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

Dermaxon, Llc, Missoula MT

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Abstract

Project Summary / Abstract Paclitaxel is widely used throughout the field of oncology with indications for the treatment of a number of solid tumors. The most commonly reported neurotoxic effect of paclitaxel is peripheral sensory neuropathy which often limits the dose and frequency of paclitaxel treatment. Neuropathic pain management is currently aimed only at reducing symptoms and treatment of chronic pain remains an unmet clinical need. Human clinical studies and animal models have indicated that the altered central processing associated with pain is maintained dynamically by ongoing peripheral input. It is likely that pain from a variety of causes, becomes chronic as a result of the damaged primary afferent fibers and corresponding neurons, and central mechanism resulting in central sensitization. T-type calcium channels and more precisely isoform Cav3.2 contributes to the firing behavior of pain sensing neurons in synaptic nerve terminals of afferent pain fibers and mechanoreceptors. Their 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 pain. Intraplantar administration of a Cav3.2 inhibitor reversed mechanical hyperalgesia induced by paclitaxel in rodents. We have designed, synthesized and characterized several novel selective T-type inhibitors that exhibit analgesic efficacy in inflammatory and chronic pain models. Our preliminary work has enabled us to formulate the central hypothesis of this proposal that, a topical treatment which selectively inhibits Cav3.2 in the skin will decrease cutaneous nociceptive input that triggers central sensitization, hence resulting in the reduction of chemotherapy- induced peripheral neuropathy, with improved efficacy and patient tolerance compared to systemic treatments. Our 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 stimulus (allodynia) in animals with paclitaxel-induced neuropathy. Our objectives in this proposal are: in Aim 1, we will complete the optimization of our topical T-type selective inhibitors, based on our previously designed chemotypes using a soft-drug approach and characterize their Cav3.2 activity and selectivity; in Aim 2 we will assess their safety, and design a topical drug-delivery system, and in Aim 3 we have selected the paclitaxel-induced neuropathy model to test the efficacy of two selected T-type channel inhibitors in vivo and using skin-nerve recording. The 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 pain, and support development of a new therapeutic topical treatment.