RELIEVING PAIN IN AMERICA

CACPR MEMBER SPOTLIGHT: Jin. Y. Ro, PhD

Jin Y. Ro, PhD , professor in the Department of Neural and Pain Sciences, joined the University of Maryland School of Dentistry in 1998 and has since been studying the neurobiological mechanisms underlying pain and analgesia in the context of persistent musculoskeletal pain conditions, such as temporomandibular disorders (TMD) and osteoarthritis (OA). His most recent research interest focuses on the central brain mechanisms that contribute to sex and age differences in endogenous pain modulation. Typically, endogenous pain modulatory systems are less efficient in chronic pain patients, which suggests that the dysfunction of the central nervous system (CNS) pain regulatory system is a significant factor in clinical pain disorders. Human studies provide compelling evidence that deficiencies in endogenous pain modulatory systems in women and in the elderly population may play a larger role in mediating sex and age differences in chronic pain conditions. Dr. Ro and his team have developed a series of rodent behavioral models to establish sex and age differences in the efficiency of descending pain modulation. By utilizing these models, they are working to uncover specific neuromodulators that mediate both sex-dependent and sex-independent components of the endogenous pain modulatory system. In collaboration with Drs. David Seminowicz and Joyce Teixeira da Silva, Dr. Ro and his team have discovered that altered functional connectivity between the anterior cingulate cortex, the periaqueductal gray, and the limbic system is associated with deficient pain modulatory function in females and older animals. Based on these findings, Dr. Ro is currently exploring whether endogenous pain modulation efficiency can be strengthened by experimentally manipulating specific brain circuits and whether such manipulation will ultimately improve management of OA or TMD pain. Notably, Dr. Ro has recently received renewed funding for one of his principle research projects, entitled, 'Peripheral receptor mechanisms in orofacial pain,' the latest chapter in his remarkable 18 years of continuous funding from the National Institute of Dental and Craniofacial Research. Recent Publication Ro JY, Zhang Y, Tricou C, Yang D, da Silva JT, Zhang R. Age and Sex Differences in Acute and Osteoarthritis-Like Pain Responses in Rats. J Gerontol A Biol Sci Med Sci. 2019 Aug 14. pii: glz186. doi: 10.1093/gerona/glz186. [Epub ahead of print] PubMed PMID: 31412104.

CACPR Member Laurels

Highlights of recent grant awards, authorships, and other CACPR member news.

Luana Colloca, MD, PhD Dr. Luana Colloca will serve as PI on a five-year, $2.9 million NIH/NCCIH grant exploring the neural correlates of hypoalgesia driven by observation. About the Project Placebo analgesic effects following the observation of a benefit in another person are similar in magnitude to those induced by directly experiencing an analgesic benefit. These observations emphasize that contextual cues substantially modulate the individual placebo analgesic effects. In this project, we propose a compelling research agenda to explore the neural mechanisms of hypoalgesia driven by observation as a foundation for future development of novel nonpharmacological pain therapies using pharmacological functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and combined EEG/fMRI. Recent Publications by Colloca Okusogu C, Colloca L. Placebo hypoalgesia: above and beyond expectancy and conditioning. Curr Opin Behav Sci. 2019;26:75-81. doi:10.1016/j.cobeha.2018.10.008. Epub 2018 Nov 13. PubMed PMID: 31538101; PubMed Central PMCID: PMC6752745. Skvortsova A, Veldhuijzen DS, Van Middendorp H, Colloca L, Evers AWM. Effects of oxytocin on placebo and nocebo effects in a pain conditioning paradigm: a randomized controlled trial. J Pain. 2019 Sep 5. pii: S1526-5900(19)30792-8. doi:10.1016/j.jpain.2019.08.010. [Epub ahead of print] PubMed PMID: 31494273. Krimmel SR, Zanos P, Georgiou P, Colloca L, Gould TD. Classical conditioning of antidepressant placebo effects in mice. Psychopharmacology (Berl). 2019 Aug 17. doi: 10.1007/s00213-019-05347-4. [Epub ahead of print] PubMed PMID: 31422429.

Susan G. Dorsey, PhD, RN, FAAN Dr. Susan G. Dorsey will serve as one of the PIs on a five-year, $2.49 million grant for the "NEAT study," which will examine the neurophysiological and transcriptomic predictors of chronic lower back pain with a focus on precision pain management. About the Project One of the most common and costly chronic pain conditions is low back pain (LBP), which produces more global disability than any other condition. Up to 39% of patients with an acute LBP episode report chronic LBP (pain lasting >3 months) and long-term disability for 2 years or longer. In this study, we will test the hypothesis that neurophysiological and gene expression differences can be used to build a predictive model that will define the chronic LBP phenotype and transcriptome and identify those LBP patients who will transition from acute to chronic pain phenotypes. Recent Publication The Use of Technology to Support Precision Health in Nursing Science. Starkweather A, Jacelon CS, Bakken S, Barton DL, DeVito Dabbs A, Dorsey SG, Guthrie BJ, Heitkemper MM, Hickey KT, Kelechi TJ, Kim MT, Marquard J, Moore SM, Redeker NS, Schiffman RF, Ward TM, Adams LS, Kehl KA, Miller JL. J Nurs Scholarsh. 2019 Sep 30. doi: 10.1111/jnu.12518. [Epub ahead of print] PMID: 31566870.

Joel D. Greenspan, PhD Recent Publications by Greenspan Khoury S, Piltonen MH, Ton AT, Cole T, Samoshkin A, Smith SB, Belfer I, Slade GD, Fillingim RB, Greenspan JD, Ohrbach R, Maixner W, Neely GG, Serohijos AWR, Diatchenko L. A functional substitution in the L-aromatic amino acid decarboxylase enzyme worsens somatic symptoms via a serotonergic pathway. Ann Neurol. 2019 Aug;86(2):168-180. doi: 10.1002/ana.25521. Epub 2019 Jun 8. PMID: 31177555. Using functional genomics approaches, this study identified a polymorphism in the L-aromatic amino acid decarboxylase (AADC) enzyme that contributes to somatic symptoms through reduced levels of 5-HT. Our findings suggest a molecular mechanism underlying the pathophysiology of multiply occurring somatic symptoms and opens new treatment options targeting the serotonergic system. Ohrbach R, Slade G, Bair E, Rathnayaka N, Diatchenko L, Greenspan JD, Maixner W, Fillingim RB. Premorbid and Concurrent Predictors of TMD Onset and Persistence. Eur J Pain. 2019 Aug 17. doi: 10.1002/ejp.1472. [Epub ahead of print] PubMed PMID: 31421009.  TMD is known to be a complex disorder, in which onset and persistence are associated with disease-related variables in multiple domains, including environmental exposure, clinical, psychological, health status, and pain processing variables. Using a more dynamic approach in order to capture change across time, many aspects of those domains were found to worsen prior to the reporting of pain, with bidirectional influences between domains and pain emergence likely. TMD onset appears to represent the cumulative effect of multiple system dysregulation.

Beth B. Hogans, MD, PhD Dr. Hogans has been elected chair of the pain education special interest group in the International Association for the Study of Pain (IASP). She was also recently quoted in a story on NPR about opioids and medical education. About IASP IASP is a global non-governmental organization that "brings together scientists, clinicians, health-care providers, and policymakers to stimulate and support the study of pain and to translate that knowledge into improved pain relief worldwide." Please contact Dr. Hogans if you would like to share information about developments in pain education locally, or if you would like to contribute news or a story to the IASP Pain Education newsletter.

David A. Seminowicz , MD, PhD Dr. David A. Seminowicz serve as PI on a four-year, $1.6 million NIH/NINDS grant on the cerebral oscillations of pain. About the Project There is substantial and growing evidence that indicates neural oscillations reflect cognitive, emotional, and sensory processes, which are all components of the pain experience. Furthermore, we can target these oscillatory patterns to alter perception. In particular, alpha band activity has been associated with chronic pain, and our extensive recent work and preliminary findings indicate that alpha can reliably predict future sensitivity to pain experienced minutes to weeks in the future in healthy subjects. In the proposed studies, we use simultaneous EEG-fMRI to continue our ongoing work on alpha oscillations as pain mechanisms and extend it to test the specificity and sensitivity of the signals and the relationship between alpha, brain networks, and pain. The proposed work would lead to improved understanding of the neurobiology of pain, identify novel brain targets for new or improved interventions, and potentially reveal a prognostic biomarker that would be useful for testing new therapeutic approaches and objectively assessing clinical improvement on an individual basis. Dr. Seminowicz will also co-lead a three-year, $1.39 million NIH/NINDS grant entitled, "Validation of a novel cortical biomarker signature for pain." About the Project Predictive biomarkers that can identify individuals at risk of developing severe and persistent pain, which is associated with worse disability and greater reliance on opioids, would promote aggressive, early intervention that could halt the transition to chronic pain. Our team has uncovered evidence of a unique cortical biomarker signature that predicts pain susceptibility (severity and duration). The biomarker signature combines resting state sensorimotor peak alpha frequency (PAF) measured using electroencephalograph (EEG) and corticomotor excitability (CME) measured using transcranial magnetic stimulation (TMS). This PAF/CME biomarker signature could be capable of predicting the severity of pain experienced by an individual, minutes to months in the future, as well as the duration of pain (time to recovery). In the initial phase of this project, we aim to undertake analytical validation of this biomarker in healthy participants using a standardized model of the transition to sustained myofascial temporomandibular pain (masseter intramuscular injection of nerve growth factor). In the second phase of this project, we then aim to perform initial clinical validation to determine whether the optimized PAF/CME biomarker signature predicts pain severity and duration in patients with new onset myofascial temporomandibular disorder (TMD). We expect our work to result in the delivery of a candidate biomarker signature ready for advanced prospective clinical validation studies.

Junfang Wu, BM, PhD Dr. Wu will serve as co-investigator for a $2.79 million grant from NIH/NINDS titled, "Dementia Following Spinal Cord Injury: Mechanism and Therapeutic Targeting." About the Project Recent evidence indicates that people suffering spinal cord injury (SCI) are at a high risk of dementia associated with substantial cognitive impairments. Yet little is known about the mechanisms of SCI-induced dementia or its relationship to age of onset or age-related neurodegenerative disorders such as Alzheimer’s disease (AD). Exosomes (Exo), containing microRNAs (miRs), proteins, and lipids from their originating cells, have emerged as potentially important regulators of secondary injury after SCI, not only locally but also systemically and in the brain. Exo release has also been hypothesized to contribute to the progression of AD. The purpose of this study is to identify the key mechanisms involved in critical yet largely ignored brain changes after SCI and test the hypothesis that SCI disrupts plasma Exo/miRs cargo content, ultimately promoting brain neuroinflammation through pro-inflammatory miRs leading to dementia, and physiologically-informed engineering of therapeutic Exo can be employed to counteract these effects.

The UM Center to Advance Chronic Pain Research (CACPR) is a multidisciplinary center composed of nationally and internationally renowned clinical and preclinical translational scientists whose principle research focus is on the physiological, genetic, and psychosocial underpinnings of the development and persistence of debilitating chronic pain conditions.

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