Browsing by Author "Nackley, Andrea G"

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    A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of fibromyalgia.
    (Pain, 2020-07-10) van Tilburg, Miranda AL; Parisien, Marc; Boles, Richard G; Drury, Gillian L; Smith-Voudouris, Julian; Verma, Vivek; Khoury, Samar; Chabot-Doré, Anne-Julie; Nackley, Andrea G; Smith, Shad B; Whitehead, William E; Zolnoun, Denniz A; Slade, Gary D; Tchivileva, Inna; Maixner, William; Diatchenko, Luda
    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 study, we examined the full mitochondrial genomes of people with a variety of chronic pain conditions. A discovery cohort consisting of 609 participants either with or without a complex persistent pain conditions (CPPCs) was examined. Mitochondrial DNA was subjected to deep sequencing for identification of rare mutations, common variants, haplogroups, and heteroplasmy associated with 5 CPPCs: episodic migraine, irritable bowel syndrome, fibromyalgia, vulvar vestibulitis, or temporomandibular disorders. The strongest association found was the presence of the C allele at the single nucleotide polymorphism m.2352T>C (rs28358579) that significantly increased the risk for fibromyalgia (odds ratio [OR] = 4.6, P = 4.3 × 10). This relationship was even stronger in women (OR = 5.1, P = 2.8 × 10), and m.2352T>C was associated with all other CPPCs in a consistent risk-increasing fashion. This finding was replicated in another cohort (OR = 4.3, P = 2.6 × 10) of the Orofacial Pain: Prospective Evaluation and Risk Assessment study consisting of 1754 female participants. To gain insight into the cellular consequences of the associated genetic variability, we conducted an assay testing metabolic reprogramming in human cell lines with defined genotypes. The minor allele C was associated with decreased mitochondrial membrane potential under conditions where oxidative phosphorylation is required, indicating a role of oxidative phosphorylation in pathophysiology of chronic pain. Our results suggest that cellular energy metabolism, modulated by m.2352T>C, contributes to fibromyalgia and possibly other chronic pain conditions.
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    Complementary Approaches for Military Women with Chronic Pelvic Pain: A Randomized Trial.
    (Journal of integrative and complementary medicine, 2022-10) Crisp, Carol D; Baldi, Robert; Fuller, Matthew; Abreu, Eduardo; Nackley, Andrea G
    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 effectiveness of noninvasive, self-explanatory mindfulness-based stress reduction (MBSR) or self-paced healthy lifestyle (HL) interventions on CPP in AD women. Methods: A 6-week, interventional prospective study with AD women aged 21-55 years at Mountain Home (MTHM), Idaho, was conducted. Women were randomly assigned to MBSR (N = 21) or HL (N = 20) interventions. The primary outcome was pain perception. The secondary outcomes were depression and circulating cytokine levels. Results: Women in the MBSR group exhibited reduced pain interference (p < 0.01) and depression (p < 0.05) alongside decreased interleukin (IL)-4 (p < 0.05), IL-6 (p < 0.05), eotaxin (p < 0.05), monocyte chemoattractant protein-1 (p = 0.06), and interleukin-1 receptor antagonist (IL-1ra) (p < 0.01) and increased vascular endothelial growth factor (p < 0.05). Women in the HL group did not have changes in pain; however, they did exhibit reduced depression (p < 0.05) alongside decreased granulocyte-macrophage colony-stimulating factor (p < 0.05) and increased tumor necrosis factor alpha (p < 0.05), stromal cell-derived factor-1 (p < 0.01), and IL-1ra (p < 0.01). Conclusions: AD women receiving MBSR or HL had reduced depression scores and altered circulating cytokine levels; however, only those receiving MBSR had reduced pain perception. Findings support MBSR as an effective and viable behavioral treatment for AD women suffering from CPP and provide premise for larger randomized controlled studies. Clinical Trial Registration: MOCHI-An RCT of mindfulness as a treatment for CPP in AD Women NCT04104542 (September 26, 2019).
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    Expression of ectopic heat shock protein 90 in male and female primary afferent nociceptors regulates inflammatory pain.
    (Pain, 2021-10-12) Wang, Yaomin; Scarneo, Scott A; Kim, Shin Hyung; Zhang, Xin; Chen, Jiegen; Yang, Kelly W; Hughes, Philip; Haystead, Timothy; Nackley, Andrea G
    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 discovery of membrane bound ectopic Hsp90 (eHsp90) on tumor cells has shown that Hsp90 induction to the plasma membrane can stabilize disease-relevant proteins. Here, we characterize eHsp90 expression in a mouse model of inflammation and demonstrate its role in nociception and pain. We found that intraplantar complete Freund adjuvant (CFA) induced robust expression of eHsp90 on the cell membranes of primary afferent nociceptors located in the L3-L5 dorsal root ganglia (DRG), bilaterally, with minimal to no expression in other tissues. Complete Freund adjuvant-induced increases in eHsp90 expression on lumbar DRG were significantly greater in females compared with males. Furthermore, exogenous Hsp90 applied to primary Pirt-GCaMP3 nociceptors induced increases in calcium responses. Responses were estrogen-dependent such that greater activity was observed in female or estrogen-primed male nociceptors compared with unprimed male nociceptors. Treatment of mice with the selective eHsp90 inhibitor HS-131 (10 nmol) significantly reversed CFA-induced mechanical pain, thermal heat pain, and hind paw edema. Notably, a higher dose (20 nmol) of HS-131 was required to achieve analgesic and anti-inflammatory effects in females. Here, we provide the first demonstration that inflammation leads to an upregulation of eHsp90 on DRG nociceptors in a sex-dependent manner and that inhibition of eHsp90 reduces nociceptor activity, pain, and inflammation. Thus, eHsp90 represents a novel therapeutic axis for the development of gender-tailored treatments for inflammatory pain.
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    Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.
    (Pain, 2018-11-13) Smith, Shad B; Parisien, Marc; Bair, Eric; Belfer, Inna; Chabot-Doré, Anne-Julie; Gris, Pavel; Khoury, Samar; Tansley, Shannon; Torosyan, Yelizaveta; Zaykin, Dmitri V; Bernhardt, Olaf; de Oliveira Serrano, Priscila; Gracely, Richard H; Jain, Deepti; Järvelin, Marjo-Riitta; Kaste, Linda M; Kerr, Kathleen F; Kocher, Thomas; Lähdesmäki, Raija; Laniado, Nadia; Laurie, Cathy C; Laurie, Cecelia A; Männikkö, Minna; Meloto, Carolina B; Nackley, Andrea G; Nelson, Sarah C; Pesonen, Paula; Ribeiro-Dasilva, Margarete C; Rizzatti-Barbosa, Celia M; Sanders, Anne E; Schwahn, Christian; Sipilä, Kirsi; Sofer, Tamar; Teumer, Alexander; Mogil, Jeffrey S; Fillingim, Roger B; Greenspan, Joel D; Ohrbach, Richard; Slade, Gary D; Maixner, William; Diatchenko, Luda
    Painful temporomandibular disorders (TMD) is the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. While many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a GWAS assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified three distinct loci that were significant in combined or sex-segregated analyses. A single nucleotide polymorphism (SNP) on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio [OR]=2.9, 95% CI: 2.02-4.27, P=2.2x10). This association was nominally replicated in a meta-analysis of seven independent orofacial pain cohorts including 160,194 participants (OR=1.16, 95% CI: 1.0-1.35, P = 2.3x10). Functional analysis in human dorsal root ganglia (DRG) and blood indicated this variant is an expression quantitative trait locus (eQTL), with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43x10). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically-determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a "work of the United States Government" for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.
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    Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons.
    (Sleep, 2020-10-09) Khoury, Samar; Wang, Qiao-Ping; Parisien, Marc; Gris, Pavel; Bortsov, Andrey V; Linnstaedt, Sarah D; McLean, Samuel A; Tungate, Andrew S; Sofer, Tamar; Lee, Jiwon; Louie, Tin; Redline, Susan; Kaunisto, Mari Anneli; Kalso, Eija A; Munter, Hans Markus; Nackley, Andrea G; Slade, Gary D; Smith, Shad B; Zaykin, Dmitri V; Fillingim, Roger B; Ohrbach, Richard; Greenspan, Joel D; Maixner, William; Neely, G Gregory; Diatchenko, Luda
    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 Pittsburgh Sleep Quality Index (PSQI) in a multi-ethnic discovery cohort (n=2,868) and found two novel genome-wide loci on chromosomes 2 and 7 associated with global sleep quality. A meta-analysis in 12 independent cohorts (100,000 individuals) replicated the association on chromosome 7 between NPY and MPP6. While NPY is an important sleep gene, we tested for an independent functional role of MPP6. Expression data showed an association of this locus with both NPY and MPP6 mRNA levels in brain tissues. Moreover, knockdown of an orthologue of MPP6 in Drosophila melanogaster sleep center neurons resulted in decreased sleep duration. With convergent evidence, we describe a new locus impacting human variability in sleep quality through known NPY and novel MPP6 sleep genes.
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    Rationale and design of a multicenter randomized clinical trial of vestibulodynia: understanding pathophysiology and determining appropriate treatments (vestibulodynia: UPDATe).
    (Annals of medicine, 2022-12) Carey, Erin T; Geller, Elizabeth J; Rapkin, Andrea; Farb, Debbie; Cutting, Haley; Akaninwor, Jasmyn; Stirling, Christopher; Bortsov, Andrey; McNulty, Steven; Merrill, Peter; Zakroysky, Pearl; DeLaRosa, Jesse; Luo, Sheng; Nackley, Andrea G

    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 VBD subtypes that may benefit from different types of treatment: 1) VBD peripheral (VBD-p), characterized by pain localized to the vulvar vestibule and 2) VBD central (VBD-c), characterized by VBD alongside one or more other chronic overlapping pain conditions (e.g. irritable bowel syndrome, temporomandibular disorder, and fibromyalgia syndrome) that affect remote body regions. Here, we describe the rationale and design of an NIH-funded multicenter clinical trial comparing the effectiveness of topical and/or systemic medication for alleviating pain and normalizing pain- relevant biomarkers among women with VBD-p and VBD-c.

    Methods

    Participants will be randomly assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml 0.02% oestradiol compound cream + oral placebo pill, 2) central treatment with the tricyclic antidepressant nortriptyline + placebo cream, 3) combined peripheral cream and central pill treatments, or 4) placebo cream and placebo pill. The treatment phase will last 16 weeks, with outcome measures and biomarkers assessed at 4 time points (0, 8, 16, and 24 weeks). First, we will compare the efficacy of treatments in alleviating pain using standardized tampon insertion with a numeric rating scale and self-reported pain on the short form McGill Pain Questionnaire. Next, we will compare the efficacy of treatments in improving perceived physical, mental, and sexual health using standardized questionnaires. Finally, we will measure cytokines and microRNAs in local vaginal and circulating blood samples using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to predict treatment response.

    Conclusion

    This is the first multicenter randomized controlled trial to evaluate the efficacy of peripherally and centrally acting medications currently used in clinical practice for treating unique VBD subtypes based on distinct clinical and biological signatures.

    Administrative information

    Vestibulodynia UPDATe is a multi-centre, two-by-two factorial designed randomized, double-blind, placebo-controlled trial registered at clinical trials.gov (NCT03844412). This work is supported by the R01 HD096331 awarded to Drs. Nackley, Rapkin, Geller and Carey by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).Key messagesPeripheral lidocaine and oestradiol and centrally-targeted nortriptyline medications are used for the treatment of pain in women with VBD, but there is a lack of data from well-powered RCTs.This two-by-two factorial RCT will test the efficacy of these medications in VBD subtypes characterized by distinct clinical characteristics and biomarker profiles.We hope that results will provide clinicians with scientific evidence of therapeutic efficacy in distinct VBD subtypes in an effort to direct and optimize treatment approaches.
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    Sensory neuron-TRPV4 modulates temporomandibular disorder pain via CGRP in mice.
    (The journal of pain, 2022-12) Suttle, Abbie; Wang, Peng; Dias, Fabiana C; Zhang, Qiaojuan; Luo, Yuhui; Simmons, Lauren; Bortsov, Andrey; Tchivileva, Inna E; Nackley, Andrea G; Chen, Yong
    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 trigeminal ganglion (TG) neurons is upregulated after TMJ inflammation, and TRPV4 co-expresses with calcitonin gene-related peptide (CGRP) in TMJ-innervating TG neurons. Here, we extended these findings to determine the specific contribution of TRPV4 in TG neurons to TMD pain, and examine whether sensory neuron-TRPV4 modulates TMD pain via CGRP. In mouse models of TMJ inflammation or masseter muscle injury, sensory neuron-Trpv4 conditional knockout (cKO) mice displayed reduced pain. Co-expression of TRPV4 and CGRP in TMJ- or masseter muscle-innervating TG neurons was increased after TMJ inflammation and masseter muscle injury, respectively. Activation of TRPV4-expressing TG neurons triggered secretion of CGRP, which was associated with increased levels of CGRP in peri-TMJ tissues, masseter muscle, spinal trigeminal nucleus, and plasma in both models. Local injection of CGRP into the TMJ or masseter muscle evoked acute pain in naïve mice, while blockade of CGRP receptor attenuated pain in mouse models of TMD. These results suggest that TRPV4 in TG neurons contributes to TMD pain by potentiating CGRP secretion. Perspective: This study demonstrates that activation of TRPV4 in TG sensory neurons drives pain by potentiating the release of pain mediator CGRP in mouse models of TMJ inflammation and masseter muscle injury. Targeting TRPV4 and CGRP may be of clinical potential in alleviating TMD pain.
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    Transforming growth factor-β-activated kinase 1 (TAK1) mediates chronic pain and cytokine production in mouse models of inflammatory, neuropathic, and primary pain.
    (The journal of pain, 2023-04) Scarneo, Scott; Zhang, Xin; Wang, Yaomin; Camacho-Domenech, Jose; Ricano, Jennifer; Hughes, Philip; Haystead, Tim; Nackley, Andrea G
    The origin of chronic pain is linked to inflammation, characterized by increased levels of pro-inflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of pro-inflammatory cytokine signaling that has been well characterized in the context of cancer and autoimmune disorders, yet its role in chronic pain is less clear. Here, we evaluated the ability of our TAK1 small molecule inhibitor, takinib, to attenuate pain and inflammation in pre-clinical models of inflammatory, neuropathic, and primary pain. Inflammatory, neuropathic, and primary pain was modeled using intraplantar complete Freund's adjuvant (CFA), chronic constriction injury (CCI), and systemic delivery of the COMT inhibitor OR486, respectively. Behavioral responses evoked by mechanical and thermal stimuli were evaluated in separate groups of mice receiving takinib or vehicle prior to pain induction (baseline) and over 12 days following CFA injection, 4 weeks following CCI surgery, and 6 hours following OR486 delivery. Hindpaw edema was also measured prior to and 3 days following CFA injection. Upon termination of behavioral experiments, dorsal root ganglia (DRG) were collected to measure cytokines. We also evaluated the ability of takinib to modulate nociceptor activity via in vitro calcium imaging of neurons isolated from the dorsal root ganglia of Gcamp3 mice. In all three models, TAK1 inhibition significantly reduced hypersensitivity to mechanical and thermal stimuli and expression of pro-inflammatory cytokines in DRG. Furthermore, TAK1 inhibition significantly reduced the activity of tumor necrosis factor (TNF)-primed/capsaicin-evoked DRG nociceptive neurons. Overall, our results support the therapeutic potential of TAK1 as a novel drug target for the treatment of chronic pain syndromes with different etiologies. PERSPECTIVE: This article reports the therapeutic potential of TAK1 inhibitors for the treatment of chronic pain. This new treatment has the potential to provide a greater therapeutic offering to physicians and patients suffering from chronic pain as well as reduce the dependency on opioid based pain treatments.