ABSTRACT:Our study examined the relationship between insomnia and the pace of biological aging in persons with HIV (PWH). We used Dunedin Pace of Aging from the Epigenome (DunedinPACE) to determine pace of biological aging in adults, ages 18 to 85 years: 34 without HIV or insomnia, 13 without HIV but with insomnia, 22 with HIV but no insomnia, and 38 with HIV and insomnia. Findings revealed that irrespective of insomnia status, PWH had a greater acceleration of biological aging (DunedinPACE) compared with those without HIV. PWH with insomnia demonstrated many of the highest values for DunedinPACE. This suggests that sleep disruption may act as an additional mechanism compounding immune aging and chronic inflammation already associated with HIV, such that PWH who also experience insomnia face a cumulative burden of risk factors that together drive a faster pace of biological aging.

Nonspecific chronic low back pain (NSCLBP) is associated with central sensitization, and both diet quality and epigenetic aging are proposed modifiable, mechanistic contributors to this process. We examined how dietary profiles and epigenetic aging affect central sensitization in NSCLBP. Participants completed dietary, epigenetic aging (DunedinPACE, GrimAge), and central sensitization indicators, including conditioned pain modulation (CPM), heat and mechanical temporal summation (TS), and pain sensitivity questionnaire (PSQ). Dietary profiles were derived from latent profile analysis of dietary inflammatory index components. Nested regression models examined how dietary profiles and epigenetic aging predict central sensitization, adjusting for age, sex, BMI, and race, followed by Benjamini-Hochberg’s false discovery rate correction. We included 200 adults with NSCLBP: mean age 44 years; 62% African American; 55% female; mean BMI 31.33 kg/m². Five tests remained significant after Benjamini-Hochberg correction. DunedinPACE acceleration increased PSQ (β = 2.936, raw p = .034, FDR p = .034), GrimAge acceleration decreased mechanical TS (β = -0.270, raw p = .008, FDR p = .016). Increased low pro-inflammatory diet increased CPM only after accounting for DunedinPACE (β = 49.788, SE = 15.433, raw p = .002, FDR p = .013) and GrimAge (β = 52.685, SE = 15.281, raw p = .001, FDR p = .013). Increased low pro-inflammatory diet decreased heat TS facilitation in the GrimAge-adjusted model (β = -22.028, SE = 8.270, raw p = .009, FDR p = .049). Diet and epigenetic aging jointly, rather than independently, shape central pain processing in NSCLBP, suggesting protective effects of healthier diets.

Prior research has established a bidirectional relationship between sleep and pain, yet this relationship remains understudied in people living with HIV (PLWH). The current cross-sectional study examined differences in sleep quality, experimental pain sensitivity using quantitative sensory testing (QST), and clinical pain severity by HIV and insomnia status. Participants included people with and without HIV as well as those with and without insomnia according to a structured clinical interview for diagnosing sleep disorders based on the DSM-5 guidelines. Participants were grouped based on the presence or absence of HIV (H+/H-) and insomnia (I+/I-) as follows: H-/I- (n=46), H-/I+ (n=37), H+/I- (n=14), and H+/I+ (n=39) (N=136). For subjective and objective sleep assessment, participants completed the Insomnia Severity Index, the RU-SATED, Dysfunctional Beliefs and Attitudes about Sleep, and actigraphy. Participants subsequently completed a standardized QST battery and reported the severity of bodily pain experienced over the past seven days. The H+/I+ group had the absolute worst quality of sleep on all subjective and objective measures. Further, the H+/I+ group demonstrated the greatest endogenous pain facilitation to cold and pressure stimuli and the least endogenous inhibition of pain via conditioned pain modulation. A greater proportion of participants in the H+/I+ group reported experiencing “severe” or “very severe” bodily pain over the past seven days compared to all other groups. Greater clinical pain severity was associated with poorer subjective and objective sleep. Future research should investigate whether behavioral treatments for insomnia also improve pain outcomes among PLWH to inform targeted and accessible interventions. Perspective This study explores the relationship between sleep disturbance and pain sensitivity across HIV and insomnia status. This work highlights the potential additive impact of HIV and insomnia on sleep and pain, which may be used to create accessible future behavioral treatments within this population. Trial Registration This study used data collected as part of the parent trial entitled “The Impact of Insomnia on Pain in HIV” (ClinicalTrials.gov ID: NCT04298658).

This secondary data analysis aimed to determine the nature of the relationship between obstructive sleep apnea (OSA) risk, biological age acceleration, and nonspecific chronic low back pain (CLBP). In total, 199 adults aged 18-82 years who filled both STOPBANG and pain questionnaires subsetted for secondary analysis. Based on the STOPBANG questionnaire, 104 had a low OSA risk and 95 had an intermediate or high OSA risk. Dunedin Pace of Aging Computed from the Epigenome (DunedinPACE), Horvath's, Hannum's, PhenoAge, and GrimAge clocks were used to determine biological age and pace of biological aging. Individuals with low OSA risk reported increased DunedinPACE compared to those with intermediate/high OSA risk (p < 0.001). There was a significant correlation between the risk for OSA and biological age acceleration measured by PhenoAge as well as pace of biological aging (p < 0.05). Mediation analysis detected indirect effects of OSA risk on chronic pain outcomes through the pace of biological aging. Targeted interventions addressing OSA risk offers a promising therapeutic strategy. This could be particularly valuable for aging populations where both accelerated biological aging and chronic pain conditions are prevalent, offering a more holistic approach to improving nonspecific chronic pain outcomes through quality of sleep and restfulness.

This cross-sectional study examined whether individualized racism, as measured by experiences of discrimination, internalized stigma of chronic pain, and perceived injustice, as well as structural racism, as measured by the Area Deprivation Index (ADI), mediates racial disparities in nonspecific chronic low back pain (CLBP) outcomes among non-Hispanic Blacks (NHBs) and non-Hispanic Whites (NHWs). 258 adults completed questionnaires assessing pain severity, pain interference, discrimination, internalized stigma, and perceived injustice. The mean pain severity and pain interference scores were 61.59 (SD = 19.98) and 47.46 (SD = 29.17), respectively. Serial mediation analysis, adjusting for age and sex, revealed that discrimination and internalized stigma mediated the association of race with pain severity and interference, with significant indirect effects: β = -1.357, 95% CI [ -2.557, -0.367] and β = -2.576, 95% CI [ -4.657, -0.721], respectively. Serial mediation analysis also revealed that discrimination and perceived injustice mediated the association of race with pain severity and pain interference, with significant indirect effects: β = -1.519, 95% CI [ -2.932, -0.400] and β = -2.804, 95% CI [ -5.330, -0.809], respectively. ADI also significantly mediated the indirect effects of race on pain severity (β = -3.138, 95% CI [-5.646, -0.962]) and pain interference (β = -4.238, 95% CI [-8.123, -1.067]). Thus, racial disparities in CLBP severity and interference may be explained by multilevel mechanisms: an individual's race is linked to discrimination, which predicts internalized stigma and perceived injustice; these factors, in turn, predict CLBP outcomes; and race also correlates with ADI, which in turn correlates with CLBP outcomes. PERSPECTIVES: Racial pain disparities are well documented. These findings suggest that intrapersonal (internalized stigma of chronic pain), interpersonal (experiences of discrimination and perceived injustice) and structural (neighborhood deprivation) racism-related factors indirectly mediate the relationship between race and chronic low back pain outcomes.

Introduction:Substantial evidence suggests that experiences of discrimination negatively influence sleep, depressive symptoms, stress, and pain. The purpose of this study was to evaluate the strength of the associations between discrimination and pain, and to determine which psychosocial risk factors help explain these associations. Methods:Participants (N = 208) underwent two study sessions, where they completed the Everyday Discrimination Scale, Perceived Stress Scale, Centers for Epidemiological Studies Depression Scale, Insomnia Severity Index, and the Brief Pain Inventory-Short Form. Demographic data was also obtained from participants. Results:Majority of the participants self-identified as women (55.3%), and Black (62%). There were positive associations between discrimination and insomnia (p < .001), depressive symptoms (p < .001), perceived stress (p < .001), pain severity (p < .001) and pain interference (p < .001). Hierarchical regressions showed that identifying as Black (p < .001), having greater depressive symptoms (p = .03), and greater insomnia symptoms (p < .001) were associated with greater pain severity in the past 24 h. Similarly, older age (p = .01), identifying as Black (p = .002), having lower education (p = .04), taking medications (p = .04), greater depressive (p < .001) and insomnia symptoms (p < .001) were associated with greater pain interference. The indirect effect of discrimination on pain severity was significant (β = .015, Bootstrap 95% CI.003-.030). Additionally, there was a significant indirect effect of discrimination on pain interference (β = .015, Bootstrap 95% CI.004-.031). Exploratory models showed an indirect effect of pain severity (β = .014, Bootstrap 95% CI.001-.029) and interference (β = .012, Bootstrap 95% CI.000 to .029) on discrimination via psychosocial risk factors. Discussion:Our findings highlight the harmful associations between discrimination, mental health outcomes, pain severity, and reduced quality of life. Additionally, these findings emphasize the need for more stress engaged research to continue exploring these potential relationships, identify cause-effect and inform the development of future interventions focused on reducing the negative impact of stress on pain outcomes - especially for minority groups who are disproportionately affected by pain disparities.

With the current pressure to reduce opioid usage in the clinical setting, there is a call for the development of adjunct therapies. Although opioids remain the primary analgesic used in the treatment of moderate to severe pain, these drugs come with negative side effects, such as increased potential for abuse. The overlap in expression of opioid and GABA receptors suggests that the 2 systems may interact. Therefore, to investigate this interaction, our study used the GABAB receptor agonist, baclofen, because it has previously been used as a treatment for spasticity and addiction and has demonstrated weak analgesic properties. Our study focused on the interaction between baclofen and opioid analgesics regarding analgesic efficacy and abuse potential. Analgesia was assessed through hot plate testing and reward was assessed through conditioned place preference testing in outbred CD1 mice. These interactions were examined with morphine, methadone, oxycodone, and fentanyl using isobolographic analyses. All opioids tested with baclofen demonstrate synergism in analgesia and no consistent significant interactions in place preference conditioning. Together these data support the use of baclofen coupled with opioids to enhance the analgesia, with no concomitant increase in abuse liability and associated common side effects of opioid drugs. Significance Statement: The combination of the commonly prescribed drug, baclofen, and a variety of opioids exhibits a synergistic analgesic effect allowing for lower doses of opioids to be used for equivalent analgesic effect. Synergistic analgesia was seen without concomitant enhanced tolerance, constipation, or reward, and across species, suggesting a beneficial interaction for pain relief. (c) 2024 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Opioids are potent analgesics often prescribed for the treatment of chronic pain, a condition affecting millions worldwide. Although pain states increase vulnerability to opioid use disorders, the neural mechanisms underlying this interaction remain incompletely understood. The ventral tegmental area (VTA) is a key site for opioid actions, and emerging evidence suggests that pain states and opioid experience both induce transcriptional, molecular, and circuit adaptations in the VTA that contribute to motivated behaviors. However, the transcriptional responses of distinct VTA cell types to each of these factors (alone or in combination) have not been identified. Here, we employed single-nucleus RNA sequencing to comprehensively define transcriptional alterations in the rat VTA to acute morphine administration in a chronic inflammatory pain model. We report that morphine induces gene expression changes primarily in glial cells and dopamine neurons, with minimal effects in other neuronal cell types. Surprisingly, VTA astrocytes and oligodendrocytes exhibited the most robust transcriptional responses to opioid exposure, despite lacking detectable opioid receptor expression. Among the most highly regulated glial genes was Fkbp5, which encodes a co-chaperone protein that acts in concert with heat shock proteins to modulate stress responses. Using pharmacological and CRISPR-based approaches in rat glial cells and human astrocytes, we demonstrate that regulation of Fkbp5 is mediated indirectly through glucocorticoid signaling rather than direct opioid receptor activation. These findings reveal that glial cells within reward circuits undergo profound transcriptional reprogramming in response to opioids through indirect, stress-hormone mediated mechanisms, highlighting a previously unappreciated non-neuronal contribution to opioid-induced neural adaptations.

There is growing evidence that psychological (e.g., optimism, pessimism, depressive symptoms) and biological factors play an essential role in the experience of chronic low back pain (CLBP). This study aimed to examine the nature of the relationship between optimism or pessimism, depressive symptoms, the pace of biological aging, CLBP severity, and interference. Using mediation analysis, we tested the hypothesis that depressive symptoms and pace of biological aging measured using the Dunedin Pace of Aging from the Epigenome (DunedinPACE) serially mediate the relationship between optimism or pessimism and CLBP severity and interference. Our sample included non-Hispanic Black and non-Hispanic White adults aged 18-82 years: 74 without pain, 56 with low-impact pain, and 77 with high-impact pain. On average, individuals with high-impact pain reported lower levels of optimism, greater pessimism, and faster DunedinPACE than those in the low-impact or no-pain group (p < .05). Mediation analyses revealed indirect associations between both optimism and pessimism with pain severity and interference serially via depressive symptoms and the pace of biological aging (p < .05). These indirect effects were not statistically significant after controlling for chronological age, sex, race, and BMI. The results suggest that psychological interventions that increase optimism and reduce pessimism may slow the biological aging process, which may improve nonspecific CLBP outcomes in non-Hispanic Black and non-Hispanic White adults.

Background/Objectives: The purpose of this preclinical pilot study was to explore the potential of green tea extract (GTE) to mitigate and/or prevent oxaliplatin-induced allodynia and axonal damage in rats, when compared to duloxetine (DLX), an ASCO-recommended treatment for established neuropathic pain. Methods: Using a randomized, placebo-controlled experimental design, Sprague Dawley rats (N = 41) received 4 intraperitoneal oxaliplatin (2 mg/kg) injections every other day over 7 days. One week prior to the first oxaliplatin dose, animals began 1 of 4 interventions (saline; GTE 100 mg/kg; DLX 3 mg/kg; GTE 100 mg/kg + DLX 3 mg/kg). A naïve group (n = 6) that received no neurotoxic oxaliplatin or intervention was added to serve as a baseline measure for sNfL. Interventions were administered daily for 4 weeks. Mechanical sensitivity (allodynia) was measured 3 times per week using von Frey testing to determine paw withdrawal thresholds. Von Frey testing began one day prior to the start of interventions to establish baselines and continued through Day 35. Groups were compared to their respective baselines to calculate changes in paw withdrawal thresholds. To measure axonal damage, alterations in serum levels of neurofilament light (sNfL) protein were measured at Day 35 using ELISA. Group differences were identified using two-way analysis of variance (ANOVA). Pearson correlation coefficient was used for correlation analysis between paw withdrawal thresholds and sNfL levels at Day 35. Partial eta-squared and Hedges’ g were used to measure effect sizes. Statistical significance was assigned at P ≤ 0.05 with a 95% confidence interval. Results: Overall, the saline group showed significant reductions in mean paw withdrawal thresholds across experimental timepoints, denoting more severe allodynia caused by oxaliplatin. Conversely, intervention groups exhibited mean paw withdrawal thresholds that were significantly greater than the saline group, indicating less allodynia. The average level of sNfL was also significantly higher in the saline group (113.58 ± 43.84 pg/mL) compared to GTE100 (72.75 ± 26.85), DLX3 (59.93 ± 20.57), and DLX3 + GTE100 (77.04 ± 24.35) intervention groups, suggesting less oxaliplatin-induced axonal damage in these groups. The naïve group exhibited the lowest levels of sNfL (45.69 ± 14.64) when compared to the oxaliplatin-receiving groups (saline and intervention). There were large effect sizes between the saline group, naïve (g = 1.88), GTE100 (g = 1.123), DLX3 (g = 1.157), and DLX3 + GTE100 (g = 1.030) groups. There was also a moderate negative correlation [r(30) = −0.38, p = 0.04] between sNfL levels and paw withdrawal thresholds. Conclusions: The preliminary findings from this pilot study suggest that GTE may be an effective, nutraceutical intervention for mitigating OIPN-associated neuropathic pain, warranting further investigation as an intervention to mitigate chemotherapy-associated neurotoxicities like OIPN.

Neuroinflammation is a major driver of secondary tissue damage after spinal cord injury (SCI). Within minutes after SCI, activated microglia and astrocytes produce proinflammatory mediators such as TNF-α, IL-6, iNOS, and COX-2 which induce tissue injury through cytotoxicity, vascular hyperpermeability, and secondary ischemia. The inflammatory cascade is amplified by chemokines like CCL2 and CXCL1 which recruit immune cells to the injured site. HuR is an RNA regulator that promotes glial expression of many proinflammatory factors by binding to adenylate- and uridylate-rich elements in the 3' untranslated regions of their mRNAs. SRI-42127 is a small molecule which blocks HuR function by preventing its nucleocytoplasmic translocation. This study aimed to evaluate the potential of SRI-42127 to suppress neuroinflammation after SCI and improve functional outcome. Adult female mice underwent a T10 contusion injury and received SRI-42127 1 h post injury for up to 5 days. Locomotor function was assessed by open field testing, balance beam, and rotarod. Immunohistochemistry was used to assess lesion size, neuronal loss, myelin sparing, microglial/astroglial activation, and HuR localization. Inflammatory mediator expression was assessed by qPCR, immunohistochemistry, ELISA, or western blot. We found that SRI-42127 treatment significantly attenuated loss of locomotor function and post-SCI pain. There was a reduction in lesion size and neuronal loss with an increase in myelin sparing. Microglia and astrocytes showed reduced activation and reduced nucleocytoplasmic translocation of HuR. There was a striking suppression of proinflammatory mediators at the epicenter along with peripheral suppression of inflammatory responses in serum, liver, and spleen. In conclusion, HuR inhibition with SRI-42127 may be a viable therapeutic approach for suppressing neuroinflammatory responses after SCI and improving functional outcome.

IntroductionChronic low back pain (cLBP) is a common health condition associated with substantial personal and economic costs. Recent literature suggests that socioeconomic status (SES) and diet quality may influence its impact.MethodsThe purpose of this study was to examine whether SES, measured via the National Area Deprivation Index (NADI), and diet quality, assessed by the dietary inflammatory index (DII), were associated with proinflammatory cytokine levels and movement-evoked pain outcomes in individuals with cLBP. We hypothesized that individuals with cLBP with lower NADI and DII scores would exhibit significantly greater pain and higher levels of inflammatory biomarkers. Participants with cLBP (n = 78) completed questionnaires assessing pain and demographic factors, along with a 24 h food recall. Inflammatory biomarkers were measured from peripheral blood samples collected prior to the completion of the questionnaires.ResultsAnalyses revealed that NADI and DII were associated with a similar profile of inflammatory biomarkers and pain outcomes and that DII varied as a function of NADI.ConclusionsThese findings offer important information for future targeting goals for treating vulnerable populations with cLBP. Future studies are warranted to determine whether the relationships among SES, diet quality, and inflammation extend to other chronic pain conditions.

In this study, we aimed to investigate if the pace of biological aging serves as a critical mediator in the relationship between chronic pain resilience and chronic low back pain intensity and disability. Two hundred seven community-dwelling non-Hispanic Black (NHB) and non-Hispanic White (NHW) adults completed the Pain Resilience Scale (PRS) and Graded Chronic Pain Scale (GCPS). Blood genomic DNA was sequenced using Illumina's MethylationEPIC, and the pace of biological aging estimated using the DunedinPACE (the Dunedin Pace of Aging Calculated from the Epigenome) algorithm. In bivariate correlations, DunedinPACE significantly correlated with pain intensity (r = 0.40), and disability (r = 0.39), at p < .05. Pain resilience negatively correlated with pain intensity (rs = -0.22), pain disability (rs = -0.30), and DunedinPACE (r = -0.11). After controlling for chronological age, sex, race, and BMI, mediation analyses revealed a significant indirect association of pain resilience on pain intensity through the pace of biological aging (β = -0.66 (SE); Boot 95% CI [-1.06, -0.25]). Similarly, DunedinPACE partially mediated the relationship between resilience and pain disability (β = -0.82; 95% CI, [-1.20 to -0.44]). We found that higher levels of resilience correlate with a slower pace of biological aging, which in turn correlates with better pain outcomes. The pace of biological aging emerged as an important potential target for future interventions studies for pain management.

OBJECTIVE:We examined the intersection between chronic pain stigma and racial discrimination, separately among Black and White US adults with chronic low back pain. METHODS:Participants completed measures of chronic pain stigma, lifetime experiences of racial discrimination, pain severity and interference. A composite variable representing the intersectionality of stigma and discrimination was created, and Black and White participants were separately categorized into 4 groups. Black participants were categorized as: (1) high discrimination/high stigma, (2) high discrimination/low stigma, (3) low discrimination/high stigma, and (4) low discrimination/low stigma. White participants were categorized as: (1) any discrimination/high stigma, (2) any discrimination/low stigma, (3) no discrimination/high stigma, and (4) no discrimination/low stigma. RESULTS:Black participants reported more frequent experiences of racial discrimination than White participants (P < .05), but there was not a racial difference in chronic pain stigma (P > .05). Among Black participants, those in the high discrimination/high stigma and low discrimination/high stigma groups reported greater pain severity and interference than those in the high discrimination/low stigma and low discrimination/low stigma groups (P < .05). Among White participants, those in the any discrimination/high stigma group reported greater pain severity and interference than those in the no discrimination/low stigma group (P < .05), but there were no differences in pain severity or interference between the any discrimination/no stigma and no discrimination/high stigma groups (P > .05). CONCLUSION:Our findings suggest that the relationship of intersectional chronic pain stigma and racial discrimination with pain is nuanced and differs across racial groups.