Vagus Nerve Stimulation Transiently Mitigates Chemotherapy-Induced Peripheral Neuropathy in Rats

Abstract

Background Chemotherapy-induced peripheral neuropathy is a severe side effect of chemotherapeutic agents. Vagus nerve stimulation attenuates neuroinflammation by activating the cholinergic anti-inflammatory pathway and thus may attenuate CIPN. Methods Adult male Sprague-Dawley rats received intraperitoneal paclitaxel injection (2 mg/kg) every other day for a total of 4 injections. Three weeks later, the left cervical vagus nerve was exposed under general anesthesia, and the rats randomly received 20-min stimulation (1 V, 2 ms, 5 Hz, 30 s ON/5 min OFF) or sham stimulation. Heat and mechanical pain sensitivity was evaluated using Hargreaves and von Frey tests before and after treatment (n=12 per group per time point). Additionally, rats receiving paclitaxel or saline but no surgery were included. Expression of representative pro- and anti-inflammatory cytokines in dorsal root ganglia was assessed by Western blotting assays and immunohistochemistry. Results Paclitaxel significantly reduced the sensitivity for heat (withdrawal latency: paclitaxel 6.16 ± 0.54 s vs saline 9.93 ± 0.78 s, p<0.001) and mechanical pain (withdrawal frequency: paclitaxel 32.22 ± 15.51% vs saline 3.33 ± 4.92%, p<0.001). Compared with sham-stimulated rats, rats receiving vagus nerve stimulation had significantly higher sensitivity for heat (withdrawal latency: VNS 10.28 ± 1.15 s vs sham 6.27 ± 0.56 s, p<0.001) and mechanical pain (withdrawal frequency: VNS 10.00 ± 9.54% vs Sham 31.67 ± 18.99%, p=0.003) on +1 day, but not 7 days later (withdrawal latency: VNS 6.97 ± 1.13 s vs Sham 6.23 ± 0.79 s, p=0.080; withdrawal frequency: VNS 21.67 ± 11.93% vs Sham 23.33 ± 7.79%, p=0.689). Western blotting assays and immunohistochemistry revealed that interleukin-10 level was elevated in the dorsal root ganglia of rats receiving vagus nerve stimulation while no apparent changes in NF-κB or TNF-α levels were observed. Conclusion Vagus nerve stimulation could transiently attenuate paclitaxel-induced hyperalgesia in rats. Future studies are needed to investigate whether stimulation with different protocols could achieve durable effects.

Neuroimmunomodulation of vagus nerve stimulation and the therapeutic implications

“…The pain threshold in the chemotherapy-treated rats significantly increased on day 1 post-VNS but not on day 7 post-VNS. IL-10 level was elevated in the dorsal root ganglia of rats treated with VNS compared with those treated with sham treatment, whereas no apparent changes in nuclear factor kappa B (NF-κB) or TNF-α levels were observed (Zhang et al, 2020 ).…”

Putative role of non‐invasive vagus nerve stimulation in cancer pathology and immunotherapy: Can this be a hidden treasure, especially for the elderly?

“…For instance, postoperative ileus was reported to reduce following low‐intensity non‐invasive VNS (25 Hz, 50 mA) that was given for 20 min prior to anesthesia in patients who had laparoscopic radical resection of colorectal cancer 111,112 . Similarly, it was also reported to help reduce the severity of peripheral neuropathy induced by chemotherapy 32 . In addition, it helps improve cancer‐related fatigue, lymphopenia, and quality of life 113 .…”

“… 111 , 112 Similarly, it was also reported to help reduce the severity of peripheral neuropathy induced by chemotherapy. 32 In addition, it helps improve cancer‐related fatigue, lymphopenia, and quality of life. 113 Thus, the importance of non‐invasive VNS cannot be overemphasized.…”

“…For these, chemotherapy, radiation therapy, and a host of other therapies are used 29–31 . However, these therapies may produce serious side effects such as nausea, vomiting, fatigue, and peripheral neuropathy especially when they are used for a very long time 32–34 . In particular, for the treatment of cancer in the elderly, the kind of therapies that should be given deserve special consideration 35 .…”

“… 29 , 30 , 31 However, these therapies may produce serious side effects such as nausea, vomiting, fatigue, and peripheral neuropathy especially when they are used for a very long time. 32 , 33 , 34 In particular, for the treatment of cancer in the elderly, the kind of therapies that should be given deserve special consideration. 35 This is because, the risk of developing cancer and death thereof, increases with age.…”