The inhibitory efect of Ph?1? toxin on diabetic neuropathic pain involves the CXCR4 chemokine receptor.

Background: Diabetic neuropathy is a common cause of painful diabetic neuropathy (PDN). C-X-C chemokine receptor type 4 (CXCR4) expression is increased in peripheral nerve samples from diabetes patients, suggesting a role for CXCR4 in PDN. Therefore, we evaluated the effects of Ph?1?, ?-conotoxin MVIIA, and AMD3100 in a model of streptozotocin (STZ)-induced PDN in rodents and na?ve model of rats with the activation of the CXCR4/stromal cell-derived factor 1 (SDF-1) signal. Methods: Diabetic neuropathy was induced by intraperitoneal (ip) injection of STZ in Wistar rats. Na?ve rats were intrathecally injected with SDF-1 to test the CXCR4/SDF-1 signal. The effects of Ph?1? intrathecal (it), ?-conotoxin MVIIA intrathecal (it), and AMD3100 intraperitoneal (ip) on rat hypersensitivity, IL-6, and the intracellular calcium [Ca2+]i content of diabetic synaptosomes were studied. Results: The drugs reduced the hypersensitivity in diabetic rats. SDF-1 (1.0 ?g/it) administration in na?ve rats induced hypersensitivity. Ph?1? (100 pmol/it) or AMD3100 (2.5 ?g/ip) reduced this hypersensitivity after 2 h treatments, while ?-conotoxin MVIIA did not have an effect. IL-6 and [Ca2+]i content increased in the spinal cord synaptosomes in diabetic rats. The drug treatments reduced IL-6 and the calcium influx in diabetic synaptosomes. Conclusions: Ph?1?, ?-conotoxin MVIIA, and AMD3100, after 2 h of treatment of STZ-induced PDN, reduced hypersensitivity in diabetic rats. In na?ve rats with CXCR4/SDF-1 activation, the induced hypersensitivity decreased after 2 h treatments with Ph?1? or AMD-3100, while ?-conotoxin MVIIA did not affect. The inhibitory effects of Ph?1? on PDN may involve voltage-dependent calcium channels