Papers of the Week

Painful Diabetic Peripheral Neuropathy (PDPN) is one of the major complications of diabetes. Currently, centrally acting drugs and topical analgesics are used for treating PDPN. These drugs have adverse effects, some are ineffective and treatment with opioids is associated with use dependence and addiction. Recent research indicates that Transient Receptor Potential Vanilloid 1 (TRPV1) expressed in the peripheral sensory nerve terminals is an emerging target to treat pain associated with PDPN. Blocking TRPV1 ion channel using specific antagonists, although effective as an analgesic, but induced hyperthermia in clinical trials. However, TRPV1 agonists are useful to treat pain by virtue of their ability to cause Ca2+ influx and subsequently leading to nerve terminal desensitization. Here, we report the effectiveness of an ultra-potent TRPV1 agonist, resiniferatoxin (RTX) nanoparticle in a topical formulation (RTX-cream; RESINIZINTM) that alleviates pain associated with DPN in animal models of diabetes. RTX causes nerve terminal depolarization block in the short-term, which prevents pain during application and leading to nerve terminal desensitization/depletion in the long-term resulting in long lasting pain relief. Application of RTX cream to the hind limbs suppresses thermal hyperalgesia in streptozotocin (STZ)-induced diabetic rats and mini-pigs without any adverse effects as compared to capsaicin at therapeutic doses, which induces intense pain during application. RTX cream also decreases the expression of TRPV1 in the peripheral nerve endings and suppresses TRPV1-mediated CGRP release in the skin samples of diabetic rats and mini-pigs. Our preclinical data confirm that RTX topical formulation is an effective treatment option for PDPN.