Abstract
Chemokine signaling has been implicated in the pathogenesis of diabetic neuropathy; however, the role of chemokine CC motif receptor 4 (CCR4) remains unknown. The goal was to examine the function of CCR4 in hypersensitivity development and opioid effectiveness in diabetic neuropathy. Streptozotocin (STZ; 200 mg/kg, intraperitoneally administered)-induced mouse model of diabetic neuropathy were used. An analysis of the mRNA/protein expression of CCR4 and its ligands was performed by qRT-PCR, microarray and/or Western blot methods. C021 (CCR4 antagonist), morphine and buprenorphine were injected intrathecally or intraperitoneally, and pain-related behavior was evaluated by the von Frey, cold plate and rotarod tests. We observed that on day 7 after STZ administration, the blood glucose level was increased, and as a consequence, hypersensitivity to tactile and thermal stimuli developed. In addition, we observed an increase in the mRNA level of CCL2 but not CCL17/CCL22. The microarray technique showed that the CCL2 protein level was also upregulated. In naive mice, the pronociceptive effect of intrathecally injected CCL2 was blocked by C021, suggesting that this chemokine acts through CCR4. Importantly, our results provide the first evidence that in a mouse model of diabetic neuropathy, single intrathecal and intraperitoneal injections of C021 diminished neuropathic pain-related behavior in a dose-dependent manner and improved motor functions. Moreover, both single intrathecal and intraperitoneal injections of C021 enhanced morphine and buprenorphine effectiveness. These results reveal that pharmacological modulation of CCR4 may be a good potential therapeutic target for the treatment of diabetic neuropathy and may enhance the effectiveness of opioids.
Highlights
Diabetes mellitus is an epidemic of the 21st century, and a recent report from the World Health Organization has shown that since 1980, the number of adults living with diabetes has nearly quadrupled to 422 million people (WHO, 2017)
The influence of streptozotocin administration on plasma glucose concentrations, neuropathic painrelated behaviors, spinal CCL17, CCL22 and CCL2 mRNA levels and CCL2 and CC motif receptor 4 (CCR4) protein levels measured on day 7 after STZ treatment
In a STZ-induced mouse model of diabetic neuropathy, we proved that the mRNA and protein levels of CCL2 are elevated in the spinal cord on day 7, when strong tactile and thermal hypersensitivity has developed
Summary
Diabetes mellitus is an epidemic of the 21st century, and a recent report from the World Health Organization has shown that since 1980, the number of adults living with diabetes has nearly quadrupled to 422 million people (WHO, 2017). Some studies, including ours, have indicated that blockade of CCchemokine receptors, CCR1 (Pawlik et al, 2020), CCR2 (Kwiatkowski et al, 2017) and CCR5 (Matsushita et al, 2014; Kwiatkowski et al, 2016; Piotrowska et al, 2016a), attenuates the neuropathic pain symptoms evoked by chronic constriction injury of the sciatic nerve in rats In this model, CCR1, CCR2 and CCR5 antagonists enhance morphine effectiveness (Kwiatkowski et al, 2016, 2017; Pawlik et al, 2020). The aim was to investigate changes in the spinal expression of CCR4 and its ligands (CCL17, CCL22, and CCL2) in a streptozotocin-induced mouse model of diabetic neuropathic pain. This study aimed to evaluate how single intrathecal and intraperitoneal injections of C021 influence the analgesic effects of morphine and buprenorphine in this model of diabetic neuropathic pain
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