Humans possess multiple biological systems that work to protect us from internal and external threats. Our somatosensory system provides us with the ability to sense temperature, touch, body positioning, and pain, both in our external environment and within our own bodies, enabling us to effortlessly interact with our environment and avoid stimuli which have the potential to cause us harm. Outside of the nervous system, our immune system protects us by surveilling our bodies for potential threats such as bacteria, viruses, and cancerous cells. Upon recognition of a foreign agent, our immune system catalyzes an inflammatory response to eliminate the threat.

These protective bodily systems (the somatosensory and immune systems) were classically viewed in isolation, studied in isolation, and are still often taught as systems which physiologically operate in isolation, but this is far from the physiological reality. In fact, a tight link between pain and inflammation has been appreciated for at least two millennia. The roman encyclopedist Aulus Celsus is credited as the first to document this link when he included dolor (pain) as one of the cardinal signs of inflammation (De medicina, c. A.D. 25). We are fascinated by the bidirectional relationship between pain and inflammation. Our lab studies the crosstalk between somatosensory neurons and non-neuronal cells such as immune cells, glia, cancer cells, and microorganisms, employing techniques that allow us to understand these interactions at the molecular, cellular, and organismal level. We believe this approach will allow us to develop new neurotherapeutics and immunotherapeutics to treat chronic pain and pain-associated inflammatory diseases.

How do interactions between sensory neurons and non-neuronal cells impact pain, inflammation, and host immunity?

Sensory neurons in the peripheral nervous system are remarkable with respect to both their anatomical and functional properties. The cell bodies of these neurons (containing the nucleus) are localized to specialized structures termed ganglia, and each neuron extends both a long-ranging projection that innervates structures in the periphery and a central projection to higher-order neurons in the CNS. At each specialized cellular compartment (e.g., peripheral terminal, soma, and central terminal), peripheral sensory neurons interact with distinct non-neuronal cell types such as immune cells, glial cells, cancer cells, and even microorganisms. Our lab is working to understand the mechanisms and physiological functions of these cellular interactions, with a particular interest in understanding 1) how sensory neurons contribute to inflammation and host immunity through immune cell modulation and 2) how immune cells influence the properties of sensory neurons to modulate pain in health and disease states.

One characteristic of immune cells that enables them to recognize potential threats and mount an inflammatory reaction is their abundant expression of pattern recognition receptors (PRRs), specialized receptors that detect molecules produced by microorganisms and damaged/aberrant host cells. Interestingly, peripheral sensory neurons also exhibit high expression of many PRRs, as well as receptors for small immunomodulatory proteins called cytokines and chemokines. In the peripheral sensory neurons that respond to painful stimuli (nociceptors), the activation of these cytokine signaling pathways can alter neuronal excitability through a rapid noncanonical mechanism which involves ion channel modulation. Our lab is working to understand how these atypical signaling pathways function in neurons, and how activating or inhibiting them can affect pain, inflammation, and host immunity in different health and disease contexts.

Much of our work to date has been focused on the role of the PRR and innate immune regulator STING, which senses bacterially derived cyclic dinucleotides, double-stranded DNA viruses, and cytosolic DNA released from damaged or neoplastic host cells. We have shown that the peripheral sensory neurons which respond to painful stimuli (nociceptors) exhibit particularly high expression of STING, and activation of neuronal STING can potently suppress pain. Notably, many research groups (including ours) have demonstrated an essential role in the STING pathway in promoting tumor immunogenicity, and our work has shown that STING pathway activators can produce both analgesic and antitumor effects through neuromodulation and immunomodulation. Thus, we believe the STING pathway is a promising potential therapeutic to treat cancer and cancer-associated pain.

What factors determine whether an individual develops chronic pain? 

Pain is frequently regarded as a symptom, but in many cases, chronic pain is the sole (or primary) complaint and does not occur secondary to another underlying disease or ailment. These chronic pain syndromes are classified as chronic primary pain conditions (CPPCs), a category that includes many conditions such as fibromyalgia, complex regional pain syndrome, and some types of headache and musculoskeletal pain disorders (e.g., temporomandibular joint disorders). Unfortunately, these CPPCs have a remarkable tendency to co-aggregate within individuals, with estimates suggesting that >80% of chronic pain patients have more than one comorbid pain condition. Given this stark reality, our lab is working to identify the biological factors that increase an individual's predisposition to develop chronic pain (e.g., vulnerability factors), as well as the protective factors that allow some individuals to resolve their pain after an injury (e.g., resilience factors). To this end, we are studying the molecular and cellular changes that occur in the somatosensory system and the immune system in chronic pain patients. We employ a combination of preclinical models which mimic chronic pain pathogenesis in humans and translational studies using biofluids and tissues procured from humans who have generously volunteered to participate in clinical research studies. 

Much of our ongoing work is focused on understanding the biological factors that contribute to chronic pain pathogenesis in temporomandibular joint disorders (TMDs), a musculoskeletal pain condition representing the most common orofacial pain condition, and one that frequently occurs comorbid with other CPPCs. We are analyzing both local (e.g., within the temporomandibular joint tissues) and systemic changes in the molecular, cellular, and functional properties of sensory neurons and immune cells to identify factors that impact TMD pain, comorbidity with other CPPCs, and clinical outcomes. In addition, we are studying the protective and maladaptive factors that impact neuroinflammation and pain resolution in neuropathic pain states (e.g., nerve injury and chronic post-amputation pain).

Our Approach & Techniques 

We pursue our research questions using both forward translational and reverse translational approaches. Using preclinical models, we can mimic many aspects of disease progression seen in humans and employ molecular genetic and pharmacological strategies to manipulate the signaling pathways and cell types involved, allowing us to characterize how this impacts chronic pain, inflammation, or immunity using a combination of in vitro and in vivo assays. We have expertise using conditional and intersectional genetic techniques to knockout genes, ablate specific cell populations, and activate or inhibit specific neuron subpopulations. We can characterize the outcomes of these manipulations using standard molecular/biochemical approaches and techniques such as behavioral phenotyping, calcium imaging, 3D in vivo bioluminescent imaging, multispectral and super-resolution confocal microscopy, single cell transcriptomics, and flow cytometry and FACS. For our reverse translational research studies, we perform a variety of proteomic, transcriptomic, and multi-omic analyses on biofluids, cells, and tissues procured from humans whose clinical outcomes we frequently follow over time. This data-centric approach helps us identify the molecules, cells, and signaling pathways that are of greatest interest to explore and validate using our preclinical models. 

Acknowledgment of Research Support 

Our research is funded by the National Institute of Dental and Craniofacial Research (NIDCR; R01DE031053-01A1, R01DE03227-01, UH2DE032202-01; R01-026728-05S1), the Office of Research on Women’s Health (ORWH; R01DE032227-01), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; UC2AR082197), and the Department of Defense (W81XWH-19-2-0037). Our work is also supported by the Department of Anesthesiology at Duke University School of Medicine.

Keywords: dorsal root ganglion (DRG); trigeminal ganglion (TG); nociceptor; pattern recognition receptor (PRR); damage-associated molecular pattern (DAMP); pathogen-associated molecular pattern (PAMP); stimulator of interferon response cGAMP interactor 1 (STING, STING1); retrograde signaling; neuroinflammation; neurogenic inflammation; infection; sepsis; head and neck squamous cell carcinoma (HNSCC); oral squamous cell carcinoma (OSCC); bone cancer pain (BCP); innate immunity; immunosuppression; inflammation; opioids; morphine; TMJ; orofacial pain; scRNAseq; RE-JOIN; multi-omics; chronic overlapping pain conditions (COPC); myofascial pain; musculoskeletal pain; myalgia; neuropathic pain; translational pain research. 

SEPTEMBER 13, 2022 – lab updates; awards & recognition

We’re excited to announce that we’ve been awarded a 4-year, $2,132,329 grant (sponsored by the National Institute of Dental and Craniofacial Research and the Office of Research on Women’s Health) for a new project, “Sexually dimorphic pain signaling mechanisms.” This award will enable our team to collaborate with a team led by Dr. Shad Smith to identify new cellular and molecular mechanisms which differentially contribute to pain in a sex hormone-dependent manner.

SEPTEMBER 1, 2022 – lab updates

We want to wish a warm welcome to two new lab members, Kyra Majors and Anna Molloy. Kyra joins our team after completing her B.S. in Biology at MIT, followed by an M.S. in Bioinformatics at NYU, bringing a unique combination of wet-lab and dry-lab skills. Anna, a Michigan native, is a recent B.A. graduate of Hope College, where she double majored in neuroscience and chemistry, receiving numerous research and academic awards along the way. Welcome to both!

AUGUST 19, 2022 – lab updates; awards & recognition

We’re very excited to announce that the National Institute of Dental and Craniofacial Research has funded our project, “Neuro-immune modulation of pain in health and disease,” an award which totals $3,311,196 over the next five years. This funding will support the Donnelly lab to study how altering crosstalk between sensory neurons, immune cells, and cancer cells can be harnessed to regulate pain, inflammation, and tumor progression. We would also like to acknowledge the important contributions of several close collaborators on this project, including Dr. Andrea Nackley (Duke Anesthesiology), Dr. Rory Goodwin (Duke Neurosurgery), Dr. Yu (Leo) Lei (University of Michigan), and Dr. Zhicheng Ji (Duke Biostatistics & Bioinformatics). We look forward to working together on this project to develop new neuro-immune therapies!

JULY 30, 2022 – lab updates; awards & recognition

Congratulations to Natalia Bojorquez, who finished her Duke Biological Sciences Undergraduate Research Fellowship (B-SURF) program and delivered an outstanding poster presentation which described her summer research project on the TGF-beta pathway. We are looking forward to having Natalia back in the lab this fall.

JULY 21, 2022 – lab updates; awards & recognition

We’re pleased to announce that the National Institute of Dental and Craniofacial Research has funded our project, “Identifying non-opioid strategies to manage oral cancer pain.” This R01 Supplement project will provide $250,000 in funding over the next year to support experiments aimed at developing new immunotherapy approaches to overcome opioid-induced immunosuppression and morphine-resistant pain. This project will be led by Dr. Yu (Leo) Lei at the University of Michigan (PI) and Dr. Donnelly (MPI), with important contributions from our collaborator Dr. Yuying Xie (Michigan State University).

JUNE 30, 2022 – lab updates

Welcome to two new lab members, Sudhish Jayachandran and Dessources Domond Jr. Sudhish is a recent NCSU graduate, where he received his B.S. in Biological Sciences and engaged in developmental biology research which provided him with expertise in histological methods and confocal microscopy. Dessources is a Union College graduate and now a 2^nd year Biomedical Engineering M.S. student at Duke, and he is joining the lab to expand his BME background by obtaining wet-lab expertise. We look forward to working together to see what we can accomplish in the lab and to helping you move forward in your career pursuits.

MAY 8, 2022 – awards & recognition

Congratulations (again) to Amanda Andriessen, who graduated with Distinction in Neuroscience and received the ‘Outstanding Senior Thesis in Neuroscience’ Award, which is granted to just 1-2 students each year. Amanda’s thesis explored a novel mechanism by which peripheral sensory neurons contribute to host defense and immunity. Amanda has contributed to many scientific discoveries in the lab beyond her senior thesis project. Amanda will apply to medical schools this summer and join the Fulbright Scholars Program later this year.

MAY 8, 2022 – awards & recognition

Congratulations to Michael Lee, who was awarded Graduation with Distinction in Biology! Over the last four years, Michael has contributed to several major discoveries in the lab (such as this Nature Communications study and this Nature study) and went on to develop his own project focused on TGF-beta signaling in pain regulation. Michael plans to take a gap year to explore the world of biotech consulting while he applies to medical schools in the fall.

MARCH 31, 2022 – awards & recognition

Congratulations to Amanda Andriessen who was selected for the prestigious Fulbright Scholarship Program! Amanda was one of just 24 Duke students and alumni to be named a Fulbright Scholar for 2022-2023. Amanda will continue her translational pain research with Dr. Rohini Kuner at the University of Heidelberg while pursuing her master’s degree in translational medicine.

DECEMBER 23, 2021 – in the news

The Pain Research Forum has announced that a news story featuring a recent study by Dr. Ru-Rong Ji’s group (led by first author, Dr. Xin Luo) was the top PRF story of 2021. Their article, entitled “Sex Specific Differences in Pain Mechanisms” described a recent publication in Neuron which discovered a novel female-specific pain mechanism driven by macrophage-neuron crosstalk. We are proud to have contributed to this important discovery. Congratulations, Xin and Ru-Rong!

DECEMBER 17, 2021 – in the news

We’re excited to share that Pain Research Forum has released a news story, “STING Immunotherapy: a complementary approach to treating bone cancer pain”, which highlights two of our recent studies focused on how activation of the STING pathway can modulate cancer pain. Several members of the Donnelly lab together with Ru-Rong Ji’s lab contributed to these studies, along with many other research collaborators.

DECEMBER 13, 2021 – awards & recognition

Congratulations to Elmira Hezarkhani, who graduated with a Distinction in Neuroscience after completing her B.S. requirements a semester ahead of schedule! Elmira conducted a senior thesis project which characterized neurological alterations associated with graft-versus-host disease (GvHD) in a novel preclinical model. Next summer Elmira will move to our neighboring rival, UNC Chapel Hill, where she will continue working towards her goal of becoming a dentist.

DECEMBER 3, 2021 – new publication

I’m excited to announce we have another new publication out now in Cell & Tissue Research. This study was a collaboration between Dr. Donnelly, Dr. Archana Kumari, Dr. Robert Bradley (University of Michigan), Dr. Charlotte Mistretta (University of Michigan), and Dr. Brian Pierchala (University of Indiana). This study provides an in-depth characterization of the nature of the peripheral nerve fibers innervating taste papillae in the anterior tongue, providing us with new insights regarding oral sensory function and the unique intercellular crosstalk taking place between peripheral sensory afferents and cells within the taste papillae.

NOVEMBER 13, 2021 – new publication

We have a new study out in Oncoimmunology! This study, led by Dr. Donnelly, Dr. Xie (Michigan State University), and Dr. Lei (University of Michigan), used preclinical and clinical modeling experiments which showed that cancer cell-intrinsic type-I interferon signaling may reduce the immunogenicity of the tumor microenvironment. Ultimately, these data will aid us as we design new immunotherapy strategies to treat cancer and cancer-associated pain.

NOVEMBER 23, 2021 – awards & recognition

Congratulations to CTPM Director, Dr. Ru-Rong Ji for once again being named among the most “Highly Cited Researchers” by scientists at Clarivate, who runs the Institute for Scientific Information. This honor highlights scientists whose work over the last decade is having a major impact in their field. Congratulations, Ru-Rong!

NOVEMBER 3, 2021 – awards & recognition

Congratulations to our collaborator, Dr. Shad Smith, who was awarded a DREAM Innovation Grant for his project entitled, “Mechanisms of Genetic Regulation of Nociception and Injury Resilience by Mras.” We look forward to continuing our collaboration and discovering how MRAS contributes to chronic pain.

OCTOBER 15, 2021 – awards & recognition

Congratulation to Amanda Andriessen who was awarded the Society for Neuroscience’s Trainee Professional Development Award. This is a competitive award given to undergraduate students “who demonstrate scientific merit and excellence in research.” Well done!

JULY 27, 2021 – new publication

Our latest Nature Communication article is now published! This project, led by Dr. Kaiyuan Wang (Ji lab) and Dr. Chris Donnelly, describes the potential therapeutic promise of STING pathway activators for metastatic bone cancer and bone cancer pain. We found that STING agonists can produce multiple protective effects by modulating the activity of sensory neurons, immune cells, and bone-resident osteoclasts, and the combination of these effects yields produces robust and long-term pain inhibition.

MAY 5, 2021 – a tribute

A very nice tribute was written by Roger Fillingim memorializing the life, career, and many accomplishments of Dr. William (Bill) Maixner, a former mentor and the founding director of Duke Anesthesiology’s Center for Translational Pain Medicine. The final paragraph of this article states it best: “leaves behind a tremendous legacy. The sheer weight of what he accomplished and its impact on the field is staggering. But, in my mind, even more, impressive is how he accomplished what he did, with humility, a spirit of collaboration and inclusion, generosity, and compassion. Bill set a standard that we could all do well to strive for—he will be missed!”

MARCH 17, 2021 – new publication

Our new Nature Communications study is now published! This study, led chiefly by Dr. Sangsu Bang from Ru-Rong Ji’s group, describes a novel immunotherapy strategy for infection-induced sepsis and pain, using small molecule agonists of the G-protein-coupled receptor GPR37. This is especially timely given the current COVID-19 pandemic. Congratulations to all!

JANUARY 13, 2021 – new publication

We’re excited to share that our manuscript describing the analgesic properties of STING pathway activators in various pathological pain conditions is now published in Nature! This sums up several years of work that involved our team and teams led by Dr. Ru-Rong Ji (CTPM), Dr. William Maixner (CTPM), Dr. Mei-Chuan Ko(Wake Forest University), and Dr. Yu (Leo) Lei (University of Michigan). A big ‘thank you’ and congratulations to all coauthors involved. Stay tuned for more studies focused on the role of STING in pain regulation and neuro-immune communication!