induces a sustained spinal release of NPY, leading to the inhibition of pronociceptive Y1R-expressing interneurons in the dorsal horn. To achieve this, they are implementing transformative neuroscience and biomedical research approaches – new innovative methods to measure neuropeptide release in vivo, a new approach to microinject AAV virus into mouse DRG, GCaMP6 imaging of neuronal activity both in the spinal cord slice and the whole animal, optogenetics coupled with patch clamp neurophysiology of adult Y1R-GFP and other Y1R transgenic mice to study the microcircuitry of pain modulation in the dorsal horn, and chemogenetic neuropharmacology using DREADDs.

PI, NIH/NINOS 2 R01 NS062306-07, 12/18/08-3/31/22: “PPAR gamma Inhibition of Spinal Pain Transmission.” Painful diabetic neuropathic pain. This R01 project was just renewed for a third five year period to study the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors as a novel class of analgesic compounds for chronic pain (Taiwo and Taylor, 2002). Three isoforms of PPAR have been identified: α, β/δ, and γ. Peripheral PPARγ is well-characterized as a key target of the thiazolinedione (TZD) class of FDA-approved anti-diabetic drugs, which includes rosiglitazone and pioglitazone. The Taylor lab has extended its potential targets to the spinal cord with our discovery of PPARγ mRNA and protein in the dorsal horn (Churi et al, 2008). They found that PPARγ agonists rapidly reduce the hyperalgesia associated with inflammation or nerve injury in a dose- and PPARγ-dependent manner (Morgenweck et al, 2013) in part via a novel non-genomic translation-independent mechanism at spinal glia (Griggs et al, 2015). This work is important and timely because TZDs are FDA-approved for diabetes and are in clinical trials for CNS neurodegenerative diseases. Therefore, their findings could lead to the rapid translation of basic science to the clinical treatment of chronic pain. Their renewal R01 application extends their studies to painful diabetic neuropathy (PDN), using the Zucker Diabetic Fatty (ZDF) rat and Leprdb/db (db/db) mouse hereditary models of type 2 diabetes. In ZDF, Dr. Taylor's group observed behavioral signs of motivational/affective pain (using a novel mechanical conflict-avoidance assay), and in both ZDF and db/db, they found elevated plasma methylglyoxal, a cellular metabolite of glucose that is markedly increased in the blood of hyperglycemic patients and contributes to PDN. To determine MG mechanism of action, they established a mouse model of MG-induced pain that includes multiple behavioral signs of spontaneous, evoked, and affective pain (using a conditioned place aversion assay), as well as molecular signs of spinal neuron activation. They are testing the central hypothesis that elevated MG in type 2 diabetes causes PDN and that this metabolic hyperalgesia can be alleviated by drugs targeting MG (Aim 1), TRPA1 (Aim 2), AC1 and Epac (Aim 3), and/or PPARγ (Aim 4), thus advancing a new pharmacotherapeutic strategy for painful diabetic neuropathy. 

Co-I (subcontract), NIH/NIDA ROI NS088518-0l, 07/01/14-06/30/19: "TLPQ-21 and C3aR1, a Novel Receptor/Ligand Interaction in Neuropathic Pain." Neuroimmune crosstalk. The central hypothesis of this proposal is that TLQP-21 activation of C3aR1 in dorsal horn of spinal cord establishes and maintains neuropathic pain. The complement 3a receptor (C3aR1) participates in microglial signaling under pathological conditions and was recently shown to be activated by the neuropeptide TLQP-21. Lucy Vulchanova previously demonstrated that TLQP-21 elicits hyperalgesia and contributes to nerve injury-induced hypersensitivity through an unknown mechanism in the spinal cord. In collaboration with her group and with Suzanne Doolen, Dr. Taylor's lab is using Ca2+ imaging in spinal slices, with a new innovative method to selectively record the activity microglial neurons, to determine whether the cellular target for TLQP-21 C3aR1 on microglia are the. Their results suggest a novel neuroimmune signaling pathway involving TLQP-21-induced activation of microglial C3aR1 that then contributes to spinal neuroplasticity and neuropathic pain. This unique dual-ligand activation of C3aR1 by a neuropeptide (TLQP-21) and an immune mediator (C3a) appears to represent a potential broad-spectrum mechanism throughout the CNS for integration of neuroimmune crosstalk at the molecular level. Suzanne Doolen is leading an effort to scale up funding of this project with an R01 submission in 2017-2018 that will focus on microglial function during neuropathic pain using a novel GCaMP6 imaging approach.  

Sponsor, NIH/NIDA KO1 DA31961-01A1, 02/01/14-01/31/19: "Glutamate Receptor Modulation of Calcium Signaling in Neuropathic Pain." Glutamate receptors. During her K01 career development award, Dr. Suzanne Doolen  found that inflammation produces an increase in dorsal horn calcium permeable (CP)-AMPAR expression and function, a shift that persists at least 21 days after injury. This suggests that CP-AMPARs drive the induction and/or maintenance of LS (described above). N-Methyl-D-aspartate receptors (NMDAR) are pivotal for synaptic plasticity. Conventional NMDARs consist of heterotetrameric structures composed of GluN1 and GluN2 subunits. In contrast, a third subunit, GluN3, assembles with NMDAR subunits to form a “nonconventional” NMDAR. While NMDAR-activity is required for acute increases in complete Freund’s adjuvant (CFA)-induced CP-AMPAR activity and behavioral hypersensitivity, little is known regarding GluN3-mediated regulation of AMPAR plasticity in chronic pain settings. Using novel GluN3 antagonists from their collaborators Dr. Steven Traynelis and Kasper Hansen, the group's current project explores these mechanisms in detail, namely, to test the hypothesis that inflammation increases CP-AMPARs in pronociceptive dorsal horn neurons that then initiates the development of LS (and thus chronic pain) by a GluN3-dependent mechanism. 

Co-PI, National Center for Complementary and Integrative Health R15AT009612-01, 07/01/17-06/30/20: “Antinociceptive Mechanisms of Spinal Manipulative Therapy for Neuropathic Pain”. Alternative medicine. This new R15 investigates the mechanism of analgesic action of spinal manipulative therapy (SMT), a non-pharmacologic, complementary and integrative health mind and body intervention that is widely used to treat chronic pain. Dr. Onifer’s group has developed an innovative rat model of a frequently used non-thrust SMT technique, low velocity variable amplitude spinal manipulation (LVVA-SM) using a custom-made motorized device. Their preliminary data in a well-characterized rat model of chronic peripheral neuropathic pain (spared nerve injury) indicate that LVVA-SM decreases behavioral signs of chronic pain (hindpaw mechanical allodynia). This applications determines whether LVVA-SM-induced anti-allodynia is mediated by endogenous activation of cannabinoid receptors in the spinal cord dorsal horn.

Endogenous Opioid Dependence. While it is accepted that dependence develops with repeated exposure to opiate drugs, the group's paper in Science (Corder et al.) was the first to provide strong evidence for endogenous opioid dependence. They found that injury initiated not only MORCA analgesia, but also a compensatory process of dependence to opioid receptor signalling, both of which could be revealed upon challenge with opiate receptor inverse agonists. Thus, µ-opioid receptor blockade during the post-hyperalgesia state precipitated hallmarks of both cellular withdrawal (cAMP overshoot that required NMDA receptor activation of adenylyl cyclase) in spinal cord neurons and physical withdrawal (jumping, paw tremor, teeth chattering, wet dog shakes, hyperalgesia) arising from the brain. They believe that this opponent process between opioid analgesia and dependence represents an allostatic state of chronic pain vulnerability in the brain, and have an R01 application to test this hypothesis with DREADD activation and inactivation of MORs in brain areas responsible for supraspinal pain modulation and opiate dependence. They are also pursuing their preliminary data that suggests that endogenous dependence develops in a subpopulation of humans after injury (Pereira et al., 2015).

Central neuropathic pain of Multiple Sclerosis. Approximately two-thirds of patients with multiple sclerosis (MS) experience neuropathic pain. Despite this, the pain of MS is understudied and not well treated. The FDA recently approved fingolimod as a disease-modifying therapy (DMT) to prevent MS relapses. Fingolimod modulates the function of the sphingosine-1-phosphate receptor-1 (S1PR1), a GPCR. To determine whether S1PR1 ligands such as fingolimod ameliorate the pain of MS, the group is using an optimized experimental autoimmune encephalomyelitis (EAE) mouse model of MS. They predict that intrathecal administration of S1PR1 agonists will target pathological processes in spinal glia so as to alleviate the central neuropathic pain of MS. Ben Shaw has submitted an F31 to pursue this project using conditional S1PR1 knockout mice, flow cytometry, small animal MRI, immunohistochemistry, and behavioral pharmacology, a project for which they have a key manuscript just published and for which they intend to submit as an R01 in 2018.

Central neuropathic pain in Women with Spinal Cord Injury. Central neuropathic pain develops in greater than 75% of both males and females suffering a spinal cord injury (SCI), and is particularly debilitating in veterans. Unfortunately, chronic neuropathic SCI pain severely impacts the quality of life of both SCI individuals and their caregivers, and is extremely difficult to manage. Analgesic drugs such as pregabalin are only partially effective in a small subset of patients. Our incomplete understanding of underlying mechanisms stalls the development of druggable targets for SCI pain. An important clue comes from the mounting evidence that intraspinal inflammation, specifically microglial activation, contributes to neuropathic pain following peripheral nerve injury, and this is sexually dimorphic. These studies suggest that sex differences may have masked the effectiveness of pharmacotherapeutics for neuropathic pain in earlier clinical trials. To address this question, in collaboration with multiple investigators within the Spinal Cord and Brain Injury Research Center at the University of Kentucky, the research group is using behavioral pharmacology and flow cytometry to examine the contribution of sex, spinal microglia, and peripheral inflammation to the development of SCI-induced pain, and investigating pioglitazone and rosiglitazone or other PPARγ agonists as new analgesics for women with SCI. Their new preliminary data suggest that PIO reduces pain in female mice at doses that are 100-1000 fold less than required to reduce pain in male mice. Since sexually dimorphic pain responses are being recognized across a variety of neuropathologies, development of effective immunomodulatory agents through the completion of their studies could have a broad impact in the fields of neuroscience and immunology.