Physical Activity Induces Nucleus Accumbens Genes Expression Changes Preventing Chronic Pain Susceptibility Promoted by High-Fat Diet and Sedentary Behavior in Mice

Abstract

Recent findings from rodent studies suggest that high-fat diet (HFD) increases hyperalgesia independent of obesity status. Furthermore, weight loss interventions such as voluntary physical activity (PA) for adults with obesity or overweight was reported to promote pain reduction in humans with chronic pain. However, regardless of obesity status, it is not known whether HFD intake and sedentary (SED) behavior is underlies chronic pain susceptibility. Moreover, differential gene expression in the nucleus accumbens (NAc) plays a crucial role in chronic pain susceptibility. Thus, the present study used an adapted model of the inflammatory prostaglandin E2 (PGE2)induced persistent hyperalgesia short-term (PH-ST) protocol for mice, an HFD, and a voluntary PA paradigm to test these hypotheses. Therefore, we performed an analysis of differential gene expression using a transcriptome approach of the NAc. We also applied a gene ontology enrichment tools to identify biological processes associated with chronic pain susceptibility and to investigate the interaction between the factors studied: diet (standard diet vs. HFD), physical activity behavior (SED vs. PA) and PH-ST (PGE vs. saline). Our results demonstrated that HFD intake and sedentary behavior promoted chronic pain susceptibility, which in turn was prevented by voluntary physical activity, even when the animals were fed an HFD. The transcriptome of the NAc found 2,204 differential expression genes and gene ontology enrichment analysis revealed 41 biologic processes implicated in chronic pain susceptibility. Taking these biological processes together, our results suggest that genes related to metabolic and mitochondria stress were up-regulated in the chronic pain susceptibility group (SED-HFD-PGE), whereas genes related to neuroplasticity were up-regulated in the non-chronic pain susceptibility group (PA-HFD-PGE). These findings provide pieces of evidence that HFD intake and sedentary behavior provoked gene expression changes in the NAc related to promotion of chronic pain susceptibility, whereas voluntary physical activity provoked gene expression changes in the NAc related to prevention of chronic

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

“… HFD presented a more intense and prolonged response to carrageenan with decreased thresholds/latencies; ( Wang et al, 2014b ) Formalin Nocifensive behaviors HFD Increased body weight at HFD w 3. C57BL/6CR presented the greatest difference to controls at HFD w 8; HFD C57BL/6CR displayed increased nocifensive behaviors in the acute phase of the formalin test; no alterations were observed in tonic phase in all strains; ( Cooper et al, 2018 ) Formalin Nocifensive behaviors HFD; ob/ob ; db/db HFD gained significantly more body weight and fat than the control group; HFD presented reduced nocifensive behavior (paw flinches) in both acute and tonic phases of the test (diet switch for 3 ws rescued the phenotype); similar results for the ob/ob and db/db models; ( Hu et al, 2018 ) PGE2 Mechanical allodynia (VF) HFD; voluntary physical activity Significantly higher body mass in HFD; PGE decreased thresholds (increased delta); this effect was sustained in HFD but not controls; voluntary physical activity counteracted this effect however physical activity was significantly higher in controls; ( Brandao et al, 2019 ) Postoperative pain Hindpaw incision Mechanical allodynia (VF) HFD HFD-fed mice (60 day protocol) developed an obese phenotype characterized by increased body weight and fat depots; Thresholds decreased after incision in both HFD and controls recovering in the latter after 14 days; allodynia lasted at least 162 days in HFD however diet switch rescued post-operative pain; ( Guillemot-Legris et al, 2018 ) Hindpaw incision dynamic plantar aesthesiometer; Hargreaves fa/fa fa/fa presented significantly increased weight compared to fa/ - (14 ws); Both obese ( fa/fa ) and lean ( fa/ -) rats presented decreased mechanical thresholds and thermal hyperalgesia; no differences were observed between the 2 groups; ( Iannitti et al, 2012 ) Hindpaw incision Mechanical allodynia (VF); nocifensive behaviors HFD There was...…”

“…The inflammatory prostaglandin E2 (PGE2)-induced persistent hyperalgesia model ( Ferreira et al, 1990 ) was used in only 1 study ( Brandao et al, 2019 ). It differs from the previous inflammatory models as it makes use of an endogenous proinflammatory molecule ( Nakanishi and Rosenberg, 2013 ).…”

“…Intraplantar injections of PGE2 lead to a decrease in the thresholds to innocuous mechanical stimuli. In HFD mice the effect was sustained at least for 7 days after the last PGE2 injection, while in the standard diet group recovered to baseline values in the same period ( Brandao et al, 2019 ).…”

“…In models of subacute and chronic pain conditions, obese animals frequently presented an exacerbation of nocifensive behaviors and/or pain-related phenotypes were sustained over longer periods of time. Such was particularly evident in models with an obvious inflammatory component such as subcutaneous inflammation (carrageenan and PGE2; Brandao et al, 2019 , Iannitti et al, 2012 , Wang et al, 2014b ), postoperative pain (skin incision; Guillemot-Legris et al, 2018 , Iannitti et al, 2012 , Song et al, 2018 ), arthritis ( Croci and Zarini, 2007 , Loredo-Perez et al, 2016 , Song et al, 2017 , Totsch et al, 2018 , Totsch et al, 2017 , Totsch et al, 2016 ) and radicular pain (perineural inflammation; Song et al, 2017 ) most certainly reflecting the proinflammatory state that has been associated with obesity ( Bastard et al, 2006 , Das, 2001 , Eichwald and Talbot, 2020 , Ellulu et al, 2017 ). In diet-induced obesity preclinical studies, it was demonstrated a spontaneous development of arthritis ( Griffin et al, 2012 ) or an aggravation in induced models (collagen-induced arthritis; Jhun et al, 2012 ), although pain-related outcomes were not directly measured – see for review ( Fang and Beier, 2014 ).…”

Running wheel exercise induces therapeutic and preventive effects on inflammatory stimulus-induced persistent hyperalgesia in mice

“…It is well established that, in this model, mice show persistent hyperalgesia up to 30 days after ending the PGE 2 injections [24] and this data was replicated in the present study. This is an appropriate model to study susceptibility and resilience to pain chronification [26,27], allowing us to assess the central hypothesis of the present study that physical exercise promotes resilience to chronic pain and can be used as a non-pharmacological therapeutic and preventive tool for this condition.…”