Scholars@Duke
Andrea Gail Nackley

Andrea Gail Nackley

Associate Professor in Anesthesiology
Anesthesiology
andrea.nackley@duke.edu
Box 3094, Mail Sort #50, Durham, NC 27710
3 Genome Court, #6120, Durham, NC 27710

Selected Publications

Vagus nerve stimulation rescues persistent pain following orthopedic surgery in adult mice.

Conference Pain · August 1, 2024 Postoperative pain is a major clinical problem imposing a significant burden on patients and society. In a survey 2 years after orthopedic surgery, 57% of patients reported persisting postoperative pain. However, only limited progress has been made in the ... Full text Link to item Cite

A mouse model of chronic primary pain that integrates clinically relevant genetic vulnerability, stress, and minor injury.

Journal Article Sci Transl Med · April 10, 2024 Chronic primary pain conditions (CPPCs) affect over 100 million Americans, predominantly women. They remain ineffectively treated, in large part because of a lack of valid animal models with translational relevance. Here, we characterized a CPPC mouse mode ... Full text Link to item Cite

Role of Blood-Brain Barrier Dysfunction in Delirium following Non-cardiac Surgery in Older Adults.

Journal Article Ann Neurol · December 2023 OBJECTIVE: Although animal models suggest a role for blood-brain barrier dysfunction in postoperative delirium-like behavior, its role in postoperative delirium and postoperative recovery in humans is unclear. Thus, we evaluated the role of blood-brain bar ... Full text Link to item Cite

Transforming Growth Factor-β-Activated Kinase 1 (TAK1) Mediates Chronic Pain and Cytokine Production in Mouse Models of Inflammatory, Neuropathic, and Primary Pain.

Journal Article J Pain · September 2023 The origin of chronic pain is linked to inflammation, characterized by increased levels of proinflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of proinflammatory ... Full text Open Access Link to item Cite

A Role for Blood-brain Barrier Dysfunction in Delirium following Non-Cardiac Surgery in Older adults.

Journal Article medRxiv · May 10, 2023 OBJECTIVE: Although animal models suggest a role for blood-brain barrier dysfunction in postoperative delirium-like behavior, its role in postoperative delirium and postoperative recovery in humans is unclear. Thus, we evaluated the role of blood-brain bar ... Full text Link to item Cite

Sensory Neuron-TRPV4 Modulates Temporomandibular Disorder Pain Via CGRP in Mice.

Journal Article J Pain · May 2023 Temporomandibular disorder (TMD) pain that involves inflammation and injury in the temporomandibular joint (TMJ) and/or masticatory muscle is the most common form of orofacial pain. We recently found that transient receptor potential vanilloid-4 (TRPV4) in ... Full text Open Access Link to item Cite

Complementary Approaches for Military Women with Chronic Pelvic Pain: A Randomized Trial.

Journal Article J Integr Complement Med · January 2023 Introduction: Active duty (AD) women suffer with chronic pelvic pain (CPP) while providers tackle diagnoses and treatments to keep them functional without contributing to the opioid epidemic. The purpose of this randomized trial was to determine the effect ... Full text Open Access Link to item Cite

Rationale and design of a multicenter randomized clinical trial of vestibulodynia: understanding pathophysiology and determining appropriate treatments (vestibulodynia: UPDATe).

Journal Article Ann Med · December 2022 BACKGROUND: Limited data are available to establish evidence-based management protocols for vestibulodynia (VBD), a chronic vulvar pain condition that affects approximately 14 million women in the U.S. For the purposes of the study, our group subdivided VB ... Full text Open Access Link to item Cite

Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain.

Journal Article Pain · June 1, 2022 Heat shock protein 90 (Hsp90) is a ubiquitously expressed integral cellular protein essential for regulating proteomic stress. Previous research has shown that Hsp90 regulates critical signaling pathways underlying chronic pain and inflammation. Recent dis ... Full text Open Access Link to item Cite

Acute inflammatory response via neutrophil activation protects against the development of chronic pain.

Journal Article Sci Transl Med · May 11, 2022 The transition from acute to chronic pain is critically important but not well understood. Here, we investigated the pathophysiological mechanisms underlying the transition from acute to chronic low back pain (LBP) and performed transcriptome-wide analysis ... Full text Link to item Cite

IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice.

Journal Article Neuron · September 1, 2021 Although sex dimorphism is increasingly recognized as an important factor in pain, female-specific pain signaling is not well studied. Here we report that administration of IL-23 produces mechanical pain (mechanical allodynia) in female but not male mice, ... Full text Link to item Cite

Epithelia-Sensory Neuron Cross Talk Underlies Cholestatic Itch Induced by Lysophosphatidylcholine.

Journal Article Gastroenterology · July 2021 BACKGROUND & AIMS: Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of antipruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus. METHODS: ... Full text Link to item Cite

Phenotypic profile clustering pragmatically identifies diagnostically and mechanistically informative subgroups of chronic pain patients.

Journal Article Pain · May 1, 2021 Traditional classification and prognostic approaches for chronic pain conditions focus primarily on anatomically based clinical characteristics not based on underlying biopsychosocial factors contributing to perception of clinical pain and future pain traj ... Full text Open Access Link to item Cite

Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons.

Journal Article Sleep · March 12, 2021 Poor sleep quality can have harmful health consequences. Although many aspects of sleep are heritable, the understandings of genetic factors involved in its physiology remain limited. Here, we performed a genome-wide association study (GWAS) using the Pitt ... Full text Open Access Link to item Cite

IL-23 Enhances C-Fiber-Mediated and Blue Light-Induced Spontaneous Pain in Female Mice.

Journal Article Front Immunol · 2021 The incidence of chronic pain is especially high in women, but the underlying mechanisms remain poorly understood. Interleukin-23 (IL-23) is a pro-inflammatory cytokine and contributes to inflammatory diseases (e.g., arthritis and psoriasis) through dendri ... Full text Link to item Cite

A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of fibromyalgia.

Journal Article Pain · December 2020 Alterations in cellular energy metabolism have been implicated in chronic pain, suggesting a role for mitochondrial DNA. Previous studies reported associations of a limited number of mitochondrial DNA polymorphisms with specific pain conditions. In this st ... Full text Open Access Link to item Cite

Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice.

Journal Article Pain · February 2020 Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes and comorbid depression, which p ... Full text Link to item Cite

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.

Journal Article Pain · March 2019 Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family ... Full text Open Access Link to item Cite

Acupuncture Resolves Persistent Pain and Neuroinflammation in a Mouse Model of Chronic Overlapping Pain Conditions.

Journal Article J Pain · December 2018 Patients with chronic overlapping pain conditions have decreased levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. Consistent with clinical syndromes, we previously demonstrated that COMT inhibition in rodents produc ... Full text Link to item Cite

Sustained stimulation of β2- and β3-adrenergic receptors leads to persistent functional pain and neuroinflammation.

Journal Article Brain Behav Immun · October 2018 Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical ... Full text Link to item Cite

A moldable sustained release bupivacaine formulation for tailored treatment of postoperative dental pain.

Journal Article Sci Rep · August 15, 2018 A moldable and biodegradable dental material was designed for customized placement and sustained delivery of bupivacaine (BP) within an extraction cavity. Microparticles comprising poly(lactic-co-glycolic acid) (PLGA) containing BP were generated via solve ... Full text Link to item Cite

miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus.

Journal Article Neuron · August 8, 2018 Increasing evidence suggests that extracellular miRNAs may serve as biomarkers of diseases, but the physiological relevance of extracellular miRNA is unclear. We find that intradermal cheek injection of miR-711 induces TRPA1-depedent itch (scratching) with ... Full text Link to item Cite

Neuroinflammation and Central Sensitization in Chronic and Widespread Pain.

Journal Article Anesthesiology · August 2018 Chronic pain is maintained in part by central sensitization, a phenomenon of synaptic plasticity, and increased neuronal responsiveness in central pain pathways after painful insults. Accumulating evidence suggests that central sensitization is also driven ... Full text Link to item Cite

Epiregulin and EGFR interactions are involved in pain processing.

Journal Article J Clin Invest · September 1, 2017 The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR ... Full text Link to item Cite

Incidence and Risk Factors for Pelvic Pain After Mesh Implant Surgery for the Treatment of Pelvic Floor Disorders.

Journal Article J Minim Invasive Gynecol · January 1, 2017 STUDY OBJECTIVE: Our aim was to assess incidence and risk factors for pelvic pain after pelvic mesh implantation. DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: Single university hospital. PATIENTS: Women who have undergone ... Full text Link to item Cite

Persistent Catechol-O-methyltransferase-dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors.

Journal Article Anesthesiology · May 2016 BACKGROUND: Patients with chronic pain disorders exhibit increased levels of catecholamines alongside diminished activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. The authors found that acute pharmacologic inhibiti ... Full text Link to item Cite

Novel intrathecal and subcutaneous catheter delivery systems in the mouse.

Journal Article J Neurosci Methods · May 1, 2016 BACKGROUND: Catheter systems that permit targeted delivery of genes, molecules, ligands, and other agents represent an investigative tool critical to the development of clinically relevant animal models that facilitate the study of neurological health and ... Full text Link to item Cite

Circulating Omentin-1 and Chronic Painful Temporomandibular Disorders.

Journal Article J Oral Facial Pain Headache · 2016 AIMS: To investigate the relationship between omentin-1 levels and painful temporomandibular disorders (TMD). METHODS: In a case-control design, chronic painful TMD cases (n = 90) and TMD-free controls (n = 54) were selected from participants in the multis ... Full text Link to item Cite

MicroRNA expression profiles differentiate chronic pain condition subtypes.

Journal Article Transl Res · December 2015 Chronic pain is a significant health care problem, ineffectively treated because of its unclear etiology and heterogeneous clinical presentation. Emerging evidence demonstrates that microRNAs (miRNAs) regulate the expression of pain-relevant genes, yet lit ... Full text Link to item Cite

Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation.

Journal Article Brain Behav Immun · November 2015 Nuclear factor-kappa B (NF-κB) is a ubiquitously expressed protein complex regulating the transcription of genes involved in inflammation and pain. Increased NF-κB activity in immune and nervous system cells is linked to several chronic pain conditions in ... Full text Link to item Cite

Alternative Splicing of G Protein-Coupled Receptors: Relevance to Pain Management.

Journal Article Mayo Clin Proc · August 2015 Drugs that target G protein-coupled receptors (GPCRs) represent the primary treatment strategy for patients with acute and chronic pain; however, there is substantial individual variability in both the efficacy and adverse effects associated with these dru ... Full text Link to item Cite

Genetic Variants in Cyclooxygenase-2 Contribute to Post-treatment Pain among Endodontic Patients.

Journal Article J Endod · August 2015 INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) have a well-established analgesic efficacy for inflammatory pain. These drugs exert their effect by inhibiting the enzyme cyclooxygenase (COX) and are commonly used for the management of pain afte ... Full text Link to item Cite

Catechol-O-methyltransferase inhibition alters pain and anxiety-related volitional behaviors through activation of β-adrenergic receptors in the rat.

Journal Article Neuroscience · April 2, 2015 Reduced catechol-O-methyltransferase (COMT) activity resulting from genetic variation or pharmacological depletion results in enhanced pain perception in humans and nociceptive behaviors in animals. Using phasic mechanical and thermal reflex tests (e.g. vo ... Full text Link to item Cite

Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia.

Journal Article PLoS One · 2015 BACKGROUND: A subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments a ... Full text Link to item Cite

Epistasis between polymorphisms in COMT, ESR1, and GCH1 influences COMT enzyme activity and pain.

Journal Article Pain · November 2014 Abnormalities in the enzymatic activity of catechol-O-methyltransferase (COMT) contribute to chronic pain conditions, such as temporomandibular disorders (TMD). Thus, we sought to determine the effects of polymorphisms in COMT and functionally related pain ... Full text Link to item Cite

3D osteoarthritic changes in TMJ condylar morphology correlates with specific systemic and local biomarkers of disease.

Journal Article Osteoarthritis Cartilage · October 2014 OBJECTIVE: To assess 3D morphological variations and local and systemic biomarker profiles in subjects with a diagnosis of temporomandibular joint osteoarthritis (TMJ OA). DESIGN: Twenty-eight patients with long-term TMJ OA (39.9 ± 16 years), 12 patients a ... Full text Link to item Cite

β2- and β3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines.

Journal Article Pain · July 2014 Decreased activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, contributes to pain in humans and animals. Previously, we demonstrated that development of COMT-dependent pain is mediated by both β2- and β3-adrenergic r ... Full text Link to item Cite

Multisystem dysregulation in painful temporomandibular disorders.

Journal Article J Pain · September 2013 UNLABELLED: Multiple physiological and psychological regulatory domains may contribute to the pathophysiology of pain in temporomandibular disorder (TMD) and other bodily pain conditions. The purpose of this study was to evaluate the relationship between m ... Full text Link to item Cite

Excess risk of temporomandibular disorder associated with cigarette smoking in young adults.

Journal Article J Pain · January 2012 UNLABELLED: Evidence suggests that the effect of cigarette smoking on chronic pain is stronger in younger than older adults. This case-control study investigated whether age modified an effect of smoking on temporomandibular disorder (TMD) in 299 females a ... Full text Link to item Cite

Cytokine biomarkers and chronic pain: association of genes, transcription, and circulating proteins with temporomandibular disorders and widespread palpation tenderness.

Journal Article Pain · December 2011 For reasons unknown, temporomandibular disorder (TMD) can manifest as localized pain or in conjunction with widespread pain. We evaluated relationships between cytokines and TMD without or with widespread palpation tenderness (TMD-WPT or TMD+WPT, respectiv ... Full text Link to item Cite

Comt1 genotype and expression predicts anxiety and nociceptive sensitivity in inbred strains of mice.

Journal Article Genes Brain Behav · November 2010 Catechol-O-methyltransferase (COMT) is a ubiquitously expressed enzyme that maintains basic biologic functions by inactivating catechol substrates. In humans, polymorphic variance at the COMT locus has been associated with modulation of pain sensitivity an ... Full text Link to item Cite

Quantification of condylar resorption in temporomandibular joint osteoarthritis.

Journal Article Oral Surg Oral Med Oral Pathol Oral Radiol Endod · July 2010 OBJECTIVE: This study was performed to determine the condylar morphologic variation of osteoarthritic (OA) and asymptomatic temporomandibular joints (TMJs) and to determine its correlation with pain intensity and duration. STUDY DESIGN: Three-dimensional s ... Full text Link to item Cite

A novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism.

Journal Article Mol Pain · June 2, 2010 BACKGROUND: Opioids are the most widely used analgesics for the treatment of clinical pain. They produce their therapeutic effects by binding to mu-opioid receptors (MORs), which are 7 transmembrane domain (7TM) G-protein-coupled receptors (GPCRs), and inh ... Full text Link to item Cite

Assessing potential functionality of catechol-O-methyltransferase (COMT) polymorphisms associated with pain sensitivity and temporomandibular joint disorders.

Journal Article Methods Mol Biol · 2010 Catechol-O-methyltransferase (COMT) is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Recently, our group demonstrated that three common haplotypes of the h ... Full text Link to item Cite

Signaling pathways mediating beta3-adrenergic receptor-induced production of interleukin-6 in adipocytes.

Journal Article Mol Immunol · July 2009 The beta(3)-adrenergic receptor (beta(3)AR) is an essential regulator of metabolic and endocrine functions. A major cellular and clinically significant consequence of beta(3)AR activation is the substantial elevation in interleukin-6 (IL-6) levels. Althoug ... Full text Link to item Cite

Characterization of NF-kB-mediated inhibition of catechol-O-methyltransferase.

Journal Article Mol Pain · March 16, 2009 BACKGROUND: Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, has recently been implicated in the modulation of pain. Specifically, low COMT activity is associated with heightened pain perception and development of musculoskel ... Full text Link to item Cite

Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs.

Journal Article PLoS One · 2009 Catechol-O-methyltransferase (COMT) is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synon ... Full text Link to item Cite

Genetic architecture of human pain perception.

Journal Article Trends Genet · December 2007 Pain is emotionally detrimental and consciously avoided; however, it is absolutely crucial for our survival. Pain perception is one of the most complicated measurable traits because it is an aggregate of several phenotypes associated with peripheral and ce ... Full text Link to item Cite

Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors.

Journal Article Pain · April 2007 Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, has recently been implicated in the modulation of pain. Our group demonstrated that human genetic variants of COMT are predictive for the development of Temporomandibular Joint ... Full text Link to item Cite

Beta2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-kappaB-independent mechanisms.

Journal Article Cell Signal · February 2007 Activation of the beta(2) adrenergic receptor (beta(2)AR) located on macrophages has been reported to possess anti-inflammatory properties, inhibiting nuclear factor kappaB (NF-kappaB) activation and cytokine production induced by pro-inflammatory stimuli. ... Full text Link to item Cite

Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure.

Journal Article Science · December 22, 2006 Catechol-O-methyltransferase (COMT) is a key regulator of pain perception, cognitive function, and affective mood. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous position, code for differences in COMT enzy ... Full text Link to item Cite

Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli.

Journal Article Pain · December 5, 2006 Variations in the gene encoding catechol-O-methyltransferase (COMT) are linked to individual differences in pain sensitivity. A single nucleotide polymorphism (SNP) in codon 158 (val(158)met), which affects COMT protein stability, has been associated with ... Full text Link to item Cite

Neonatal chronic hind paw inflammation alters sensitization to intradermal capsaicin in adult rats: a behavioral and immunocytochemical study.

Journal Article J Pain · December 2005 UNLABELLED: The present studies were conducted to examine functional consequences of postnatal chronic inflammation, initiated during a critical developmental period, on capsaicin-evoked hyperalgesia and neuronal activation in adulthood. Rats received a un ... Full text Link to item Cite

Basal and carrageenan-induced pain behavior in Sprague-Dawley, Lewis and Fischer rats.

Journal Article Physiol Behav · June 2, 2005 Individual differences in pain sensitivity are believed to reflect the interplay of many factors, including genetics. Inbred rat strains can be used to study the impact of genetic factors on pain sensitivity. Inbred Lewis (LEW) and Fischer 344 (FIS) rat st ... Full text Link to item Cite

Genetic basis for individual variations in pain perception and the development of a chronic pain condition.

Journal Article Hum Mol Genet · January 1, 2005 Pain sensitivity varies substantially among humans. A significant part of the human population develops chronic pain conditions that are characterized by heightened pain sensitivity. We identified three genetic variants (haplotypes) of the gene encoding ca ... Full text Link to item Cite

Activation of cannabinoid CB2 receptors suppresses C-fiber responses and windup in spinal wide dynamic range neurons in the absence and presence of inflammation.

Journal Article J Neurophysiol · December 2004 Effects of the CB2-selective cannabinoid agonist AM1241 on activity evoked in spinal wide dynamic range (WDR) neurons by transcutaneous electrical stimulation were evaluated in urethane-anesthetized rats. Recordings were obtained in both the absence and th ... Full text Link to item Cite

Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinociception in models of acute and tonic nociception.

Journal Article Brain Res · October 17, 2003 The effects of neurotoxic destruction of catecholaminergic projections to the spinal cord on cannabinoid antinociception were examined in models of acute and tonic nociception. High performance liquid chromatography was used to quantify monoamine levels in ... Full text Link to item Cite

A peripheral cannabinoid mechanism suppresses spinal fos protein expression and pain behavior in a rat model of inflammation.

Journal Article Neuroscience · 2003 The present studies were conducted to test the hypothesis that systemically inactive doses of cannabinoids suppress inflammation-evoked neuronal activity in vivo via a peripheral mechanism. We examined peripheral cannabinoid modulation of spinal Fos protei ... Full text Link to item Cite

Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation.

Journal Article Neuroscience · 2003 Activation of cannabinoid CB(2) receptors attenuates thermal nociception in untreated animals while failing to produce centrally mediated effects such as hypothermia and catalepsy [Pain 93 (2001) 239]. The present study was conducted to test the hypothesis ... Full text Link to item Cite