Abstract
Current investigations underline the important roles of C–C motif ligands in the development of neuropathic pain; however, their participation in diabetic neuropathy is still undefined. Therefore, the goal of our study was to evaluate the participation of macrophage inflammatory protein-1 (MIP-1) family members (CCL3, CCL4, CCL9) in a streptozotocin (STZ)-induced mouse model of diabetic neuropathic pain. Single intrathecal administration of each MIP-1 member (10, 100, or 500 ng/5 μl) in naïve mice evoked hypersensitivity to mechanical (von Frey test) and thermal (cold plate test) stimuli. Concomitantly, protein analysis has shown that, 7 days following STZ injection, the levels of CCL3 and CCL9 (but not CCL4) are increased in the lumbar spinal cord. Performed additionally, immunofluorescence staining undoubtedly revealed that CCL3, CCL9, and their receptors (CCR1 and CCR5) are expressed predominantly by neurons. In vitro studies provided evidence that the observed expression of CCL3 and CCL9 may be partially of glial origin; however, this observation was only partially possible to confirm by immunohistochemical study. Single intrathecal administration of CCL3 or CCL9 neutralizing antibody (2 and 4 μg/5 μl) delayed neuropathic pain symptoms as measured at day 7 following STZ administration. Single intrathecal injection of a CCR1 antagonist (J113863; 15 and 20 μg/5 μl) also attenuated pain-related behavior as evaluated at day 7 after STZ. Both neutralizing antibodies, as well as the CCR1 antagonist, enhanced the effectiveness of morphine in STZ-induced diabetic neuropathy. These findings highlight the important roles of CCL3 and CCL9 in the pathology of diabetic neuropathic pain and suggest that they play pivotal roles in opioid analgesia.
Highlights
Diabetes mellitus is the first non-infectious disease recognized as an epidemic of the twenty-first century [United Nations Resolution 61/225]
The Effect of macrophage inflammatory protein-1 (MIP-1) Members on Mechanical Nociceptive Threshold Measured by the von Frey Test Single i.t. administration of CCL3 diminished the nociceptive threshold to mechanical stimuli, and this effect was still observed at 1,440 min following injection (Figure 1A); at 60 min following administration of 500 ng CCL3, its pronociceptive effect had not yet been detected (Figure 1A)
The current study has shown that in the lumbar spinal cord of STZinduced diabetic neuropathic mice, a marker of microglia activation is upregulated in correlation with increased protein levels of CCL3 and CCL9 as measured on day 7, suggesting that these chemokines are very important in the development of diabetic neuropathy and that their source are microglial cells
Summary
Diabetes mellitus is the first non-infectious disease recognized as an epidemic of the twenty-first century [United Nations Resolution 61/225]. One of its main consequences is peripheral nerve damage, which leads to the development of neuropathic pain [1]. It is well established that glial cells, especially microglia, are responsible for its initiation These cells, when activated, release a broad spectrum of nociceptive factors together with cytokines; among those molecules, chemokines seem to be especially important. It was postulated that C–C (CCL2, CCL3), C–X–C (CXCL1, CXCL5, CXCL12), and X–C (XCL1) motif chemokine ligands play a crucial role in the development of neuropathic pain, including the pain accompanying diabetes [7,8,9,10]. Determining the role of C–C motif chemokine ligands in the MIP-1 family (namely, CCL3, CCL4, CCL9) in the development of diabetic neuropathy is highly important. It has already been shown that STZ administration increases blood glucose concentration, which is correlated with the development of long-lasting hypersensitivity to mechanical and thermal stimuli [6, 12, 13]
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