Abstract
Painful diabetic neuropathy (PDN) is one of the most common complications in the early stage of diabetes mellitus (DM). Endomorphin-2 (EM2) selectively activates the μ-opioid receptor (MOR) and subsequently induces antinociceptive effects in the spinal dorsal horn. However, the effects of EM2-MOR in PDN have not yet been clarified in the spinal dorsal horn. Therefore, we aimed to explore the role of EM2-MOR in the pathogenesis of PDN. The main findings were the following: (1) streptozotocin (STZ)-induced diabetic rats exhibited hyperglycemia, body weight loss and mechanical allodynia; (2) in the spinal dorsal horn, the expression levels of EM2 and MOR decreased in diabetic rats; (3) EM2 protein concentrations decreased in the brain, lumbar spinal cord and cerebrospinal fluid (CSF) in diabetic rats but were unchanged in the plasma; (4) the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) was significantly higher in diabetic rats than in control rats; and (5) intrathecal injection of EM2 for 14 days in the early stage of PDN partially alleviated mechanical allodynia and reduced MOR expression in diabetic rats. Our results demonstrate that the EM2-MOR signal may be involved in the early stage of PDN.
Highlights
Diabetic neuropathy is the most common complication of diabetes mellitus (DM)
The expression of MOR decreased significantly from day 14 (43.9% of control, p < 0.05, Figures 4B,D) to day 28 (14.3% of control, p < 0.05, Figures 4B,D). These results suggest that the decrease in EM2 and MOR in the spinal cord was consistent with the progressive mechanical allodynia in diabetic rats
The distributions of EM2-ir structures, including neuronal cell bodies, dendritic processes, axonal fibers and terminals, in the nervous system have been studied extensively. These results indicate that the reduction in EM2 levels in the spinal dorsal horn occurs at the early stage of diabetes, which might be correlated with the progressive painful diabetic neuropathy (PDN)
Summary
Diabetic neuropathy is the most common complication of diabetes mellitus (DM). It is known that painful diabetic neuropathy (PDN) in diabetic patients and animal models occurs at the early stage of the disease prior to the appearance of overt clinical symptoms (Ziegler, 2008). Streptozotocin (STZ)-induced type 1 diabetic rats developed PDN as early as 2 weeks after STZ injection (Malcangio and Tomlinson, 1998; Kou et al, 2014; Castelli et al, 2016). PDN could benefit from opioid-based therapies, the clinical use of opioids has been hampered by significant side effects, such as gastrointestinal complications, respiratory depression, tolerance and dependence with longterm use (Zhao et al, 2010; Wu et al, 2011; Banafshe et al, 2014). Searching for more selective and effective therapeutics with fewer side effects is important for treating PDN
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