Impaired AMPK‑CGRP signaling in the central nervous system contributes to enhanced neuropathic pain in high‑fat diet‑induced obese rats, with or without nerve injury

Abstract

Obesity is associated with increased sensitivity to pain, including neuropathic pain, but the precise mechanisms are not fully understood. Recent evidence has revealed that AMP-activated protein kinase (AMPK) in the central nervous system (CNS) regulates the neuropeptide calcitonin gene-related peptide (CGRP), a principal neurotransmitter of the class C nerve fiber, which serves an important role in initiating and maintaining neuropathic pain. AMPK has been demonstrated to be downregulated in the CNS in obesity. The present study hypothesized that obesity may lead to increased sensitivity to neuropathic pain by downregulating AMPK and upregulating CGRP expression levels in the CNS. Sprague-Dawley rats consuming a high-fat diet (HF) for 12 weeks developed obesity; they exhibited significantly decreased levels of phospho (p)-AMPK and increased CGRP expression levels in the spinal cord (SC) and dorsal root ganglion (DRG), respectively, compared with rats consuming a low-fat (LF) diet. HF-fed rats that underwent spared nerve injury (SNI) also exhibited lower p-AMPK and higher CGRP expression levels in the SC and DRG, compared with the corresponding LF-diet rats. The 50% paw withdrawal threshold (PWT; as measured by Von Frey testing) was significantly lower in HF-fed compared with LF-fed rats, with or without SNI. Through intrathecal treatment, the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) or the CGRP antagonist CGRP8-37 decreased CGRP expression levels and increased the 50% PWT; however, the AMPK inhibitor dorsomorphin augmented CGRP expression levels and further reduced the 50% PWT in HF-fed rats, but not LF-fed rats, with or without SNI. The results indicated that blocking the AMPK-CGRP pathway may enhance neuropathic pain in HF-induced obesity, with or without nerve injury. Targeting AMPK in the CNS may be a novel strategy for the prevention and treatment of obesity-associated neuropathic pain.

Infiltration of Blood-Derived Macrophages Contributes to the Development of Diabetic Neuropathy

“…Firstly, the reduction of body weight in the DNP may be a confounding factor for pain behavior. A recent clinical study shows that abnormal body weight (underweight and obese) decreased the pain threshold [28]. These findings suggest that the reduction of body weight may contribute to pain hypersensitivity.…”

Sirt2 in the Spinal Cord Regulates Chronic Neuropathic Pain Through Nrf2-Mediated Oxidative Stress Pathway in Rats

“…The rat model of neuropathic pain was induced by unilateral SNI as previously described (Decosterd and Woolf, 2000;Guo et al, 2019). Briefly, rats were anesthetized by inhalation of 3% isoflurane, and a section was made directly through the biceps femoris muscle to expose the sciatic nerve and its three terminal branches: the common peroneal, tibial and sural nerves.…”

“…Lumbar intrathecal catheter implantation was conducted as previously described (Størkson et al, 1996;Guo et al, 2019). Briefly, under 3% isoflurane anesthesia, an incision lateral to the midline was made and the polyethylene catheter was inserted into the subarachnoid space.…”

“…Mechanical allodynia was assessed by measuring the paw withdrawal threshold (PWT) in response to the stimulation of Von Frey filaments, as previously described (Chaplan et al, 1994;Guo et al, 2019). Briefly, rats were acclimatized in a plastic cage with a mesh bottom for 20 min prior to testing.…”

Diet, body weight and pain susceptibility – A systematic review of preclinical studies

“…paw incision ( Guillemot-Legris et al, 2018 , Iannitti et al, 2012 , Song et al, 2018 ). In the specific case of neuropathy models, most commonly lesions in the peripheral nervous system were used to model neuropathic pain like in the spared nerve injury (SNI; Decosterd and Woolf, 2000 ) model –( Cristino et al, 2016 , Guo et al, 2019 ) – but 1 model of perineural inflammation was also used ( Song et al, 2017 ). It should be noted that, while neuropathies and neuropathic pain are a common event in obesity models – see for review ( Islam et al, 2013 , Jolivalt et al, 2016 , O'Brien et al, 2014 , Preguica et al, 2020 ) – only models with an effective lesion in neuronal tissues were considered in this section.…”