Analgesic effect of auricular vagus nerve stimulation on oxaliplatin induced peripheral neuropathic pain in rodent model

다국어 초록 (Multilingual Abstract)

A primary adverse effect of chemotherapy involves the onset of peripheral neuropathy occurring within a few hours, leading to the manifestation of neuropathic pain symptoms in the extremities. Previous studies have investigated the analgesic effects of invasive vagus nerve stimulation (VNS) to alleviate chemotherapy-induced peripheral neuropathy (CIPN). However, evidence supporting the analgesic impact of non-invasive auricular vagus nerve stimulation (aVNS) remains inconclusive.
This study aimed to explore the efficacy of non-invasive aVNS in alleviating pain symptoms caused by CIPN. To establish the rodent model of CIPN, the oxaliplatin (6 mg/kg) was administered to the rats via intraperitoneal injection. Mechanical and cold allodynia were assessed using von Frey test and acetone test, respectively. To evaluate the analgesic effects of aVNS with different frequency parameters, CIPN model animals were treated with either of 2, 20, or 100 Hz aVNS (5 V, 20 min, square wave).
Results showed that the aVNS at 20 Hz demonstrated the most significant analgesic effect. The mechanical and cold allodynia symptoms were alleviated in CIPN animals treated with 2, 20, or 100 Hz aVNS. While the 2 or 100 Hz aVNS showed the weak and transient analgesic effects, the 20 Hz aVNS induced significant analgesic effect that lasted at least for 4 hours. The immunohistochemistry (IHC) analysis at the brain level, specifically within the locus coeruleus (LC), revealed a greater expression of c-Fos in the CIPN animals with aVNS treatment compared to the sham treatment. To elucidate the analgesic effect via the adrenergic descending pathway, the α1-, α2-, or β-adrenergic receptor antagonists were administered to the spinal cord of CIPN animals before the 20 Hz aVNS treatment. Only the β-adrenergic receptor antagonist propranolol could block the analgesic effect of aVNS.
These findings suggest that the 20 Hz aVNS used in this study mediates analgesic effects in CIPN pain induced by oxaliplatin through the activation of β-adrenergic receptors.

목차 (Table of Contents)

• Abstract ----------------------------------------------------- i
• Contents ----------------------------------------------------- iii
• List of Figures ------------------------------------------------------ v
• 1. Introduction ------------------------------------------------------ 1
• 2. Materials and methods ---------------------------------------------- 4
• 2.1) Animal ------------------------------------------------------ 4
• 2.2) Oxaliplatin administration ---------------------------------- 4
• 2.3) Behavioral experiments ---------------------------------- 5
• 2.4) Non-invasive aVNS treatment ---------------------------------- 6
• 2.5) Antagonist treatment -------------------------------------------- 6
• 2.6) Immunohistochemistry (IHC) ---------------------------------- 7
• 2.7) Statistical Analysis -------------------------------------------- 8
• 3. Results ------------------------------------------------------ 9
• 3.1) Successful induction of pain symptoms in CIPN model animals -------------------------------------------------------------------------- 9
• 3.2) Alleviating pain symptoms of CIPN with various frequencies of aVNS treatment ---------------------------------------------------- 12
• 3.3) Activation of LC of CIPN animals in response to 20 Hz aVNS treatment ---------------------------------------------------- 15
• 3.4) The mediation of the aVNS-induced analgesic effect by spinal β-adrenergic receptors ------------------------------------------ 18
• 4. Discussion --------------------------------------------------- 22
• 4.1) VNS suppresses pain ----------------------------------------- 22
• 4.2) The analgesic effects of VNS is mediated by the adrenergic system ------------------------------------------------------------- 23
• 4.3) Analgesic effect of aVNS on the CIPN involves specific subtype of adrenergic receptor in the spinal cord ---------------------- 24
• 4.4) Limitation ---------------------------------------------------- 24
• 5. Conclusion --------------------------------------------------- 26
• 6. References --------------------------------------------------- 27
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