Biology subjects

Caxaria, S.

Publications and source records attributed to Caxaria, S..

5 recordsLinked to original sources

bioRxiv2026

Transient silencing of spinal nociceptive neurons leads to a long-term reduction in joint pain mediated by recruitment of opioid activity.

Chronic inflammatory joint pain remains inadequately treated despite current therapies, creating urgent clinical need for non-addictive alternatives in an era of heightened opioid-related concerns. A promising new approach involves conjugates of botulinum toxin and substance P (SP-BOT), which, when infused locally or spinally, have been shown to produce temporary pain relief in neuropathic mouse models, with its effects declining after approximately 100 days as the construct loses activity. However, its long-term efficacy in inflammatory pain models was unknown. Unexpectedly, in a mouse model of ankle inflammatory arthritis, a single intrathecal injection of SP-BOT at the peak of pain sensitivity produced a persistent reduction in mechanical hyperalgesia that lasted for weeks beyond the loss of construct activity. Furthermore, this late-phase pain relief exhibited a striking mechanism in that a single injection of the opioid antagonist naltrexone partially reversed the anti-hyperalgesia generated by SP-BOT. These data indicate that SP-BOT-mediated neuronal silencing initiates two distinct phases of pain relief. An initial, direct phase is followed by a second, sustained phase that maintains pain alleviation and is driven by endogenous opioid mechanisms.

pharmacology and toxicology↗

bioRxiv2025

Paradoxical Phenotype of Fibromyalgia Neutrophils with Elevated Baseline Inflammation but Blunted Response to Stimulation

Fibromyalgia (FM) is a severe pain condition of unknown etiology. Here, we performed transcriptomics analyses of peripheral neutrophils exposed to an inflammatory stimulus, comparing responses of neutrophils obtained from FM patients versus healthy controls. We observed a state of inflammation in neutrophils from FM patients. However, FM neutrophils were unable to efficiently respond to lipopolysaccharide (LPS). This impairment was especially characteristic of FM patients with no improvement after 5 years after diagnosis in comparison with those who did improve. Blood plasma from FM patients directly stimulated a wide range of primary sensory neurons in vitro and induced pain hypersensitivity when injected into mice. Further analysis identified NF-{kappa}B suppression as a key biological process associated with low-grade inflammation and LPS non-responsiveness in neutrophils from FM patients. The clinically used NF-{kappa}B activator, bryostatin, alleviated hypersensitivity in mice treated with FM plasma, pointing to controlled inflammation induction through reactivation of the NF-{kappa}B pathway as a possible therapeutic target for FM treatment. Our whole blood single-cell RNA sequencing replicated this NF-{kappa}B-driven inflammation observed in bulk analyses transcriptomics in FM patients and revealed that this inflammatory signature is strongly pronounced not only in neutrophils, but across a broad range of immune cells.

molecular biology↗

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↗

bioRxiv2024

Novel therapies for cancer-induced bone pain

1.Cancer pain is a growing problem, especially with the substantial increase in cancer survival. Reports indicate that bone metastasis, whose primary symptom is bone pain, occurs in 65-75% of patients with advanced breast or prostate cancer. We optimized a preclinical in vivo model of cancer-induced bone pain (CIBP) involving the injection of Lewis Lung Carcinoma cells into the intramedullary space of the femur of C57BL/6 mice or transgenic mice on a C57BL/6 background. Mice gradually reduce the use of the affected limb, leading to altered weight bearing. Symptoms of secondary cutaneous heat sensitivity also manifest themselves. Following optimization, three potential analgesic treatments were assessed; 1) single ion channel targets (targeting the voltage-gated sodium channels NaV1.7, NaV1.8, or acid-sensing ion channels), 2) silencing {micro}-opioid receptor-expressing neurons by modified botulinum compounds, and 3) targeting two inflammatory mediators simultaneously (nerve growth factor (NGF) and tumor necrosis factor (TNF)). Unlike global NaV1.8 knockout mice which do not show any reduction in CIBP-related behavior, embryonic conditional NaV1.7 knockout mice in sensory neurons exhibit a mild reduction in CIBP-linked behavior. Modified botulinum compounds also failed to cause a detectable analgesic effect. In contrast, inhibition of NGF and/or TNF resulted in a significant reduction in CIBP-driven weight-bearing alterations and prevented the development of secondary cutaneous heat hyperalgesia. Our results support the inhibition of these inflammatory mediators; and more strongly their dual inhibition to treat CIBP, given the superiority of combination therapies in extending the time needed to reach limb use score zero in our CIBP model.

neuroscience↗

bioRxiv2022

Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia

Fibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2-4% of the population. The prevailing view that fibromyalgia results from central nervous system dysfunction has recently been challenged with data showing changes in peripheral nervous system activity. Using a mouse model of chronic widespread pain through hyperalgesic priming of muscle, we show that neutrophils invade sensory ganglia and confer mechanical hypersensitivity on recipient mice, whilst adoptive transfer of immunoglobulin, serum, lymphocytes or monocytes have no effect on pain behaviour. Neutrophil depletion abolishes the establishment of chronic widespread pain in mice. Neutrophils from patients with fibromyalgia also confer pain on mice. A link between neutrophil derived mediators and peripheral nerve sensitisation is already established. These observations suggest new approaches for targeting fibromyalgia pain through an understanding of the mechanisms that cause altered neutrophil activity and interactions with sensory neurons. Significance statementWe used a back-translational model in mice to demonstrate the pro-nociceptive role of neutrophils in fibromyalgia. Adoptive transfer of neutrophils from mice with chronic widespread pain or from patients with fibromyalgia can confer mechanical pain to recipient naive mice, sensitise evoked action potential firing of spinal cord neurons and produce phenotypic changes in cell surface expression of neutrophil proteins that cause infiltration of neutrophils into dorsal root ganglia. These data provide the framework for an immunological basis of chronic widespread pain in fibromyalgia mediated by polymorphonuclear granulocytes.

neuroscience↗