High frequency electrical stimulation reduces neuronal HMGB1 release

Abstract

Abstract Chronic pain affects the daily lives of millions of Americans and presents an economic burden of $600 Billion per year. Opiods and other pharmaceutical approaches for the management of chronic pain have notorious detremental side effects. Thus, there is a need for understanding of pain for better therapeutics. Neuroinflammation is closely associated with chronic pain and targeting molecular mediators of neuroinflammation may present a novel opportunity for pain treatment. High mobility group box 1 protein (HMGB1), a key mediator of injury- and infection-elicited inflammation, is involved in the pathology of persistent pain. We recently reported that neuronal HMGB1 is required for mediating inflammation and hyperalgesia following nerve injury (Yang H et al. PNAS, 2021). High frenquency (HF) electrical nerve stimulation has achieved clinical success for chronic pain, but the underlying mechanisms are not clear. Here we assess the effects of HF stimulation in modulating HMGB1 release by sensory neurons. Using microelectrode arrays (MEAs) in cultured dorsal root ganglia (DRG) harvested from transgenic mice that express light-sensitive channel rhodopsin in sensory neurons, we observe that light-evoked HMGB1 release from DRGs is significantly reduced with HF stimulation (HMGB1 levels in unstimulated group = 5.3 ± 0.5 ng/ml; in light exposed group = 25.8 ± 6.0 vs. light + HF stimulation = 8.2 ± 2.1* pg/ml, n=6, *: P<0.01). In agreement, HF stimulation (10 min/per day X 3 days) significantly reduces mechanical hyperalgesia and HMGB1 levels in inflamed paws in C57BL/6 mice subjected to sciatic nerve ligation injury. These studies suggest HF stimulation as a novel therapeutic approach to modulate neuronal HMGB1 release for the treatment of pain Supported by grant from NIH 2R35GM118182-06, to KJT and SSC