Biology subjects

Morgan, O. B.

Publications and source records attributed to Morgan, O. B..

3 recordsLinked to original sources

bioRxiv2025

Stress, Epigenetic Remodeling and FKBP51: Pathways to Chronic Pain Vulnerability

Stress is thought to contribute to the persistence of pain and comorbid anxiety, yet the underlying mechanisms remain unclear. In our pre-clinical model, sub-chronic stress exacerbated subsequently induced inflammatory pain and accelerated the development of comorbid anxiety. DNA methylation analysis of spinal cord tissue after stress exposure revealed hypomethylation in the Fkbp5 promoter site for the canonical FKBP51 transcript and other stress-related genes. However, most epigenetic changes in key regulatory regions did not correlate with changes in gene expression assessed by RNA sequencing, suggesting that stress exposure had remodeled the epigenome without altering gene activity and primed genes for hyper-responsiveness to future challenges. FKBP51 inhibition during stress exposure reduced the exacerbation of inflammatory pain by stress and reversed several stress-induced DNA methylation changes in promoter regions of genes associated with stress and nociception, including Rtn4, Cdk5 and Nrxn1, but not Fkbp5. These results indicate that sub-chronic stress leads to the hypomethylation of Fkbp5 and increased susceptibility to chronic pain driven by FKBP51, but reversing Fkbp5 hypomethylation is not necessary to prevent chronic pain vulnerability, which is likely driven by complex epigenetic regulation of multiple stress-regulated genes.

neuroscience↗

bioRxiv2024

Acute and early stress axis modulation in joint disease permanently reduces pain and emotional comorbidities

Chronic pain affects 20-30% of the population and imposes a significant socio-economic burden as it is often accompanied by substantial emotional comorbidities such as anxiety and depression. Yet, the mechanisms underlying the interactions between the sensory and emotional aspects of chronic pain remain poorly understood. Here, we investigated the role of FKBP51, a regulator of the stress response, in mediating both sensory and emotional symptoms of chronic pain. Inhibition of FKBP51, via genetic deletion or pharmacological blockade, in persistent joint pain reduced fast-onset sensory, functional and activity-related symptoms, as well as late anxio-depressive comorbidities. FKBP51 inhibition after the establishment of the hypersensitive state provided only temporary symptoms relief, while acute inhibition at disease onset protected from the full development of sensory and anxio-depressive symptoms for up to 6 months. Our results also indicated that early pain symptoms could predict the late sensory and emotional outcomes of chronic pain. RNA sequencing of spinal cord tissue revealed that late FKBP51 inhibition transiently altered nociceptive genes associated with mechanical hypersensitivity. In contrast, early inhibition persistently downregulated the Naaa gene, a key regulator of the transition to chronic pain, and reorganized spinal cilia. Our results indicate that early FKBP51 inhibition after injury can persistently reduce chronic pain and prevent the onset of associated emotional comorbidities by modulating critical spinal neurobiological pathways that play pivotal roles in the transition to chronic pain. Significance statementOur study reveals that early inhibition of FKBP51, a modulator in the stress axis, at the onset of joint damage provides sustained pain relief and significantly delays or prevents emotional comorbidities in a sex-dependent manner. In contrast, FKBP51 inhibition initiated after chronic pain is established results in only temporary symptoms improvement. These findings highlight a critical therapeutic window during which timely intervention can prevent the transition from acute to chronic pain. By establishing a predictive link between early therapeutic response and long-term outcomes, this work has important clinical implications for proactive and personalized chronic pain management.

neuroscience↗

bioRxiv2023

Predicting hypersensitivity and comorbid depressive-like behavior in late stages of joint disease using early weight bearing deficit

Chronic pain is a hallmark of joint diseases and is often accompanied by negative affective symptoms such as low mood, anxiety and memory dysfunction. Whether these may be the results of the more obvious sensory and functional symptoms of joint pain is poorly understood and this likely contributes to the difficulty in adequately managing this condition. Here, we have used two mouse models to address this lack of knowledge. Using a model of ankle inflammation and a model of knee osteoarthritis, we found that these models of joint pain induced weight bearing deficits of different magnitude but relatively similar mechanical allodynia that lasted at least 3 months. However, the models were accompanied by very different affective outcomes, as only the model of knee osteoarthritis, that led to significant early changes in activity and sleep patterns, was accompanied by an increase in negative affective behaviors, including cognitive impairments and depressive-like behavior. The models also had different molecular profiles at both spinal and hippocampal levels. Importantly, the functional outcomes measured in the early stages of the disease stage strongly correlated with sensory and emotional profiles at 3 months, suggesting that early functional measures may be used as predictors of the long-term symptoms associated with persistent joint pain. In conclusion, the predictive value of early measures of functional impact of joint disease could prove useful in the clinics for adapted therapeutic approaches for the prevention of emotional comorbidities and better pain management for patients with joint pain.

neuroscience↗