Abstract
This study focused on the relationship between extracellular-regulated kinase (ERK) and obesity-induced increases in neuropathic pain. We fed rats a high-fat diet to establish the obesity model, and rats were given surgery to establish the chronic compression of the dorsal root ganglia (CCD) model. U0126 was applied to inhibit ERK, and metformin or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) was applied to cause AMP-activated protein kinase (AMPK) activation. Paw withdrawal mechanical threshold (PWMT) were calculated to indicate the level of neuropathic pain. The data indicated that compared with normal CCD rats, the PWMT of obese CCD rats were decreased, accompanied with an increase of ERK phosphorylation, NAD(P)H oxidase 4 (NOX4) protein expression, oxidative stress and inflammatory level in the L4 to L5 spinal cord and dorsal root ganglia (DRG). Administration of U0126 could partially elevate the PWMT and reduce the protein expression of NOX4 and the above pathological changes in obese CCD rats. In vitro, ERK phosphorylation, NOX4 protein expression increased significantly in DRG neurons under the stimulation of palmitic acid (PA), accompanied with increased secretion of inflammatory factors, oxidative stress and apoptosis level, while U0126 partially attenuated the PA-induced upregulation of NOX4 and other pathological changes. In the rescue experiment, overexpression of NOX4 abolished the above protective effect of U0126 on DRG neurons in high-fat environment. Next, we explore upstream mechanisms. Metformin gavage significantly reduced neuropathic pain in obese CCD rats. For the mechanisms, activating AMPK with metformin (obese CCD rats) or AICAR (DRG neurons in a high-fat environment) not only inhibited the ERK-NOX4 pathway, but also improved oxidative stress and inflammation caused by high-fat. In conclusion, the AMPK-ERK-NOX4 pathway may has a pivotal role in mediating obesity-induced increases in neuropathic pain.
Highlights
Obesity and pain are two serious public health problems in our society
This view is based on the following evidences: (1) Under high-fat environment, the neuropathic pain of obese rats, the expression of p-extracellular-regulated kinase (ERK) and NAD(P)H oxidase 4 (NOX4) in nervous tissue increased, accompanied by increased inflammation, oxidative stress and apoptosis
(2) Rescue experiments showed that overexpression of NOX4 abolished the anti-oxidative stress, anti-inflammation, and anti-apoptotic effects produced by an ERK inhibitor
Summary
Recent studies have shown that obesity has a close relationship with increased neuropathic pain [1,2,3], including chronic pain [4]. The molecular mechanisms underlying neuropathic pain induced by obesity have not been thoroughly elaborated. The MAPK/ERK www.aging-us.com pathway has a pivotal role in many neurodegenerative diseases [6], and targeting the ERK signaling pathway is an innovative therapeutic strategy for treating neurodegeneration [7]. Our previous study has reported that the ERK pathway is an important mechanism in neuropathic pain in rats with a chronic compression of dorsal root ganglia (CCD) model, and targeting ERK with U0126 or lentivirus expressing ERK shRNA significantly alleviates chronic compression of dorsal root ganglia (DRG)-induced neuropathic pain [8, 9]
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