Effect of ω-conotoxin MVIIA and Phα1β on paclitaxel-induced acute and chronic pain

AbstractThe treatment with the chemotherapeutic agent paclitaxel produces a painful peripheral neuropathy, and is associated with an acute pain syndrome in a clinically significant number of patients. However, no standard therapy has been established to manage the acute pain or the chronic neuropathic pain related to paclitaxel. In the present study, we evaluated the analgesic potential of two N-type voltage-gated calcium channel (VGCC) blockers, ω-conotoxin MVIIA and Phα1β, on acute and chronic pain induced by paclitaxel. Adult male rats were treated with four intraperitoneal injections of paclitaxel (1+1+1+1mg/kg, in alternate days) and the development of mechanical hyperalgesia was evaluated 24h (acute painful stage) or 15days (chronic painful stage) after the first paclitaxel injection. Not all animals showed mechanical hyperalgesia 24h after the first paclitaxel injection, but those that showed developed a more intense mechanical hyperalgesia at the chronic painful stage. Intrathecal administration (i.t.) of ω-conotoxin MVIIA (3–300pmol/site) or Phα1β (10–300pmol/site) reduced the mechanical hyperalgesia either at the acute or at the chronic painful stage induced by paclitaxel. When administered at the acute painful stage, ω-conotoxin MVIIA (300pmol/site, i.t.) and Phα1β (300pmol/site, i.t.) prevented the worsening of chronic mechanical hyperalgesia. Furthermore, Phα1β (30-300pmol/site, i.t.) elicited less adverse effects than ω-conotoxin MVIIA (10-300 pmol/site, i.t.). Taken together, our data evidence the involvement of N-type VGCC in pain sensitization induced by paclitaxel and point out the potential of Phα1β as a safer alternative than ω-conotoxin MVIIA to treat the pain related to paclitaxel

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