2023 Pain Consortium Symposium on Advances in Pain Research: Resilience and Pathways to Recovery

June 6-7, 2023

Natcher Conference Center
NIH Campus, Bethesda MD

Co-chairs:

Melissa Ghim, PhD | NIDCR
Devon Oskvig, PhD | NIA

Poster Abstracts

(Alphabetical by Presenting Author)

Poster 1

Mental Health Outcomes in Chronic Pain Patients During the COVID-19 Pandemic 

Titilola Akintola, Maya Delity, Nicole Antkiewicz, Joyce Chung, Lauren Atlas

Background 

The COVID-19 pandemic has extensive physical and psychosocial implications for everyone, with a disproportionate effect in chronic pain (CP) populations⁶. The effects of stressors may also be heightened for CP patients, many of whom have experienced reduced access to pain management due to the scaling down of non-emergent health services³. Earlier studies in the pandemic observed both increases and decreases in the mental health and functional outcomes within different CP condition groups^{1 4, 5}. This could be due, in part, to behavioral factors, the varying needs of CP patients over differing time periods or other potential moderating factors of outcomes in CP patients⁷.  

 Objective 

However, to our knowledge, no published studies looked at the trajectory of mental health outcomes over time during the pandemic. To address this gap, we investigated mental health outcomes in people with CP controlling for the effects of age, sex, comorbid mental health condition, pain severity in the CP patients. We also examined the trajectory of mental health scores CP patients over the 6-month survey duration.  

 Results 

Our online survey recruited surveyed >3,500 participants to provide biweekly responses to multiple behavioral, mental and psychosocial measures for a 6-month period between April 2020-May 2021. These analyses focused on 2,153 participants who provided both baseline and biweekly self-report measures of physical and mental health outcomes. At the end of the study, participants were asked to complete the Chronic Pain Graded Scale (CPGS) as well as other measures including resilience via the Brief Resilience Scale and social support via the PROMIS Instrumental Support tools. 35% of participants reported having chronic pain lasting longer than 6 months and 83% were women and 92% were White. We found that having a chronic pain condition was associated with worse mental health outcome score (b = 0.32, p<0.001). We also found significant main effects of having a comorbid mental health condition being associated with worse mental health outcomes (b = 0.28, p<0.001). In addition, female sex (b = 0.08, p < 0.001) and younger age (b =-0.12, p < 0.001) were associated with worse mental health outcomes. Looking at the trajectories of outcomes over the course of the study, we found that while mental health outcome scores reduced across time in the overall sample population, in patients with chronic pain, worse mental health scores were sustained across the 6-month survey period (p = 0.016). 

 Significance 

Our results showed that participants with chronic pain experienced significantly worse mental health that was sustained over the course of the study during the first year of the pandemic. These effects were over and beyond the effects of comorbid mental health conditions on mental health outcomes. Future analyses will investigate the potential moderating effects of factors including self-reported social support, resilience, and pain condition type on mental health outcome trajectories. 

Poster 2

Preliminary Findings on the Relationship between Executive Function, Psychological Factors, and Resting-State Functional Connectivity in Chronic Low Back Pain Patients 

 Behnaz Jarrahi, Gary Glover, Beth Darnall and Sean Mackey

Objective: To investigate the impact of chronic pain with or without opioid use on brain functional network architecture and its association with executive function and psychological factors in chronic low back pain (CLBP) patients. 

 Specific aims: (1) Elucidate the relationship between executive function and intrinsic functional connectivity in CLBP, (2) investigate the correlation between psychological constructs and intrinsic functional connectivity in CLBP, and (3) examine the group differences in intrinsic functional network architecture in CLBP on and off opioid. 

 Background: CLBP is a prevalent chronic pain condition, yet its underlying mechanisms remain unclear. While opioid analgesics are potent drugs for pain management, their efficacy and potential for abuse make their long-term use controversial. Executive function, which includes cognitive processes such as decision making and working memory, can be affected by chronic pain and opioid use. Psychological factors such as pain catastrophizing is a risk factor for poor outcomes while resilience is considered a buffer. Converging evidence suggests the importance of interoceptive awareness in chronic pain disorders. However, the relationship between these cognitive and psychological factors and intrinsic functional connectivity in CLBP is not fully understood. To further explore this relationship, we collected resting-state fMRI data from ten opioid-naive and ten opioid-taking CLBP patients and performed group independent component analysis and graph theory. Opioid-naïve patients completed computerized neuropsychological tasks measuring executive function, including the Cambridge Gambling Task (CGT), an analogue of the Wisconsin Card Sorting test (intra/extra-dimensional set shift; IED), the test of visuospatial paired-associates learning (PAL) and a battery of questionnaires, comprising the Pain Catastrophizing Scale (PCS), Pain Resilience Scale (PRS), Multidimensional Assessment of Interoceptive Awareness (MAIA II) and Short Form McGill Pain Questionnaire (SF-MPQ). We used multivariate analyses of covariance (MANCOVA) to examine the association of these factors with intrinsic connectivity (FDR-corrected p < 0.05). 

 Results and Significance:  The CGT delay aversion, which is linked to impulsivity, showed a positive association with between-network connectivity involving the basal ganglia and sensorimotor network, but a negative association with between-network connectivity involving bilateral frontal network and default-mode network (DMN). The CGT Risk adjustment was found to be positively associated with within-network connectivity of DMN. Total errors in the IED task were positively correlated with the within-network connectivity of the self-referential network, which is comprised of the medial prefrontal cortex. PAL first attempt memory showed a negative association with within-network connectivity of the dorsal attention network, while PAL total errors were positively associated with between-network connectivity of the bilateral frontal network and basal ganglia. There was a significant positive association between the PCS magnification and within-network connectivity of the DMN, and between the PCS rumination and within-network connectivity of the dorsal attention network. There was also a positive association between the PCS helplessness and between-network connectivity involving the sensorimotor and salience networks. There was a significant negative association between the PRS cognitive/affective positivity and within-network connectivity of DMN and a positive association between the PRS behavioral perseverance and between-network connectivity involving the DMN and salience network. There was a significant negative association between the MAIA attention regulation and within-network connectivity of DMN and between the MAIA emotional awareness and within-network connectivity of the central executive network. The global efficiency values were positively correlated with pain in opioid-naïve but not in opioid-taking CLBP. This suggests that as sensory dimension of the pain intensity increases, opioid-naïve patients tend to exhibit more efficient information transfer across a network of brain regions, including the salience, central executive, and sensorimotor networks. Such phenomenon was not observed in opioid-taking CLBP. Significant findings in DMN, salience, sensorimotor and cognitive networks are particularly noteworthy, given their role in the neurobiology of chronic pain. Funding: NIH K25 DA048179 and P01 AT006651S1. 

Poster 3 

Promotional and Resilience Factors for Physical Activity in Pediatric Chronic Pain

William R. Black, Jennifer Christofferson, Lora L. Black, Cara M. Hoffart, Dustin P. Wallace

Objectives: This study sought to identify self-reported promotional and resilience factors for physical activity (PA) engagement in adolescents with chronic musculoskeletal pain. Specific Aims:  Via semi-structures interviews, participants were asked to discuss specific things that a) “prevented” or “got in the way” of engaging in physical activity, and b) “helped” them to engage in PA when having pain. Background: Chronic pain in children and adolescents is associated with functional, physical, and psychosocial challenges. Effective interventions integrate psychological approaches (e.g., cognitive-behavioral, acceptance-based, and mindfulness) with PA. However, despite benefits of PA on functional outcomes and pain, adherence to physical activity is often suboptimal. Patient perspectives, voices, and lived experiences are poorly characterized in adherence literature for pediatric chronic pain. Furthermore, while much of the pediatric pain literature has been focused on reducing barriers to PA engagement and pain coping, resilience factors for pain coping are receiving greater attention; however, even the extant resilience literature in chronic pain has focused on pain coping, with less known about unique resilience factors that may be affect PA engagement. This study explores patient perspectives of their personal promotional and resilience factors that impact their participation in PA.Methods: 60-minute semi-structured interviews were conducted with adolescents who had a history of chronic musculoskeletal pain. Interview topics investigated multiple factors that affect pain coping and PAE engagement, including “things” that help patients engage in activities even when their pain feels worse, times that they chose not to engage in an activity due to motivation levels or emotional factors (e.g., a bad mood), and times when they avoided or engaged in an activity due to their perceived ability to complete the activity. Interviews were transcribed and coded utilizing grounded theory. The analyses and themes presented in this study focus on promotional and resilience factors for PA.Results: Ten patients completed interviews (Mage = 15.9 years; 90% assigned female at birth). Patients of factors associated with engagement in PA, such as acknowledging small goals and “wins” (e.g., “seeing” progression, motivation to “keep going”, doing home exercises even if they are uncomfortable) and engaging in benefit-finding (e.g., resumption of activities of interest, self-motivation, knowing that it is “helping”). Participants also noted that recognizing long-term gains (e.g., “it will be better in the long run”, “looking at the bigger picture”), and experiencing a connection between PA, mood, and pain (e.g., “ ..easier to do PA if you have a positive mindset”, “… going for a walk and putting that frustration into [PA]… helped let it out.” Significance: This study provides insight into aspects of the patient pain experience that may be addressed to improve PA. Incorporating activities of benefit finding and encouraging a focus on long-term gains is likely to be beneficial. Participants also noted that acknowledging accomplishing smaller and more progressive goals and that being aware of how PA is related to their mood and pain increased their motivation to engage in PA. These strategies may serve as explicit treatment targets to improve both intermediate and longer-term adherence to PA.

Poster 4 

Exploring the Overlap between Social and Physical Pain: Implications for Suicide Risk

Sarah L. Brown, Ph.D.

Objective: Explain how the overlap between social and physical pain influences suicide risk.
Background: The need to belong is one of life’s most fundamental needs, playing a vital role in physical and psychological well-being (Baumeister & Leary, 1995). The pain overlap theor (Eisenberger & Lieberman, 2004) and it’s supporting evidence suggests that physical and social pain 1) Share neural structures, 2) have similar cognitive or computational mechanisms, 3 influence the induction or regulation of each other, and 4) are similarly influenced by trait and individual factors. The severity hypothesis Bernstein & Claypool, 2012) posits the severity of social exclusion differentially influences an individual’s sensitivity to social and physical pain. I developed a comprehensive transdiagnostic model of suicide risk and social pain that integrates theories of social exclusion, social pain, and suicide risk. This theory posits social exclusion leads to both suicide ideation (SI) and suicidal behaviors (SB) through shared or interconnected systems. Minor or infrequent social exclusion leads to adaptive responses that would reduce suicide risk (e.g., sensitivity to threat or pain; help seeking or reaffiliation). However, severe insults or chronic social exclusion leads to maladaptive cognitive, affective, and neurophysiological responses that increase risk for SI (e.g., hypersensitivity to rejection), and facilitate engagement in SB (e.g., emotion regulation deficits, insensitivity to physical pain and threat).

Results: In a series of studies I have been systematically testing the proposed model. Study 1 provided partial support for the proposed model, such that acute social exclusion (via Cyberball) resulted in an adaptive response to social pain (i.e., greater fear of death, greater objective pain sensitivity, greater attentional biases toward social exclusion content) that would buffer against suicide risk. Study 2 examined the impact of repeated rejection on suicide risk. Specifically, we found that rejection sensitivity, which results from repeated rejection, was positively associated with SI (cognitive-affective reactions) through greater feelings of thwarted belonging and perceived burden (perceptions of rejection). Study 3 (ongoing) designed to test whether perceived chronic social exclusion (autobiographical recall) elicits maladaptive responses to social pain that would increase risk for SB in a sample that is high-risk for suicide. Virtual reality SB scenarios serve as a proxy for SB and allow for experimentally testing the proposed model. Specifically, we hypothesized maladaptive responses of impaired decision-making (deficits in value comparisons) and blunted physiological arousal (blunted sympathetic arousal and blunted parasympathetic withdrawal) would be associated with increased risk for virtual reality SB.
Implications & Future Directions: Social exclusion may be a common cause for both SI and SB via the body’s interconnected social and physical pain system. Considering the impact of both physical and social pain may be critical to preventing and treating chronic pain states associated with elevated suicide risk. Examining these associations among individuals with chronic pain conditions or psychiatric conditions with chronic interpersonal stressors (e.g., post-traumatic stress disorder, borderline personality disorder) may be critical as these individuals may be particularly vulnerable to suicide due to the overlap between social and physical pain.

5 - Mitchell Max Award Finalist 

Improved Prediction of Spine Surgery Outcomes using Dynamic Features Derived from Mobile Health Monitoring 

Madelyn R. Frumkin, Jacob K. Greenberg, Ziqi Xu, Jingwen Zhang, Justin Zhang, Saad Javeed, Chenyang Lu, Wilson Z. Ray, Thomas L. Rodebaugh  

Background: Chronic back pain (CBP) is the costliest health condition in the United States, with an estimated $134.5 billion in spending from 1996 to 2016. A significant challenge in determining the appropriate course of treatment is that the cause of CBP is often unclear. Although thousands of patients per year have surgery to address degenerative spine disease, it is now well-established that a large proportion pain-free adults also have degenerative spine imaging findings. Consequently, 10-40% of patients who undergo spine surgery experience ongoing impairment. Existing predictive models of spine surgery outcomes have relied on static patient characteristics (e.g., pain levels, psychological comorbidities). These features have limitations, including that they may be subject to recall bias and often offer limited actionable insights. The goal of the current study was to examine whether dynamic features derived from preoperative mobile health (mHealth) monitoring improved prediction of spine surgery outcomes.  

 Specific Aims: In this study, we examined: 1) individual differences in biopsychosocial processes involved in CBP using mHealth monitoring and 2) utility for predicting spine surgery outcomes.  

 Method: Adults undergoing lumbar surgery for degenerative disease were prospectively recruited from a single center. Traditional static measures of physical and psychological health were collected via patient report and chart review. For approximately three weeks prior to surgery, patients also completed mHealth monitoring, which included Ecological Momentary Assessment (EMA) of subjective pain, mood, catastrophizing, and disability five times daily and passive monitoring of activity and arousal with wrist-worn Fitbit trackers. Multilevel dynamic structural equation models were used to assess individual differences in dynamic relationships among subjective EMA and objective Fitbit data. Using logistic regression models with Leave-One-Out Cross-Validation, we then compared predictive performance of models derived from traditional static versus dynamic mHealth features. Outcomes included a clinically important change in PROMIS pain interference (reduction ≥ 6 points). 

 Results: 107 patients were included (average age = 59 years, 53% female). At 1-month post-surgery, 46% (n = 49) had clinically important improvement in pain interference. Traditional static features predicted pain interference only slightly better than chance, with an area under the receiver operating characteristic (AUROC) of .58. Dynamic EMA (AUROC = .70) and Fitbit (AUROC = .67) features alone showed improved prediction. However, combining static and dynamic features resulted in the best prediction (AUROC = .79). Shapley values suggested that the most influential features in the combined model were: 1) preoperative PROMIS pain interference score, 2) the intercept of catastrophizing derived from preoperative EMA, and 3) the degree to which step count predicted subsequent pain reports preoperatively. Follow-up analyses showed that controlling for preoperative pain interference, a stronger tendency for greater activity to dynamically predict increased subjective preoperative pain was associated with lower postsurgical pain interference (β = -2.95, p = .002).  

 Significance: Our findings highlight the utility of preoperative mHealth monitoring for predicting spine surgery outcomes and identifying mechanisms that may be targeted to improve outcomes. Specifically, patients for whom activity does not dynamically predict pain may benefit from further assessment and intervention around psychosocial mechanisms of CBP. 

6 - Mitchell Max Award Finalist 

Unveiling the link between BDNF rs6265 Polymorphism and Severe Neuropathic Pain in Female Cancer Survivors

Taichi Goto, Diane Von Ah, Xiaobai Li, Lichen Xiang, Catherine Kwiat, Christopher Nguyen, Chao-Pin Hsiao, Leorey N. Saligan

Objective
The study examined the associations between brain-derived neurotrophic factor (BDNF)
rs6265 polymorphism and neuropathic pain symptoms within the cancer-related
psychoneurological (PN) symptom clusters (bodily pain, fatigue, depression, anxiety, sleep disturbance, and neuropathic pain) reported by female cancer survivors.

Specific aim(s)
The study specifically aimed 1) to identify patient clusters based on the cancer-related
PN symptoms, 2) to examine the associations between the patient cluster groups and BDNF rs6265 polymorphism, and 3) to explore the relationships between neuropathic pain symptoms and BDNF rs6265 polymorphism.

Background
Cancer and its treatment can cause various PN symptoms that persist for months or
even years after treatment completion, affecting the quality of life of cancer survivors.
However, the underlying mechanisms of these cancer-related PN symptoms remain unclear. One potential contributor to experiencing persistent, distressing PN symptoms is BDNF rs6265 polymorphism, resulting in a substitution of methionine for valine (Val66Met) in the BDNF gene. This polymorphism has been associated with several PN symptoms, including anxiety and depression. However, the relationship between BDNF rs6265 polymorphism and PN symptoms, particularly neuropathic pain symptoms, in female cancer survivors has not been fully explored.

Results and Significance
The study enrolled 393 female cancer survivors who provided informed consent to
participate in an Institutional Review Board-approved study. The study participants were 93% White, 75% married or living with a partner, and 72% with advanced educational degrees (undergraduate or graduate degree). PN symptoms were assessed using Patient-Reported Outcomes Measurement Information System questionnaires and the 36-Item Short-Form Health Survey. Using the PN symptom scores for bodily pain, fatigue, depression, anxiety, sleep disturbance, and neuropathic pain, patients were clustered into two groups using hierarchical clustering. One cluster group (named Cluster Group 1) had higher (worse) PN symptom scores, except for bodily pain. Group 1 also had more participants carrying the Met/Met genotype (p = .002). To investigate the relationship between BDNF rs6265 and neuropathic pain symptoms, we compared neuropathic pain scores across genotypes for all study participants regardless of symptom cluster group affiliation. Pairwise comparisons showed that participants with the Met/Met genotype reported significantly higher neuropathic pain scores than those with the Val/Val (p = .004) and Val/Met (p = .004) genotypes. Furthermore, an exploratory regression analysis revealed the association between the neuropathic pain symptom scores and BDNF rs6265 Met/Met genotype (slope = 9.30, p < .001).

Significant differences were observed for the number of participants based on
demographic characteristics among the genotypes, such as differences in race (p = .005), clinical cancer stages (p = .02), and radiation therapy (p = .04); hence sub-analyses were performed. The sub-analyses conducted only on White, Stage III, or patients who received radiation therapy confirmed the findings of the initial analysis that participants with the Met/Met genotype reported significantly higher neuropathic pain scores than the other genotypes. Our findings provide new insight into the associations between BDNF rs6265 polymorphism and neuropathic pain. This knowledge prompts further investigations to understand the mechanisms underlying these associations to inform the development of new treatment strategies for alleviating these symptoms. 

Poster 7 

Novel non-viral reprogramming strategies to treat discogenic back pain via engineered extracellular vesicles

Shirley N. Tang, Ana I. Salazar-Puerta, Safdar Khan, Devina Purmessur & Natalia Higuita-Castro

Objective: The goal of our research program is to establish novel non-viral reprogramming-based cell therapies to convert degenerate intervertebral disc (IVD) cells associated with discogenic back pain (DBP), into a healthy pro-anabolic, anti-nerve/vascular phenotype, using engineered extracellular vesicles (eEVs). Currently, there is a lack of effective non-addictive strategies to treat IVD-associated chronic low back pain, which is of critical concern given its socio-economic burden and role in the opioid crisis. We aim to address this gap and transform spine research, by providing a safe and efficacious therapy for DBP by reprogramming IVD cells. Specific Aims: Previous studies by our group demonstrate that non-viral delivery of FOXF1 or Brachyury to degenerate human nucleus pulposus (NP) cells increases healthy phenotypic markers and extra cellular matrix (ECM) accumulation, and decreases key catabolic/inflammatory factors and pain markers. More recently, we have reported that delivery of FOXF1 via eEVs increases IVD tissue hydration and decreases pain behaviors in a mouse model of DBP. These findings highlight the potential of  developmental transcription factors as effective therapy to restore IVD structure and to treat symptoms of DBP. Currently, we are evaluating the synergistic reprogramming potential of multiple developmental transcription factors in relevant models of DBP (Aim 1), and optimizing our eEV preparations to enable targeted delivery to NP and annulus fibrosus (AF) cells in the diseased IVD (Aim 2). Background: Non-addictive treatments for low back pain (LBP) are a research priority given the socio-economic burden of LBP on communities affected by the opioid crisis. IVD degeneration is a significant cause of LBP, and it is considered to be a key molecular driver of back pain onset. Moreover, benefits of surgical interventions are short-lived and can significantly alter spinal kinematics leading to adjacent segment disc disease. Although biological strategies such as viral gene delivery and cell-based therapies have shown promise, their implementation is restricted due in part to potential tumorgenicity/immunogenic  responses and limited cell survivability. Minimally invasive non-viral gene delivery methods such as eEVs can overcome these limitations due to their enhanced biocompatibility and biostability, low immunogenicity, and tuning capabilities. Our central hypothesis is that directly reprogramming a patient’s own degenerate IVD cells into a healthy phenotype via eEV delivery of developmental transcription factors, will restore
IVD structure/function and limit nerve/vascular ingrowth associated with pain. Results and Significance: Our data demonstrates the synergistic potential of FOXF1 and Brachyury to further enhance a healthy pro-anabolic NP cell phenotype, and Mohawk or Scleraxis to drive a healthy pro-anabolic phenotype in degenerate human AF cells. Furthermore, we demonstrate that we can enhance eEV tropism towards AF or NP cells to enable targeted payload delivery to specific regions in the IVD. Non-viral eEV-based
reprogramming of diseased NP and AF cells in situ has never been applied to treat patients with acute or early degeneration associated with DBP. The impact of this strategy lies in its potential to target native diseased IVD cells in a safe and efficacious manner in situ to restore structure/function to the IVD while limiting symptoms of pain.

Poster 8 

Kappa-Opioid Receptor-Expressing Neurons in the Ventral Tegmental Area Modulate Persistent Pain

Ruby A. Holland; Kelly M. Smith; Michael C. Chiang; Jeffrey E. Okoro; Isabel M. Bleimeister; Samantha A. Sherman; Ava V. Zoltanski; Eileen K. Nguyen; Sarah E. Ross

Objective: The objective of this study is to determine the role of kappa-opioid receptor-expressing neurons in the ventral tegmental area in multiple dimensions of pain.
Specific aims: The specific aims of this study are to 1) characterize the projection-specific anatomy of VTAKOR neurons, 2) determine the function of VTAKOR neurons in acute and persistent pain behaviors, and 3) dissect the projection-specific contributions of VTAKOR neurons to nociception, aversion, and negative affect.

Background: Chronic pain is a debilitating condition in which patients experience intense pain in response to innocuous stimuli, which can long outlast the resolution of the originating injury or diseas e. Unfortunately, mu opioid agonists remain a mainstay of pain therapy despite dangerous side effects and limited efficacy in chronic pain. Furthermore, there are even fewer treatment strategies available to address the equally paralyzing negative affective consequences of chronic pain, such as anxiety and depression. Thus, there is a great need to further our understanding of the neural circuitry underlying mood and reward signaling in the context of chronic pain. The kappa-opioid receptor (KOR) is an inhibitory GPCR which is expressed throughout mesolimbic dopamine circuitry. In aversive states, both KOR and its endogenous ligand dynorphin are upregulated in key brain regions involved in reward, stress, and memory. In chronic pain, pharmacological manipulation of KORs in mesolimbic pathways has been shown to modulate pain-associated aversion and negative affect, without altering sensory thresholds. While mesolimbic KORs have been investigated in aversion generally, much remains unknown about the anatomy and function of KOR-expressing neurons emanating from the VTA (VTAKOR neurons), and the projection-specific roles of these neurons in the multifaceted chronic pain response.

Results: We found that VTAKOR neurons are primarily dopaminergic but also contain unique subpopulations which express glutamate and GABA markers. VTAKOR neurons project to CNS regions throughout the ascending and descending pain modulatory pathway, including the spinal cord, rostral ventromedial medulla (RVM), ventrolateral periaqueductal gray (vlPAG), and the lateral parabrachial nucleus (lPBN), as well as mesolimbic regions implicated in aversion and negative affect such as the nucleus accumbens (NAc), caudate-putamen (CPu), medial prefrontal cortex (mPFC), and lateral hypothalamus (LH). Dynorphin-expressing neurons which project to the VTA were also identified in many of these regions. Chemogenetic activation of VTAKOR neurons increases thermal and mechanical sensory thresholds and modulates anxiety-like and depressive-like behaviors. Capsaicin injection into the hind paw induced a robust, persistent hyperalgesia which was also attenuated through chemogenetic activation of VTAKOR neurons. Interestingly, chemogenetic inhibition of VTAKOR neurons had no effect on acute sensory thresholds or capsaicin-induced hypersensitivity.

Significance: Taken together, the results of these experiments challenge the preeminent hypothesis that the KOR system solely mediates the affective components of pain. The completion of these aims will also serve to uncover the extent to which divergent VTAKOR projections contribute to chronic pain behaviors. Uncovering the precise mechanisms by which the KOR/dynorphin system modulate both nociception and pain-associated negative affect will advance the pain field and pave the way for the development of novel pain therapeutics.

Poster 9 

Examining the pain experience of post-curative-therapy sickle cell patients

Nwamaka P. Ijeh, Hayley A. Owens, Michelle A. Singh, Deepika S. Darbari, Matthew M. Hsieh, Swee Lay Thein, M. Catherine Bushnell, Eleni Frangos

Background & Aims: Curative therapies (CT) for sickle cell disease (SCD), such as gene therapy or hematopoietic stem-cell transplants, have shown successful reversal of sickling conditions that underlie painful vaso-occlusive crises, the main cause of acute and chronic pain. However, despite therapeutic success, some SCD patients still experience chronic pain. The purpose of the present ongoing study is to better understand the neural and behavioral mechanisms underlying persistent pain in SCD patients that have undergone curative therapy compared to matched healthy controls (HCs).

Methods: Twenty-seven participants have completed the study thus far: post-CT SCD = 11, 8 with persistent pain, 10 females, 37.27 ± 7.5 years; and race-, sex-, and age-matched HCs = 16, 12 females, 29.1 ± 8.51 years. Post-CT SCD patients participated after their post-curative-therapy procedure (5.35 ± 4.51 years). All participants completed a set of pain questionnaires; post-CT SCD patients were asked to retrospectively complete a second set of pain questionnaires specific to their condition ~1 month prior to treatment. Quantitative sensory tests included tactile discrimination (2-point discrimination and punctate thresholds), pressure and thermal pain thresholds and tolerance, and assessments of temporal summation and descending pain modulation (conditioned pain modulation [CPM]). The analyses were conducted using non-parametric two-tailed unpaired t-tests with a significance level of p < 0.05.

Preliminary Results: Thus far, post-CT SCD patients report a significant decrease in average pain pre- (7.3 ± 1.8; 0=no pain, 10=pain as bad as you can imagine) vs. post-curative therapy (1.8 ± 2.1; p < 0.001). Tactile sensitivity, heat detection, threshold, and tolerance, and cold detection and tolerance were each comparable between post-CT SCD patients and HCs. Post-CT SCD patients had greater cold pain thresholds (p = 0.04), pressure pain thresholds (p = 0.05), and tolerance (p = 0.012) compared to HCs, as well as increased central sensitization (D pain intensity rating (last-first): post-CT SCD 3.5 ± 2.2, HCs 1.7 ± 1.7; p = 0.04), while after sensations remained comparable to HCs. Lastly, HCs had a significant CPM effect, while post-CT SCD patients did not.

Conclusion: The preliminary results indicate that post-curative-therapy SCD patients exhibit an overall decrease in average pain after CT and that CT may reduce the sensitivity of noxious stimuli to levels comparable to HCs. Nevertheless, the increased central sensitization and lower endogenous pain control in post-CT SCD patients compared to HCs indicate potential mechanisms for persistent pain after curative therapy.

Poster 10 

Pain Unpleasantness and Effort Valuation: Behavioral Evidence for a Domain-General Valuation System

Nicholas Madian, Shruthi Satyanarayana, Hayley Owens, Nwamaka Ijeh, Haley Prakke, Eleni Frangos

Objective: To explore one of the key predictions of an influential neuroeconomic theory: that the subjective values (SVs) that individuals assign to stimuli, and the degree of pleasantness or unpleasantness those stimuli elicit, all emerge from a unitary, domain-general mental process.

Specific Aim: To determine the extent to which the degree of experienced unpleasantness evoked by thermal heat pain stimuli predicts willingness to engage in physically effortful tasks for monetary rewards.

Background: An influential neuroeconomics theory asserts that animals have evolved the capacity to determine which sensory stimuli are associated with the greatest net survival benefits, and that they do so by computing SVs for these stimuli. The neural mechanisms underlying the computation of SVs are thought to be domain-general, enabling comparisons of value across different stimulus valences (i.e., rewarding or punishing) and modalities (e.g., pain, effort, taste, touch, etc.). It has also been suggested that certain affective experiences, such as the unpleasantness of various sensations (e.g., pain and effort), are the experiential component of this valuation process. The theory predicts that the SV and the experienced unpleasantness of many different types of stimuli should all be closely associated, but this remains largely untested, as previous research has for the most part examined only one type of stimulus at a time and has measured valuation and sensation separately. The goal of this study was to investigate the relationship predicted to exist between pain sensation and effort valuation in healthy volunteers. Pain and effort were specifically chosen as they appear especially relevant to the study of chronic overlapping pain conditions (COPCs). Thermal heat pain stimuli were administered to healthy volunteers via thermode, and the evoked experience of unpleasantness was measured via visual analogue scale (VAS). Effort valuation was operationalized by the willingness to engage in a physically effortful task for a variable cash reward, assessed using the Effort Expenditure for Rewards Task (EEfRT). The effects of pain unpleasantness on the probability of choosing the hard task was modeled using generalized estimating equations (GEE).

Results and Significance: The degree of unpleasantness evoked by higher levels of thermal heat pain stimuli significantly predicted willingness to engage in the physically effortful task (OR = 0.64 [0.50, 0.84], p = 0.001). This suggests that the unpleasantness of painful stimuli and the valuation of effortful stimuli are closely related, and that the theory that both are driven by a unitary, underlying neural process could be correct. The existence of such a mechanism might have major implications for the understanding and treatment of COPCs, which are characterized not only by abnormal sensitivity to pain, but also to a variety of other unpleasant stimuli, including effort. It has been proposed that COPC symptoms are due at least in part to some unknown dysfunction of the central nervous system; perhaps this dysfunction is related to the computation of SVs. Future research will employ neuroimaging to identify brain regions and networks involved in the computation of SVs and the experience of unpleasantness and will investigate their potential contribution to COPCs.

Poster 11 

Treating negative affect and chronic pain reduces intersectional health-related stigma in patients with chronic low back pain  

Samantha M. Meints, Madelyn A. Crago, Jenna M. Wilson, Ajay D. Wasan, W. Michael Hooten, Robert R. Edwards 

BACKGROUND: Patients with chronic low back pain (CLBP) often experience high levels of negative affect (NA), including depression and anxiety. CLBP patients with NA experience greater pain, are at risk for opioid misuse, and have worse pain treatment outcomes. Such experiences put these patients at risk for intersectional health-related stigma (i.e., pain-, mental health- and opioid-related stigma). 

SPECIFIC AIMS: We capitalized on a randomized clinical trial of antidepressants (AD), fear-avoidance physical therapy (EFAR), and the combination of the two (AD+EFAR) to examine the effect of treatment on intersectional health-related stigma (IHRS) among patients with CLBP and high NA. 

METHODS: Participants (N=79) completed the Internalized Stigma of Chronic Pain (ISCP) scale, the Self-Stigma and Perceived Public Stigma scale (SSPPS), and the Brief Opioid Stigma Scale (BOSS) at three timepoints: baseline, 8 weeks, and 16 weeks. The ISCP assesses the subjective experience and self-application of chronic pain-related stereotypes, and consists of five subscales: Alienation, Social Withdrawal, Stigma Resistance, Stereotype Endorsement, and Discrimination Experience. The SSPPS assesses mental health stigma and consists of 2 subscales: Self-stigma and Perceived Public Stigma. The BOSS measures stigma related to opioid use and consists of three subscales: Aware, Agree, and Harm. Of note, language in this measure was revised to assess prescription opioid use rather than opioid addiction.  We conducted mixed-model ANOVAs to examine treatment-related changes in IHRS over time and whether changes in opioid-related stigma differed between those prescribed and not prescribed opioid medications. 

RESULTS: Participants (M_age=53, SD=14) were mostly female (57%), White (88%), and non-Hispanic (91%). Results showed significant reductions in Alienation (ηp²=.23), Social Withdrawal (ηp²=.26) and Stereotype Endorsement (ηp²=.08.) scales of the ISCP as well as an increase in Stigma Resistance (ηp²=.14) but no changes in the Discrimination Experience (ηp²=.03) subscale. Regarding mental health-related stigma, there were significant reductions in both Self-Stigma (ηp²=.26) and Perceived Public Stigma (ηp²=.07). Lastly, there was a significant decrease in the Awareness subscale of the BOSS but only among patients prescribed opioid medications (ηp²=.07). There were no changes over time for this subscale among patients not prescribed opioids (ηp²=.01) nor were there significant changes in the Harm (ηp²<.01) or Agree (ηp²<.01) subscales of the BOSS among any patients. There were also no time X group interactions indicating that changes in IHRS did not differ across treatment groups. 

SIGNIFICANCE: Participation in a clinical trial aimed at reducing CLBP and NA resulted in meaningful reduction in internalized, perceived, and endorsed stigma related to chronic pain and mental health. However, while those taking opioid medications had a reduction in perceived stigma about their opioid medication use, they did not experience reductions in their internalized or endorsed stigma. It is possible that interacting with study staff and providers who focused on treating pain and NA rather than reducing opioids altered perceived stigma of opioid use but, because internalized and endorsed stigma are entrenched in a broader societal context, it may require greater time to observe changes. Future research may generate ways to optimize treatments in order to reduce IHRS among people with CLBP.  

Poster 12 

Motor cortex stimulation drives endogenous opioid signaling in descending pain control circuits

Mercer Lindsay, Nicole; Baer, Thomas; Schnitzer, Mark J.; and Scherrer, Grégory

Objective: To improve the efficacy and duration of motor cortex stimulation-induced pain relief.
Aims: We dissect the mechanism underlying chronic pain relief after motor cortex stimulation (MCS), identify features of stimulation that produce antinociception, and use this information to improve MCS treatment in a mouse model of trigeminal neuropathic pain.

Background: The heavy burden of chronic pain and the Opioid Epidemic has prompted an urgent, worldwide search for alternative, non-addictive methods of analgesia. One promising alternative is non-invasive electrical or magnetic stimulation of the motor cortex (MC). While MC stimulation (MCS) has repeatedly been found to reduce chronic pain in human subjects and to decrease nocifensive behaviors in rodent models, major questions remain about the mechanism of action and how to improve MCS efficacy. In addition, imaging studies in human subjects suggest endogenous opioid signaling in descending pain control circuits may play a role in MCS-induced pain relief.

Results and significance: Here, we developed a mouse-sized transcranial magnetic stimulation (TMS) device to mimic the most common non-invasive technique in human subjects. This device passes an electric current through a wire wrapped around an iron core, inducing a magnetic field. Using this TMS device in mice with a chronic constriction injury of the infraorbital nerve, we observe a dose-dependent decrease in reflexive and affective pain behaviors after motor cortex stimulation. We further found that this decrease in pain behaviors is blocked by subcutaneous injection of naloxone, a nonselective antagonist of mu-, delta-, and kappa-opioid receptors, before TMS of the motor cortex. This result confirms that MCS relies on endogenous opioid signaling during or after stimulation to reduce pain. Next, we used cutting-edge viral and genetic tools to identify candidate brain regions activated during MCS, focusing on pain experience-related areas such as the amygdala, periaqueductal gray, rostral ventromedial medulla, and anterior insular cortex. We identified the rostral ventromedial medulla (RVM), a key node in the descending pain control pathway, as having both an increase in density of the immediate early gene Fos after MCS and dense expression of mu-opioid receptors (MOR). We found that intracranial naloxone injection in the RVM alone prevented MCS-induced antinociception while intracranial injection of an enkephalinase inhibitor (i.e., to prolong the duration of endogenous opioid activity in the RVM after MCS) enhanced both the efficacy and duration of antinociception. Together this data show that MCS drives neural activity and endogenous opioid relief in the descending pain control pathway. Finally, we use high-density electrophysiological recordings in the RVM to record the simultaneous activity of hundreds of neurons in response to the chronic injury as well as during and after MCS. Together, our data implicate endogenous opioid signaling in the descending pain control regions in MCS-induced antinociception and suggest that therapeutic improvement can be achieved through attention to the mechanism of action in this pathway.

Poster 13 Mitchell Max Award Finalist

Uncovering therapeutic spinal cord targets for the treatment of neuropathic pain

Tyler S. Nelson, Samantha Perez-Miller, Abigail Hellman, Bradley K. Taylor, Rajesh Khanna

Objective: The development of alternative, safe, and efficacious non-opioid therapeutics for the treatment of neuropathic pain.

Background: Nociceptor activation normally provides a protective function that can reduce tissue damage in the face of potentially hazardous stimuli. However, after tissue damage occurs, pathological changes within peripheral or central neurons can lead to chronic neuropathic pain, which persists after the injury has healed and serves no protective function. Neuropathic pain affects 7-8% of the general population yet is poorly responsive to analgesic drugs, including opioids. Therefore, the need for the development of novel therapeutics for the treatment of neuropathic pain is significant. Neuropeptide Y (NPY) in the spinal cord dorsal horn exhibits long-lasting inhibitory control of nociceptive transmission after peripheral nerve injury. Dorsal horn neurons that express the neuropeptide Y1 receptor (Y1-INs), an inhibitory G protein-coupled receptor, are well positioned to mediate the anti-nociceptive actions of NPY in the setting of neuropathic pain. We hypothesize that spinal Y1-INs represent a promising pharmacotherapeutic target for the treatment of high-impact chronic neuropathic pain.

Specific Aim(s): The aims of this study were to: (i) determine if Y1-INs are necessary and sufficient for the manifestation of peripheral nerve injury-induced mechanical and cold hypersensitivities, (ii) test for conservation of Npy1r expression across the dorsal horn of mammalian species, (iii) trial intranasal administration of an NPY Y1 agonist as a non-invasive approach to treat chronic pain, and (iv) perform an in silico screen for potential novel small molecule NPY Y1 agonists for the future treatment of pain.

Results and Significance: We pharmacologically targeted Y1-INs with intrathecal administration (i.t) of the Y1 receptor selective agonist [Leu³¹, Pro³⁴]-NPY. We found that [Leu³¹, Pro³⁴]-NPY (0.1-10 µg / 5 µL, i.t.) dose-dependently reduced spared nerve injury (SNI)-induced mechanical and cold hypersensitivity (p<0.05, n=8-11 mice/group). Similarly, chemogenetic inhibition of Y1-INs with clozapine N’ oxide (3.0 mg/kg, i.p.) completely abolished nerve injury-induced mechanical and cold hypersensitivity (p<0.05, n=7 mice/group). Conversely, chemogenetic activation of Y1-INs in un-injured mice induced multiple signs of pain including spontaneous nocifensive behaviors (lifting of hindpaw, licking, guarding, biting) (p<0.05, n=3-5 mice/group) and heat, cold, and mechanical hypersensitivities (p<0.05, n=7-8 mice/group). Chemogenetic activation of Y1-INs also induced robust conditioned place aversion (p<0.05, n=7-8 mice/group). Furthermore, activation of Y1-INs with wireless spinal optogenetics produced a frequency-dependent decrease in mechanical and cold withdrawal thresholds (p<0.05, n=8 mice/group). Next, using fluorescence in situ hybridization, we determined that spinal Npy1r expression is conserved across the dorsal horn of mouse, porcine, macaque, and human spinal cords; promising results for future pre-clinical to clinical translation. Lastly, we tested intranasal administration of [Leu³¹, Pro³⁴]-NPY for the non-invasive treatment of chronic pain and discovered a robust inhibition of nerve injury-induced mechanical hypersensitivity in both mice and pigs. Together, these results demonstrate Y1-INs are a pharmacotherapeutic target for the treatment of neuropathic pain. Capitalizing on the enormous potential of inhibition of Y1-INs for the treatment of pain, we are currently testing novel NPY Y1 small molecule agonists from an in-silico screen for efficacy as future therapeutics for chronic pain management.

Poster 14 

Morphine-mediated proinflammatory glial-immune actions are enhanced by early-life immune activation from prenatal alcohol exposure that paradoxically prolongs pathological pain following nerve injury.

 Andrea A. Pasmay, Ariana N. Pritha, Melody S. Sun, Diane C. Jiminez, Minerva Murphy, Daniel D.Savage, Fernando F. Valenzuela, Erin. D. Milligan, Shahani Noor.

Background: Chronic pain affects 11% - 40% of US adults, with considerable population variations due to environmental and psychosocial factors. A limited understanding of mechanisms and factors that influence chronic pain exists, and improvement in identifying populations “at risk” is sorely needed. Recent advances in identifying individuals susceptible to developing peripheral neuropathy are based on preclinical work demonstrating that adverse in-utero conditions such as prenatal alcohol exposure (PAE) create a vulnerability for chronic neuropathy from minor injury. These reports show physiological adaptations reprogram and prime neuroimmune responses during adulthood. Our reports show that PAE acts as a risk factor for developing pathological sensitivity to light touch (i.e., allodynia), a clinical symptom observed in chronic pain patients. While the role of proinflammatory cytokines in generating chronic neuropathy has been established in animal models, recent reports newly identify that PAE causes heightened production of proinflammatory cytokines including interleukin-1β (IL-1β) in the adult CNS following minor nerve injury. Interestingly, substantial neuroimmune overlap exists between PAE and opioidmediated immune actions involving both of the innate immune receptors, TLR4 and NLRP3 inflammasome that induce mature IL-1β production. Preclinical studies convincingly support that opioids exert negative consequences for pain due to proinflammatory actions on primed CNS glia, opposing the beneficial effects of opioids on pain relief. Therefore, we hypothesize that PAE interacts with morphine (opioid)-mediated immune actions following nerve injury that results in chronic neuroimmune function and worsens pain outcomes. Although unknown, a novel class of non-coding RNAs, circular RNAs, may be involved in these aberrant neuroimmune interactions. 

Objective: To identify how morphine treatment under PAE conditions results in chronic pathological neuroimmune function and promotes allodynia following nerve injury.

Specific aim(s): Utilizing a peripheral nerve injury model of chronic constriction injury, we examined (1) the effect of morphine (10 mg/kg) treatment on the chronicity of allodynia in adult PAE mice and considered potential sex differences, (2) the cellular and molecular mediators of morphine-induced prolonged allodynia, utilizing single-nucleus transcriptomics and NLRP3 blocking studies, and lastly, (3) explored regulatory roles of non-coding circular RNAs as a potential mechanism of neuroimmune interactions during chronic pain and morphine treatment. 

Results: Here, we report that; 1) PAE in the presence of ongoing neuropathy interacts with morphine and paradoxically prolongs allodynia in both males and females, with the duration of allodynia being sex-dependent, 2) NLRP3 inflammasomes play necessary roles underlying morphine’s proinflammatory effects, 3) astrocytes and other glial cells may release pain enhancing molecules from morphine treatment, and 4) a novel non-coding circular RNA, circVopp1, may be linked to regulatory roles in neuroimmune dysfunction and chronic pain as a consequence of PAE.

Conclusions and Significance: These preclinical data support that PAE creates biological vulnerability to chronic pain development and adverse outcomes from opioid use. Thus, individuals with PAE can be predictive of poor chronic pain outcomes from opioid pain therapies. Modulating NLRP3 actions and circular RNAs are novel targets to mitigate neuroimmune dysfunction and develop effective strategies for pain management in populations who are at risk for opioid use.  

Poster 15 

Sex-specific mediators in the accelerated development of tolerance and hyperalgesia in a rat model of traumatic burn injury

Jennifer E. Nyland, Ann Sipe, Sara Mills-Huffnagle, Corinne Augusto

Objective: The overall objective of this research program is to identify sex-specific mechanisms underlying the accelerated development of tolerance and hyperalgesia following traumatic burn injury and to identify potential targets for sex-specific interventions to treat acute pain and prevent the transition to chronic pain.

Specific aim(s): The first aim of the overall project is to fully characterize our model of
traumatic burn injury in both male and female rats using evoked and spontaneous assessments of pain and well-being. Aim 1a: Identify sex differences in the onset and duration of hyperalgesia following traumatic burn injury; Aim 1b: Determine which behavioral assays or combination of assays best capture pain following traumatic burn injury in males and females. Background: Non-fatal burns are a leading cause of morbidity, disfigurement, and disability and typically require prolonged hospitalization. The management of acute pain following traumatic burn injury is of immense clinical interest as reports suggest that burn-related pain is currently undertreated. This is partially due to a dramatic increase in pain sensitivity (hyperalgesia and allodynia) and to the accelerated development of tolerance to opioid analgesics commonly seen in severe, traumatic injuries. Furthermore, the chronification of pain following traumatic burn injury is of particular concern, as over half (52%) of all burn survivors develop chronic pain. In a recent study of major thermal burn injuries, 32% of women compared with 5% of men had severe chronic pain one year after injury. This suggests that sex-specific differences influence the development of chronic pain after traumatic injuries.

There are currently few well-developed models to study traumatic burn pain. Like other pain models, assessments used to measure pain are highly inconsistent. As a result, only about 11% of all pain drugs entering Phase 1 clinical trials—after showing efficacy in preclinical animal models—ever achieve FDA approval. Compared with the 20% overall success rate of non-cancer therapeutics, the FDA has cited the lack of translatable preclinical models to assess pain as a key factor responsible for this dismal success rate. Our research program is aimed to elucidate the mechanisms driving sex-specific processing and modulation of pain following traumatic burn injury. Through the combination of genetic, molecular, and behavioral approaches, our research will address sex-specific immune and neuroendocrine contributors underlying the vast sex-specific differences in pain perception.

Results and Significance: We are in the early stages of model characterization and have thus far begun to investigate sex-specific differences in the onset and duration of hyperalgesia and allodynia in relation to changes in gait as measured by CatWalk XT (Noldus) following traumatic burn injury. Our long-term goal is to better understand pain generated from traumatic burn injuries so that we may better understand how to treat it. Substantial evidence suggests that the underlying mechanisms differ based on sex, yet the mechanisms for this are currently unknown. Successful completion of the proposed work will lead to a well-characterized model to study burn pain and selection of the most robust pain assessments to use in future research.

Poster 16

Adolescent Alcohol Exposure Augments Mechanical Allodynia and Alters the Excitatory to Inhibitory Balance in Nociceptive Circuitry of the Prelimbic Cortex 

J. Daniel Obray, Erik T. Wilkes, and L. Judson Chandle

Objective: To determine whether changes in pain sensitivity following adolescent intermittent ethanol (AIE) exposure are accompanied by altered neuronal plasticity at neurons in the prelimbic (PrL) cortex that receive input from the basolateral amygdala (BLA) and to determine whether further changes occur following a pain challenge in adulthood. 

Specific Aims:  

Aim 1: Determine if AIE exposure promotes BLA mediated feed-forward inhibition of PrL pyramidal neurons that project to the ventrolateral periaqueductal gray (vlPAG) following a pain challenge in adulthood.  

Background: Alcohol use disorder and pain are often comorbid. Studies from adult preclinical rodent models indicate that this relationship may be bidirectional, with chronic pain enhancing ethanol consumption and chronic alcohol consumption and withdrawal driving hyperalgesia. Similarly, following AIE, pain sensitivity is enhanced into adulthood. Currently, the changes in neural circuitry underlying hyperalgesia following AIE are poorly understood. We have previously demonstrated that the PrL cortex is vulnerable to insults arising from AIE exposure. The PrL cortex plays an important role in modulating descending pain pathways with a key subpopulation of PrL neurons projecting to the vlPAG (PrL^PAG). These neurons may either facilitate or inhibit nociception based on the subpopulation of vlPAG neurons they activate. Neurons projecting from the BLA to the PrL cortex drive robust feedforward inhibition of PrL^PAG neurons. This feedforward inhibition is mediated by activation of PrL parvalbumin (fast-spiking) interneurons (PVINs). We chose to investigate whether AIE exposure in conjunction with a pain challenge in adulthood would alter plasticity at synapses between BLA neurons and PrL PVIN and PrL^PAG neurons.  

Methods: Parvalbumin-Cre rats underwent ethanol vapor exposure beginning at PD 28 and continuing until PD 54. Sensitivity to both mechanical and thermal stimuli was assessed weekly from PD 24 to PD 80. Rats then underwent surgery and received viral infusions to drive expression of channelrhodopsin in BLA neurons, to tag PVINs in the PrL with mCherry, and to label PrL^PAG neurons with green retrobeads. After recovering, rats underwent a pain challenge consisting of an intraplantar injection of either saline or carrageenan. Brains were extracted 24 hours after the intraplantar injection for slice electrophysiology. 

Results: To date, we have found that AIE exposure enhances mechanical allodynia in both male and female rats. Following AIE, the ratio of light-evoked excitatory/inhibitory (oE/I) neurotransmission at PrL PVINs is decreased while at PrL^PAGneurons the oE/I ratio is enhanced. AIE did not significantly alter the light-evoked AMPA/NMDA (oAMPA/NMDA) ratio at PVINs or PrL^PAGneurons. The carrageenan pain challenge enhanced pain sensitivity in all rats, with no differential effects based on sex or AIE-exposure. In female rats, the carrageenan pain challenge enhanced the oE/I and oAMPA/NMDA ratios at PVINs while in male rats, the carrageenan pain challenge enhanced the oAMPA/NMDA ratio at PrL^PAGneurons. 

Significance: Enhanced mechanical allodynia following AIE exposure may contribute to an increased risk of developing an alcohol use or opioid use disorder in adulthood. Further, by understanding how adolescent alcohol use changes nociceptive circuits in the prefrontal cortex, targeted treatments may be developed to help alleviate heightened pain sensitivity.    

Poster 17 

Understanding Pain Mechanisms in Carpometacarpal Osteoarthritis: A Comparison of Early- and End-Stage Disease Severity

Tamara Ordonez Diaz, Yenisel Cruz-Almeida, Terrie Vasilopoulos, Thomas W. Wright, Jennifer A. Nichols

Carpometacarpal osteoarthritis (CMC OA) affects 85% of postmenopausal women and is a challenging disease to treat due to the complex interplay between pain, disease severity, and physical function. Despite the significant burden of this condition, effective treatments and consensus on selecting a treatment are lacking. This study aimed to understand alterations in pain mechanisms and how they relate to disease severity in patients with CMC OA.  

We recruited 15 women with end-stage CMC OA (Eaton-Littler of III or IV) [age 68.1 ± 10.4 years] and 16 women with early-stage CMC OA (Eaton-Littler of I or II) [59.9 ± 11.2 years]. Disease severity was classified from radiographs using the Eaton-Littler scale. Self-reported physical and psychological function measures were collected. The participants also underwent quantitative sensory testing (QST) at seven body sites. T-tests and chi-square statistics were performed for the demographic and clinical variables.  Linear mixed models to control for the within-subject nature of the assessments across multiple body sites were performed on the experimental pain variables.  

The results showed that participants with end-stage CMC OA had significantly higher self reported pain (p=0.01) and physical functional disability (p=0.01) than those with early-stage OA. Pain detect scores were also higher in participants with end-stage OA (p=0.05), but both groups scored below the threshold for the presence of a neuropathic pain component. Somatosensory differences were also observed across thermal and mechanical stimuli. Specifically, site differences were found for the vibratory detection threshold (p<0.01), cold pain threshold (p<0.01), and cold pain rating (p=0.01). Although cohort differences were not always significant, our findings still suggest that end-stage OA participants experience a more substantial decline in these thresholds. Age and interactions with age were also significant for all stimuli apart from the heat assessments. These results highlight that distinguishing between changes attributed to aging versus those related to OA is essential.  

Overall, the findings suggest that women with end-stage CMC OA display a loss of sensory function compared to women with early-stage CMC OA. These somatosensory alterations in the affected sites likely reflect changes in the peripheral nervous system. However, limitations of this study include the small sample size and the lack of inclusion of healthy age-matched controls. Future studies with larger sample sizes and more comprehensive testing methods may provide further insights into the central differences in pain mechanisms in patients with CMC OA. Nonetheless, this is the first study to perform a comprehensive QST assessment in participants with CMC OA prior to surgical treatment. These results highlight the importance of developing a multimodal approach to treating CMC OA by incorporating both somatosensory and psychological assessments. The differences illustrated in this study have the potential to provide the baseline needed for the development of improved treatment options.

Poster18 

Investigating the role of mu-opioid receptors in the sensory and affective symptoms of neuropathic pain 

E. A. PEKARSKAYA, R. A. SERAFINI, J. G. SOARES, F. HOUGH, S. KALACHIKOV, V. ZACHARIOU, J. A. JAVITCH

Objective: To investigate the possibility that mu-opioid receptor (MOR) dysregulation underlies neuropathic pain (NP) symptoms and assess whether the atypical antidepressant and MOR agonist tianeptine (TIA) is effective at reverting behavioral and neurobiological changes induced by NP. 

Specific Aims: 

Aim 1. Assess the efficacy of TIA in the treatment of sensory and affective behavioral changes induced by NP

Aim 2. Investigate molecular and transcriptional changes caused by NP and following treatment with TIA

Background: NP is characterized by increased pain sensitivity and is frequently associated with affective symptoms. First-line treatments include tricyclic antidepressants that target monoamines such as dopamine, serotonin, and norepinephrine. However, many patients experience unpleasant side effects and/or do not respond to these medications, indicating a need for novel therapeutics. An alternative target is the MOR, well known for regulating both perception of pain and the reward pathway. The atypical antidepressant TIA is an efficacious MOR agonist whose antidepressant effects are MOR-dependent. It also lacks many side effects typically observed with opioid analgesics, such as tolerance, physical dependence, and withdrawal, making it a promising option for both the painful and mood-related symptoms of chronic pain. However, how and where TIA acts to alleviate behavioral changes is unclear. 

One candidate region is the habenula (Hb), a brain area that is dysregulated in NP and which has the densest MOR expression in the brain. Under chronic pain conditions, MOR expression/function is blunted in multiple other brain regions, though expression in the Hb has yet to be investigated. We propose that MOR expression/function decreases in the Hb during NP, and as a short-acting MOR agonist, tianeptine alleviates the sensory and affective symptoms of NP by stimulating the remaining MORs and reverting the transcriptional effects of NP.

Methods and Results: C57BL/6J mice underwent sham or tibial-sparing SNI surgery. Ten weeks after surgery, animals were administered vehicle saline or tianeptine (2x/day, i.p, two weeks) before behavioral testing. Chronic TIA alleviated allodynia in the Von Frey without causing generalized analgesia in the hot plate. TIA also ameliorated several emotional manifestations of chronic pain, as measured by marble burying (OCD/anxiety-like), open field (anxiety-like), and novelty-suppressed feeding (depression-like). We are using brain tissue from these animals to investigate the molecular and transcriptional changes induced by NP. We are performing single probe proximity ligation assays to quantify habenular MOR expression. Bulk sequencing of the NAc, a region downstream of the Hb, shows that TIA reverses transcriptional changes induced by SNI. We will complete single-nucleus RNA sequencing of the Hb to identify which signaling pathways are essential for TIA treatment, both during chronic pain and following treatment with tianeptine.  

Significance: Decreased MOR availability has been implicated in the pathophysiology of chronic pain, and novel treatments are needed. We demonstrate that TIA functions as an efficacious treatment option for both the sensory and affective symptoms of NP. This work also contributes to the limited but growing knowledge of MORs in the Hb during chronic pain, providing a basis for improved pharmacological interventions. 

Poster 19 

Elucidating the role of RUNX1 in human pain perception 

Haley Prakke, Nwamaka Ijeh, Hayley Owens, Miroslav Backonja, Michael Iadarola, Andrew Mannes, Eleni Frangos

 Background: Runt-related transcription factor 1 (RUNX1) controls the expression of specific nociceptors in somatosensory neurons. In animals, a complete knockout of the RUNX1 gene results in a profound loss of thermal nociception while mechanical nociception remains intact. While a complete deletion of RUNX1 in humans is neonatal lethal, mutations do exist and clinically manifest as easy bruising, bleeding, infections, and blood-related malignancies. Although the clinical manifestations of RUNX1 mutations can produce pain, it remains unclear whether mutations in the RUNX1 gene, in humans, disrupt nociception. Thus, the purpose of this study is to phenotype patients with RUNX1 mutations to elucidate its role in human pain perception.       

Methods: Seven patients with heterozygous mutations in the RUNX1 gene were recruited along with 19 healthy age-matched controls (RUNX1 40.7 + 12.2, HC 40.2 + 10.1; p = 0.92). The Brief Pain Inventory and painDETECT were administered to assess potential clinically-pain. A series of thermal (hot and cold) thresholds were performed on the ventral forearm, and pressure and pinprick thresholds were performed on the thumbnail and thenar, respectively. The analyses were conducted using non-parametric two-tailed unpaired t-tests with a significance level of p < 0.05.      

Results: Although RUNX1 patients had significantly greater pain severity and interference compared to HCs, their average pain was relatively low (1.86/10; 0 = no pain, 10 = pain as bad as you can imagine). No group differences were found in mechanical pain thresholds (pressure [kg/cm²]: RUNX1 5.12 + 3.84, HC 6.86 + 0.53; p = 0.31; pinprick [nM]: RUNX1 331.9 + 68.1, HC 358.7 + 41.0; p = 0.59) or pain tolerance (pressure tolerance [kg/cm²]: RUNX1 7.02+3.19, HC 8.54 + 7.02; p = 0.33). Detection of cool sensations were comparable between groups (RUNX1 28.1°C + 1.17°C, HC 29.2°C + 0.40°C; p = 0.44). However, RUNX1 patients (37.7°C + 0.50°C) had higher warm detection thresholds compared to controls (34.7°C + 0.29°C; p < 0.001). No group differences were found in cold pain thresholds (RUNX1 9.87°C + 3.30°C, HC 10.8°C + 1.83°C; p = 0.98) or heat pain thresholds (RUNX1 43.2°C + 0.62°C, HC 43.8°C + 0.71°C; p = 0.73). Lastly, no group differences were found in cold pain tolerance (RUNX1 0.58°C + 0.58°C, HC 0.79°C + 0.39°C; p = 0.83) or heat pain tolerance (RUNX1 48.8°C + 0.68°C, HC 48.2°C + 0.36°C; p = 0.40)      

Conclusion: The present findings indicate that RUNX1 patients experience more clinically related pain compared to HCs, likely due to the clinical manifestations of the RUNX1 mutation, but the severity is low and not neuropathic in nature. Furthermore, heterozygous mutations in the RUNX1 gene in humans do not interfere with nociceptive responses, but instead, decrease warmth discrimination, which suggests these mutations may have subtle downstream effects on thermoreceptors specific to warmth.  

Poster 20 

Variability of arginine vasopressin and associations with stress and pain in patients living with sickle cell disease 

Keesha Powell-Roach  

Background - In patients with sickle cell disease (SCD), pain results in an amalgam of negative physical, emotional, and financial consequences such as stress, suffering, frequent emergency room visits, long hospital stays, and work and academic absenteeism. Although SCD was first recognized over 100 years ago, progress in therapies has lagged significantly, with pain continuing to be the hallmark symptom for over 100,000 Americans living with SCD. A significant barrier to adequately address the pain of SCD is the insufficient information about underlying mechanisms affecting the variable degree and types of pain experienced by patients. In fact, the multiple biological and psychological factors (i.e., environmental stress) known so far to contribute to other pain conditions are under-studied in SCD. A growing body of evidence now supports the interaction of genetics and stress in influencing pain. Given the limitations of prior research, our proposal is based on the scientific premise that identification of genetic contributions to pain phenotypes, and their interactions with psychological variables, will result in greater understanding of SCD pain, which may lead to improved medical management. Vasopressin is a hormone that acts on the kidneys for an anti-diuretic function, and affects vasodilation. The arginine vasopressin receptor 1A is a 7-transmembrane domain G-protein polypeptide that is involved in stress and pain. The rs10877969 SNP in the receptor gene promoter (AVPR1A) is associated with aspects of acute pain and stress-related pain. Psychosocial factors have also been well-established in affecting other pain phenotypes, including via interactions with biological variables.  

Specific aim(s) - This work involves recruiting and characterizing a cohort of 50 adults with SCD to study biological effectors of the vasopressin system for mechanistic insight. We will explore the variability in arginine vasopressin (surrogate copeptin) plasma concentration and associations with pain and stress.  

Objective –In the cross-sectional study of 50 adults living with SCD (mean age, 39.78 (±8.45), the goal of this study is to characterize environmental stress-related pain in SCD studying clinical and experimental pain. 

Results and Significance – Data analysis in progress. 

 

Poster 21

Mast cell contribution to pelvic tactile allodynia and sensitization of the parabrachial nucleus in a non-invasive murine model of endometriosis  

Roman K, Acharya S, Prasoon P, Taylor B 

Objective: To test the hypothesis that mast cell (MC) activity in lesions drive pelvic tactile allodynia sensitization of the parabrachial nucleus (PBN) in a mouse model of endometriosis (EM).  

Specific aims(s): 1) Investigate whether MC activity contributes to pelvic tactile allodynia in EM mice and 2) assess whether noxious stimulation to the pelvic region is associated with neuronal sensitization in the PBN.  

Background: Endometriosis (EM) impacts approximately 10% of women globally (Zondervan et al., 2020). Although human EM lesions are infiltrated with mast cells (MCs) (Matsuzaki, 1998) and noxious colorectal stimulation increases neuronal activity in the parabrachial nucleus (PBN) (Dunckley, 2005), it is unclear how MCs and the PBN contribute to EM-CPP. Here, we characterized pelvic tactile allodynia in a new non-invasive mouse model of EM (Fattori et al., 2020). 

Methods: C57BL/6J (B6) donor mice (6-weeks old) received a subcutaneous injection of estradiol benzoate (EB; 10µg) and 4 days later each uterine horn was excised, placed in Hank’s Balanced Salt Solution (HBSS), and minced. Recipient mice received an intraperitoneal injection of either HBSS (500µl; “Shams” or HBSS+minced uterine horn (500µl; “EM mice”) extracted from donors. To assess pelvic tactile allodynia in EM mice, von Frey (vF) was conducted before (baseline) and 7, 14, 21, and 28 days after tissue injection. We then administered the MC stabilizer ketotifen (Keto; 4.5mg/kg) or 0.9% saline on day 28 and vF thresholds were assessed at 3, 9, 18, and 36 hrs. In a separate experiment, to determine whether EM sensitized the PBN to pelvic stimulation, the PBN from Shams and EM mice was intracranially injected with an AAV9-GCamp6s cre-independent virus and implanted with a fiber photometry probe on day 14. We recorded changes to neuronal activity in vivo after repeated application of the 6g vF filament to the pelvic region on day 28.  

Results: 1) In Sham mice, neither saline (n=6) nor Keto (n=7) changed mechanical thresholds at any timepoint. In EM mice, Keto (n=8) but not saline (n=7) reversed hypersensitivity at the 9, 18, and 36 hr. timepoints (p<0.05). 2) Stimulus-evoked neuronal activity in the PBN was greater in EM mice as compared to Sham mice (p<0.05).  

Significance: MC stabilizers may serve as effective therapeutics to treat EM-CPP. Parabrachial mechanisms may serve an important role in the development of pelvic tactile allodynia in EM mice.  

Poster 22 

How pain begins: Intraoperative sampling from long duration human surgical procedures  

Matthew R. Sapio, Anthony F. Domenichiello, Alison Manalo, Taichi Goto, Dragan Maric, Tracy S. Williams, David S. Schrump, Jeremy L. Davis, Andrew M. Blakely, Michael J. Iadarola, Andrew J. Mannes 

Objective. The overall goal of this study is to understand the molecular alterations that occur in response to surgery by analyzing transcriptional alterations at the wound edge.  

Specific aims. 1) To establish foundational data for incision-induced early responses to injury in human skin. 2) To understand the molecular basis of acute and sustained transcriptional alterations at the wound edge using RNA-Seq. 3) To use these data to understand the first transduction events in signaling tissue damage and pain.  

Background. This presentation is based on a clinical trial registered at ClinicalTrials.gov (A single cohort study collecting interval timed incisional epidermal and dermal tissue samples during surgical procedures to profile temporal response of tissue after noxious stimuli. NCT04224870). In total, 12 patients (5M, 7F) were enrolled in the study.  The subjects were predominantly white (10/12) with one black and one other ethnicity reported. Inside the operating room, skin samples were excised by the surgeon at the incisional edge placed in abdominal skin. Care was taken to avoid regions of skin compressed by retractors or damaged by other surgical manipulations outside the initial incision. Samples were collected in a longitudinally during the course of the surgery, with the first sample being taken at the time of the initial incision (time zero) and subsequent samples at 1 hour, 2 hours, 4 hours, and 6 hours. If the surgery lasted 8 hours or longer, a sample was taken at closure. The longest time point was at 12 hrs, 44 minutes after incision. Biopsy samples spanned the epidermis and dermis, but excluded subcutaneous adipose tissue.  

Results and Significance. Using RNA-Seq we processed data from each time point and each patient in the study. We found little overall variation between subjects, and determined that the major source of variation was the effect of injury on gene expression. Accordingly, most genes continually increased or continually decreased over time after the initial inicision. This is consistent with the wound being remaining unapproximated during the surgical procedure likely reflecting continual trauma as the wound does not have the opportunity to complete healing and repair processes. We hypothesized that the major gene transcription events are related to the initiation of wound healing, immune cell recruitment and transduction of inflammatory and pain signaling cytokines. We found that the most significant genes induced by this paradigm were cytokine signaling pathways including those for interleukins and the pleiotropic cytokine oncostatin M. Additionally, several genes were strongly induced related to innate immune activation, the initiation of wound healing, and several other functions. In aggregate this paradigm strongly induces many interrelated pathways, and induced genes that likely participate in overlapping functions simultaneously. Finally, to examine the initiation of nociception, we looked for strongly induced secreted proteins for which a receptor is expressed on dorsal root ganglion neurons. This tissue-to-nerve communication likely participates in molecular communication between damaged tissue and sensory neurons in humans. 

Poster 23 

Influence of Parental Beliefs Regarding Opioid Analgesic Use on Children’s Pain Management

Amanda L. Stone, Elias Mihan, Stephen Bruehl

Objective: To improve understanding of parent factors that may influence in-home postoperative pain management decisions regarding opioid analgesics for management of children’s pain.

Background: Ambulatory surgical procedures in children have risen to ≈2.3 million yearly with two-thirds of children reporting significant pain for 2-3 days post-surgery and 1 in 5 children experiencing pain for 1-2 weeks. Inadequate management of children’s postoperative pain can have significant consequences including reduced quality of life, respiratory issues, dehydration, and nausea that can increase health care costs due to emergency department visits, provider phone calls, and readmissions. In contrast, overuse of opioid analgesics for children’s postoperative pain management can lead to greater respiratory depression and other adverse opioid side effects. At present, limited evidence is available regarding what factors contribute to appropriate versus inappropriate outpatient management of children’s postoperative pain, and concern regarding the appropriate use of opioid analgesics is increasing. Parents’ decisions to administer analgesics are likely influenced by both their own characteristics and their perception of their child’s pain and distress.

Specific aim(s): Aim 1. Develop a measure of parental beliefs regarding opioid analgesics for children’s pain management. Aim 2. Evaluate the relation of parental beliefs regarding opioid analgesics for children’s pain management to parental psychological factors and decision making regarding opioid analgesic use.

Results and Significance: The Beliefs about Opioids for Pediatric Pain (BOPP) measure was administered to a sample of parents (n = 319) recruited through ResearchMatch to evaluate the psychometric properties of 18 proposed items. Through examination of item response distributions and factor analysis, 6-items performed the best and clearly clustered into two subscales: (1) Positive Opioid Beliefs (e.g., “opioid pain medication can be very helpful”) and (2) Parent Worry about Opioid Decisions (e.g., “it would be hard to decide whether or not my child should receive opioid pain medication following surgery”). Both subscales demonstrated acceptable internal consistency > α = 0.8 and had minimal overlap (r = -.17). The Positive Opioid Belief subscale was significantly associated with higher parental lifetime opioid exposure, depression, catastrophizing about children’s pain, and child opioid exposure. The Parent Worry about Opioid Decisions subscale was significantly associated with lower parental opioid exposure, higher catastrophizing about children’s pain, lower child opioid exposure, and younger parent and child age. In a preliminary evaluation of predictive validity in the 7-days following tonsillectomy surgery using electronic diaries (n = 36), the Positive Opioid Belief subscale predicted more adminstrations of opioid analgesics while the Opioid Worry subscale predicted higher parental stress at the time of opioid administration. Better understanding of potentially modifiable parent factors that influence opioid administration for children’s pain in the home context can help inform interventions to enhance pediatric pain management.

Poster 24 

Divergent changes in PBN excitability in a mouse model of neuropathic pain

María L Torruella-Suárez, Benjamin Neugebauer, Krystal Flores-Felix, Asaf Keller, Yarimar Carrasquillo, Nathan Cramer

The parabrachial nucleus (PBN) is an important sensory processing and relay station for pain neurotransmission. Data from in vivo and histological studies have shown that PBN neurons are largely responsive to noxious stimuli and become hyperexcitable following injury. These phenotypes are hypothesized to underlie changes in affect and sensory thresholds that can be observed in animals following injury. Our work finds that this PBN hyperexcitability is preserved in ex vivo brain slice preparations using the cuff model of neuropathic pain. Recording from PBN neurons ipsilateral to the cuff 7 to 11 days after surgery, we find a significant injury-induced increase in spontaneously-firing neurons in male mice. When we examined the firing types of PBN neurons, we observed regular-spiking (RS), late-firing, and reluctant populations. Within the spontaneously-firing RS population, evoked firing was increased after injury. In non-spontaneous neurons, however, injury decreased the evoked firing of RS neurons, demonstrating that injury does not increase PBN activity in all neurons. Distinct PBN outputs have been linked to specific aspects of the nocifensive response, and the projection from the PBN to the central amygdala has been shown to be potentiated following injury. When we examined central amygdala-projecting PBN neurons, we did not observe changes in excitability following injury, demonstrating that the hyperactive PBN population can be partly defined through projection targets. Ex vivo slice electrophysiology allows for the examination of intrinsic and synaptic properties that may underlie these injury-induced changes in the PBN. By showing that PBN hyperactivity and hyperresponsivity is preserved ex vivo, our work demonstrates that this kind of mechanistic examination is feasible. Future experiments will aim to identify PBN populations vulnerable to injury-induced hyperexcitability and use pharmacological strategies to identify the mechanism underlying this injury-induced plasticity.

Poster 25 

Molecular sensors and tools for studying opioid signaling

Kayla Kroning, Noam Gannot, Jiaqi Shen, Lequn Geng, Peng Li, Wenjing Wang

Opioid signaling plays a critical role in various physiological processes, including pain modulation, reward and respiration suppression. Therefore, opioids remain the most effective pain medications, but also suffer from severe side effects. There is an urgent need for a better understanding of the opioid signaling, such as the regulation of endogenous opioid peptides and the function of the mu-opioid receptor (MOR) in different neuronal populations. The overall objective is to design molecular sensors and tools for studying opioid signaling. The specific aims include: 1) To design opioid sensors for mapping opioids across the brain with high spatial resolution, and 2) to design genetically-encoded chemical-activatable opioid peptides to manipulate endogenous opioid receptor activity in selective neuronal populations.

We have designed a single-chain fluorescent integrator for opioids that can detect MOR agonists and generate an irreversible fluorescent signal. This opioid integrator is selective for MOR agonists, including synthetic opioids and endorphins. It will enable whole-brain mapping of synthetic opioids to study their bioavailability in the brain and endogenous opioid peptides to study endogenous opioid peptide regulation at cellular resolution. We have also designed a genetically-encoded chemical-activatable opioid peptide that shows higher activity in activating MOR upon addition of the chemical ligand, shield-1. This new tool can be genetically introduced to selective neuronal populations to activate opioid receptors selectively to readout their effects in pain modulation and addiction. Overall, these new classes of opioid sensors and tools will enable unprecedented study of the opioid signaling to uncover opioid signaling’s role in pain and addiction.

Poster 26

Nonpharmacologic approaches to recovery from chemotherapy-induced deficits: preliminary evidence for the effect of partnered dance

Lise Worthen-Chaudhari, Patrick Schnell, Jewel Crasta, Karen Hock, Jacqueline Wilder, Kristen Lantis, Courtney Bland, Joseph Martis, Madeleine Hackney, Maryam Lustberg

Objective: To investigate partnered, Adapted Argentine Tango dance (Tango) as a non-pharmacologic solution for chemotherapy-induced neuropathy (CIN) symptoms.

Specific Aim: To evaluate the effect of Tango training among breast cancer survivors (> 40 years) with CIN and measurable postural control deficits[1,2] (n=16). To accomplish this aim, Tango was offered 2x per week (wk) for 8wks. A minimum dose of 10 minutes of movement-to-music was delivered per session. We assessed treatment effect in terms of patient-reported outcomes (PROs), biomechanical measures of postural control, and clinical measures of function. Specifically, we assessed the PRO EORTC CIPN-20 total score; the resultant variability (RMSr) and sample entropy calculated using the increment method (complexity) of center of pressure (COP) during 30 seconds of bilateral quiet standing with eyes-closed (QEC); the Timed-up-and-Go (TUG); and the TUG performed with a cognitively challenging dual task (TUGCog).

Exploratory Aim: To investigate the effect of listening to music on central and behavioral mechanisms, in concert. To achieve this aim, we explored how listening to music during a challenging balance task (QEC) affected central activity (EEG (gamma band); n=2) in addition to postural control (n=12) among participants who had completed the Tango intervention.

Background: Up to 80% of breast cancer (BC) survivors treated with chemotherapy experience a high rate of neurotoxic symptoms such as chemotherapy-induced neuropathy (CIN)[3]. These debilitating symptoms affect multiple domains of health – sensorimotor, cognitive, psychosocial, emotional – with limited management options[4]. Despite high symptom burden, a dearth of evidence has left BC survivors with insufficient CIN care and persistent functional deficits that impede quality of life across the survivor’s lifespan. A critical need exists to identify interventions capable of relieving this symptom burden. Ideally, interventions would be enjoyable, non-pharmacologic, and holistic. Our preliminary data indicate that partnered, Adapted Argentine Tango dance (Tango) is one such intervention[5–9]. In substantiation of these preliminary results, we present interim results from our ongoing randomized controlled study on the topic (R21-AG068831; NCT05114005).

 Results: Sixteen BC survivors enrolled (age 60.3(9.8) years) and twelve completed the intervention by the time of this submission. Aim1: Intervention effects were detected for PROs, postural control, and function after 4 and/or 8wks of Tango training and retained at 1-month follow up (Table1). Exploratory Aim: After completing Tango training, listening to music during performance of a challenging balance task improved neuromotor stability while reducing central gamma activity (Table2).

Significance: CIN-related deficits improved with Tango training. Tango-trained survivors demonstrated improved neuromotor control and reduced gamma activity during performance of the QEC challenging balance task when listening to Tango music versus performing the same challenging balancing task in silence (Table 2). Further study is required to investigate the potential for dance training and music listening to relieve CIN- related deficits, including chronic pain, among older survivors.