Topical selective T-type blockers for the treatment of neuropathic pain

Project SummaryAbstract Paclitaxel is widely used throughout the field of oncology with indications for the treatment of a number of solid tumorsThe most commonly reported neurotoxic effect of paclitaxel is peripheral sensory neuropathy which often limits the dose and frequency of paclitaxel treatmentNeuropathic pain management is currently aimed only at reducing symptoms and treatment of chronic pain remains an unmet clinical needHuman clinical studies and animal models have indicated that the altered central processing associated with pain is maintained dynamically by ongoing peripheral inputIt is likely that pain from a variety of causesbecomes chronic as a result of the damaged primary afferent fibers and corresponding neuronsand central mechanism resulting in central sensitizationT type calcium channels and more precisely isoform Cavcontributes to the firing behavior of pain sensing neurons in synaptic nerve terminals of afferent pain fibers and mechanoreceptorsTheir expression pattern is consistent with their critical roles at regulating light touch perception and noxious mechanical cold and chemical sensations and is essential to build up the allodynic symptoms of neuropathic painIntraplantar administration of a Cavinhibitor reversed mechanical hyperalgesia induced by paclitaxel in rodentsWe have designedsynthesized and characterized several novel selective T type inhibitors that exhibit analgesic efficacy in inflammatory and chronic pain modelsOur preliminary work has enabled us to formulate the central hypothesis of this proposal thata topical treatment which selectively inhibits Cavin the skin will decrease cutaneous nociceptive input that triggers central sensitizationhence resulting in the reduction of chemotherapyinduced peripheral neuropathywith improved efficacy and patient tolerance compared to systemic treatmentsOur hypothesis is strongly supported by our direct experimental findings showing that our submicromolar lead compound is not intrinsically rewarding but profoundly decreases spontaneous pain and hypersensitivity to normally innocuous stimulusallodyniain animals with paclitaxel induced neuropathyOur objectives in this proposal arein Aimwe will complete the optimization of our topical T type selective inhibitorsbased on our previously designed chemotypes using a soft drug approach and characterize their Cavactivity and selectivityin Aimwe will assess their safetyand design a topical drug delivery systemand in Aimwe have selected the paclitaxel induced neuropathy model to test the efficacy of two selected T type channel inhibitors in vivo and using skin nerve recordingThe identification of lead compounds that are active in preclinical paclitaxel induced neuropathy models will set the stage for the generation of new topical pain therapeutics for use in adult and pediatric patients suffering from chronic painand support development of a new therapeutic topical treatment PROJECT NARRATIVEPublic Health RelevanceTherapeutic activity of the antineoplastic agent paclitaxel is impaired by significant occurrence of sensory neuropathy resulting in treatment delaydose modificationand in severe casesdiscontinuation of the treatment impacting patient outcomeOur objective in this proposal is to design and deliver topically Cavblockers that will decrease abnormal neuronal hyperactivity of intradermal Cavchannels andexamine their potential as novel therapeutic agents to treat paclitaxel induced neuropathyThis STTR Phasewill generate data necessary to validate our proposed target intradermal Cavfor the treatment of paclitaxel induced neuropathy in adult and pediatric patients