An improved behavioural assay demonstrates that ultrasound vocalizations constitute a reliable indicator of chronic cancer pain and neuropathic pain

<p>Abstract</p> <p>Background</p> <p>On-going pain is one of the most debilitating symptoms associated with a variety of chronic pain disorders. An understanding of mechanisms underlying on-going pain, i.e. stimulus-independent pain has been hampered so far by a lack of behavioural parameters which enable studying it in experimental animals. Ultrasound vocalizations (USVs) have been proposed to correlate with pain evoked by an acute activation of nociceptors. However, literature on the utility of USVs as an indicator of chronic pain is very controversial. A majority of these inconsistencies arise from parameters confounding behavioural experiments, which include novelty, fear and stress due to restrain, amongst others.</p> <p>Results</p> <p>We have developed an improved assay which overcomes these confounding factors and enables studying USVs in freely moving mice repetitively over several weeks. Using this improved assay, we report here that USVs increase significantly in mice with bone metastases-induced cancer pain or neuropathic pain for several weeks, in comparison to sham-treated mice. Importantly, analgesic drugs which are known to alleviate tumour pain or neuropathic pain in human patients significantly reduce USVs as well as mechanical allodynia in corresponding mouse models.</p> <p>Conclusions</p> <p>We show that studying USVs and mechanical allodynia in the same cohort of mice enables comparing the temporal progression of on-going pain (i.e. stimulus-independent pain) and stimulus-evoked pain in these clinically highly-relevant forms of chronic pain.</p

Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain

Pain is one of the most severe and debilitating symptoms associated with several forms of cancer. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells and tumor cells. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve-specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pai

COVID‐19 Affects Short‐Term, But Not 90‐Day, Outcome in Patients With Stroke Treated With Mechanical Thrombectomy

Background COVID‐19 is associated with an increased stroke risk. Moreover, outcome at discharge was worse in patients with large‐vessel occlusion stroke with concomitant COVID‐19 receiving endovascular treatment (ET). We aimed to investigate the impact of concomitant COVID‐19 on later functional outcome in patients with large‐vessel occlusion stroke treated with ET. Methods We analyzed patients from the GSR‐ET (German Stroke Registry–Endovascular Treatment), an observational multicenter registry of patients with large‐vessel occlusion stroke receiving ET. Baseline characteristics, procedural parameters, discharge parameters, and functional outcome at 90 days were compared between patients with concomitant COVID‐19 and propensity score–matched controls (ratio, 1:4; matched for age, sex, prestroke modified Rankin Scale score, and stroke severity), and multivariable ordinal regression analysis was performed. Results Among 4010 patients receiving ET between February 2020 and December 2021, 72 (1.8%) had concomitant COVID‐19. Compared with 224 matched patients without COVID‐19, they (n=56) were more severely affected, with a higher median National Institutes of Health Stroke Scale (NIHSS) score after 24 hours (NIHSS score, 14.5 [interquartile range {IQR}, 9–22] versus 12 [IQR, 6–18.75]; P=0.015), and NIHSS score and modified Rankin Scale score at discharge (NIHSS score, 12 [IQR, 6.75‐16.75] versus 6 [IQR, 2–13]; P=0.001; and modified Rankin Scale score, 5 [IQR, 4–5] versus 4 [IQR, 2–5]; P=0.023), but functional outcome at 90‐day follow‐up was similar (modified Rankin Scale score, 4 [IQR, 4–6] versus 4 [IQR, 2–6]; P=0.34). After adjustment for prespecified confounders, COVID‐19 was associated with worse functional outcome at discharge (common odds ratio [OR], 0.40 [95% CI, 0.19–0.80]; P=0.011), but not at 90‐day follow‐up (common OR, 0.72 [95% CI, 0.32–1.60]; P=0.43). Conclusions COVID‐19 affected short‐term, but not 90‐day, functional outcome in patients with large‐vessel occlusion stroke treated with ET. Hence, ET should not be withheld in patients with concomitant COVID‐19