Regular ArticleModerate exercise training attenuates inflammatory mediators in DRG of Type 1 diabetic rats
Introduction
Pain is a significant consequence of diabetic neuropathy. Diabetes mellitus is the most common cause of neuropathy in the United States, and 25% of diabetic patients with neuropathy suffer from neuropathic pain, resulting in a significant adverse effect on quality of life measures (Van Acker et al., 2009). Unfortunately, available medical treatment is relatively ineffective with limited efficacy and is complicated by side effects and dependency (Barbano et al., 2003). Accumulating evidence suggests that the activation of inflammatory cascades in the peripheral and central nervous systems plays a key role in the development and persistence of neuropathic pain states induced by physical or toxic injury to peripheral nerve (Gonzalez-Clemente et al., 2005, Herder et al., 2009, King, 2008).
In diabetes, there is evidence of systemic immune activation. Patients with painful neuropathy show increased levels of IL-2 in blood and increased levels of TNFα mRNA and protein in blood (Uceyler et al., 2007). The elevated level of serum TNFα in Type 1 diabetes patients suggests that TNFα may play a pathogenic role in the development of diabetic neuropathy (Gonzalez-Clemente et al., 2005, Kaul et al., 2010). Studies on patients with Type 2 with or without polyneuropathy exhibit a different immune profile and specific neuropathic deficits, suggesting that inflammation is associated with diabetic neuropathic impairments involving a number of immune mediators such as C-peptide, IL-2 receptor, IL1β and TNFα (Empl et al., 2001, Uceyler et al., 2007). Previously, we have shown that the inflammatory mediators in the dorsal root ganglia are altered with the development of pain in Type 2 model of diabetes (Galloway and Chattopadhyay, 2013). Although earlier studies have demonstrated the effects of moderate to intense physical exercise on pain perception (Rossi et al., 2011), not many have shown the effects of moderate exercise that may change the endogenous opioid content as well as the levels of inflammation in DRG of Type 1 diabetic animals with painful neuropathy. Hyperglycemia causes p38 mitogen-activated protein (p38) kinase activation (Igarashi et al., 1999), which can be induced by changes in the release of proinflammatory cytokines. Previously we have shown that viral vector mediated release of enkephalin modified the activation of p38 MAPK in Type 1 diabetic DRG (Chattopadhyay et al., 2008). This study also explores the possibility whether exercise can alter the endogenous opioid, enkephalin and stress associated markers, thus reducing pain related behaviors. It is well known that the heat shock protein (HSP) molecular chaperones protect cells from stressful insults. Diabetes is generally associated with lower HSPs (Padmalayam, 2014). A low HSP state promotes increased activation of inflammatory cytokines (Hooper and Hooper, 2009). Moreover, exercise training is a non-pharmacological and noninvasive treatment method. To avoid any intense exercise (up to 33 m/min for 20 min) induced increases in inflammatory markers and adverse effect on hyperglycemia in Type 1 diabetic animals (Bortolon et al., 2012), this study chose a moderate exercise regimen (10 m/min for 60 min). The current study explored the effect of moderate exercise on pain perception and also on the changes in enkephalin as well as the inflammatory mediators in the peripheral nervous system of Type 1 diabetic animals after 6 weeks of exercise regimen. Hence, moderate exercise may provide an alternative therapeutic approach for this disabling and difficult-to-treat complication of diabetes avoiding systemic side effects of the treatment.
Section snippets
Experimental design
Experiments were performed on male Sprague Dawley rats weighing approximately 250–280 g (Charles River, USA) in compliance with approved institutional animal care and use protocols. The rats were divided into four groups: naïve controls (n = 8), control exercise (n = 8), diabetic sedentary (n = 8) and diabetic exercise (n = 8) and were trained to run in the motorized wheels for six weeks. For the nociceptive analysis, animals from each group were tested after six weeks of exercise training by a blinded
Exercise did not alter body weight and blood glucose levels in STZ-diabetic animals
The Type 1 model of STZ-diabetic rats presented lower body weight compared to control rats. The change in body weight in the STZ-diabetic sedentary group was not significantly different than that of the STZ-diabetic exercise group (Fig. 1a). Physical exercise did not decrease the blood glucose levels in diabetic exercised animals after 6 weeks of exercise regimen. Furthermore, the blood glucose level was also unaffected by exercise in control exercised rats (Fig. 1b). We measured blood glucose
Discussion
Our data clearly demonstrates that exercise delays the progression of thermal and mechanical hyperalgesia as well as cold allodynia in STZ-induced diabetes. This study focuses on the benefit of moderate exercise to reduce the risk of exercise induced hypoglycemia and inflammation in Type 1 diabetic animals. Studies have shown that there is a modest increase in IL-6, IL1β and TNF-α in Type 1 diabetic patients following intense exercise (Campbell et al., 2014, Nemet et al., 2002). The present
Authors' contributions
HY carried out the behavior tests and biochemical assays. DI and MF carried out the behavior tests and exercise regimen. VT carried out biochemical assays and reviewed the manuscript. MC contributed to the design and analysis of the study, behavior test and wrote the manuscript.
Conflict of interests
The authors declare that they have no conflict of interests.
Acknowledgments
This work was funded by American Diabetes Association (Grant #7-12-BS-021) to MC. We acknowledge Jessica Meyers, Ryan Pattnaik and Valerie Zeer for helping with the animal exercise.
References (42)
- et al.
Increases in inflammatory mediators in DRG implicate in the pathogenesis of painful neuropathy in type 2 diabetes
Cytokine
(2013) - et al.
Inflammation, heat shock proteins, and type 2 diabetes
Cell Stress Chaperones
(2009) - et al.
Nociceptive and inflammatory effects of subcutaneous TNFalpha
Pain
(2000) - et al.
Extended swimming exercise reduces inflammatory and peripheral neuropathic pain in rodents
J. Pain
(2007) Beneficial effects of treadmill training in experimental diabetic nerve regeneration
Clinics (Sao Paulo)
(2010)Long-lasting delayed hyperalgesia after subchronic swim stress
Pharmacol. Biochem. Behav.
(2000)- et al.
Exercise training attenuates acute hyperalgesia in streptozotocin-induced diabetic female rats
Clinics (Sao Paulo)
(2011) Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics
Diabetes Metab.
(2009)- et al.
Pharmacotherapy of painful diabetic neuropathy
Curr. Pain Headache Rep.
(2003) Moderate exercise improves leucocyte function and decreases inflammation in diabetes
Clin. Exp. Immunol.
(2010)