Biology subjects

Arcangeletti, M.

Publications and source records attributed to Arcangeletti, M..

3 recordsLinked to original sources

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↗

bioRxiv2024

Analgesic targets identified in mouse sensory neuron somata and terminal pain translatomes

The relationship between transcription and protein expression is complex. We identified polysome-associated RNA transcripts in the somata and central terminals of mouse sensory neurons in control, painful (+ Nerve Growth Factor (NGF)) and pain-free conditions (Nav1.7 null mice). The majority (98%) of translated transcripts are shared between male and female mice in both the somata and terminals. Some transcripts are highly enriched in the somata or terminals. Changes in the translatome in painful and pain-free conditions include novel and known regulators of pain pathways. Antisense knockdown of selected somatic and terminal polysome-associated transcripts that correlate with pain states diminished pain behaviour. Terminal-enriched transcripts encoding synaptic proteins (e.g. Synaptotagmin), non-coding RNAs, transcription factors (e.g. Znf431), proteins associated with trans-synaptic trafficking (HoxC9), GABA generating enzymes (Gad1 and Gad2) and neuropeptides (Penk). Thus, central terminal translation may well be a significant regulatory locus for peripheral input from sensory neurons.

neuroscience↗

bioRxiv2023

Chemogenetic silencing of NaV1.8 positive sensory neurons reverses chronic neuropathic and bone cancer pain in FLEx PSAM4-GlyR mice

Drive from peripheral neurons is essential in almost all pain states, but pharmacological silencing of these neurons to effect analgesia has proved problematic. Reversible gene therapy using long-lived chemogenetic approaches is an appealing option. We used the genetically-activated chloride channel PSAM4 -GlyR to examine pain pathways in mice. Using recombinant AAV9-based delivery to sensory neurons, we found a reversal of acute pain behavior and diminished neuronal activity using in vitro and in vivo GCaMP imaging upon activation of PSAM4 -GlyR with varenicline. A significant reduction in inflammatory heat hyperalgesia and oxaliplatin-induced cold allodynia was also observed. Importantly, there was no impairment of motor coordination, but innocuous von Frey sensation was inhibited. We generated a transgenic mouse that expresses a CAG-driven FLExed PSAM4 -GlyR downstream of the Rosa26 locus that requires Cre recombinase to enable the expression of PSAM4 -GlyR and tdTomato. We used NaV1.8 Cre to examine the role of predominantly nociceptive NaV1.8+ neurons in cancer-induced bone pain (CIBP) and neuropathic pain caused by chronic constriction injury (CCI). Varenicline activation of PSAM4 -GlyR in NaV1.8-positive neurons reversed CCI-driven mechanical, thermal, and cold sensitivity. Additionally, varenicline treatment of mice with CIBP expressing PSAM4 -GlyR in NaV1.8+ sensory neurons reversed cancer pain as assessed by weight-bearing. Moreover, when these mice were subjected to acute pain assays, an elevation in withdrawal thresholds to noxious mechanical and thermal stimuli was detected, but innocuous mechanical sensations remained unaffected. These studies confirm the utility of PSAM4 -GlyR chemogenetic silencing in chronic pain states for mechanistic analysis and potential future therapeutic use. Significance statementChronic pain is a massive problem. Peripheral nerve block is effective in many chronic pain conditions, demonstrating the importance of peripheral drive in chronic pain. We used chemogenetic tools based on the modified ligand-gated chloride channel PSAM4 -GlyR to silence dorsal root ganglion neurons in vitro and in vivo. This approach reduces pain-like behavior in acute and chronic pain models, including resistant pain conditions like neuropathic pain or cancer-induced bone pain. We generated a mouse line that expresses PSAM4 -GlyR in a Cre-dependent manner, providing a useful research tool to address not only the role of nociceptive sensory neurons in pain states but also the function of genetically defined sets of neurons throughout the nervous system in normal and pathological conditions.

neuroscience↗