Chemotheraphy-induced peripheral neuropathy (CIPN) limits life saving anti-cancer treatment, can be permanent and negatively impacts quality of life. It is thus important to dissect the critical signaling pathways involved in development an maintenance of CIPN and identify therapeutic strategies to prevent or treat CIPN. The NMDA receptor (NMDAR) signaling complex plays a key role in central sensitization of chronic pain. While NMDAR antagonists are efficacious in decreasing pain sensitization, they have limited therapeutic uses because they disrupt normal physiological processes (e.g. motor function, memory and cognition). The NMDAR signaling complex consists of many protein partners including the scaffold postsynaptic density 95 kDA (PSD95) protein, the neuronal enzyme nitric oxide synthase (nNOS) and its adaptor protein NOS1AP. Disruption of specific steps downstream of NMDAR activation offers the opportunity to decrease pain sensitization while avoiding some of the broader side effects associated with upstream receptor blockade. Our preliminary studies suggest that the interface between nNOS and NOS1AP represents a previously unrecognized candidate target for the development of new analgesics for CIPN.
Aim 1 will determine whether disruption of nNOS interactions with its upstream or downstream protein partners bias NMDAR signaling in a functionally selective manner using biochemical and cell based assays.
Aim 2 will evaluate the therapeutic potential of disrupting the nNOS-NOS1AP protein-protein interface for suppressing neuropathic pain induced by the chemotherapeutic agent paclitaxel and correlate antinociceptive efficacy of intrathecally administered agents with disruption of the nNOS-NOS1AP complex in lumbar spinal cord of paclitaxel-treated rats.
Aim 3 will identify signaling pathways downstream of NOS1AP that underly the ability of nNOS-NOS1AP inhibitors to attenuate paclitaxel-induced neuropathic pain. In this project, the mechanism by which peptide and small molecule protein-protein interaction inhibitors to selectively block NMDAR-induced hypersensitivity in a paclitaxel-induced neuropathic pain model will be elucidated. If confirmed, a new generation of modulators of pathological pain could be developed by targeting this interaction.
Inadequate treatment of chronic pain results in a significant socioeconomic burden in terms of both medical costs and lost productivity. This proposal seeks to validate NOS1AP, an adaptor protein downstream of neuronal nitric oxide synthase, as a therapeutic target for treating neuropathic pain resulting from chemotherapy treatment by disrupting protein-protein interactions. This approach offers potential for maximizing therapeutic efficacy of novel inhibitors likely to exhibit favorable analgesic profiles without the unwanted sie effects of conventional treatments on motor function, abuse liability or memory.
|Lee, Wan-Hung; Carey, Lawrence M; Li, Li-Li et al. (2018) ZLc002, a putative small-molecule inhibitor of nNOS interaction with NOS1AP, suppresses inflammatory nociception and chemotherapy-induced neuropathic pain and synergizes with paclitaxel to reduce tumor cell viability. Mol Pain 14:1744806918801224|
|Robinson, Sean; Courtney, Michael J (2018) Spatial quantification of the synaptic activity phenotype across large populations of neurons with Markov random fields. Bioinformatics 34:3196-3204|
|Lee, Wan-Hung; Li, Li-Li; Chawla, Aarti et al. (2018) Disruption of nNOS-NOS1AP protein-protein interactions suppresses neuropathic pain in mice. Pain 159:849-863|
|Panoz-Brown, Danielle; Iyer, Vishakh; Carey, Lawrence M et al. (2018) Replay of Episodic Memories in the Rat. Curr Biol 28:1628-1634.e7|
|Lin, Xiaoyan; Dhopeshwarkar, Amey S; Huibregtse, Megan et al. (2018) Slowly Signaling G Protein-Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence. Mol Pharmacol 93:49-62|
|Slivicki, Richard A; Saberi, Shahin A; Iyer, Vishakh et al. (2018) Brain-Permeant and -Impermeant Inhibitors of Fatty Acid Amide Hydrolase Synergize with the Opioid Analgesic Morphine to Suppress Chemotherapy-Induced Neuropathic Nociception Without Enhancing Effects of Morphine on Gastrointestinal Transit. J Pharmacol Exp Ther 367:551-563|
|Slivicki, Richard A; Xu, Zhili; Kulkarni, Pushkar M et al. (2018) Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence. Biol Psychiatry 84:722-733|
|Panoz-Brown, Danielle; Carey, Lawrence M; Smith, Alexandra E et al. (2017) The chemotherapeutic agent paclitaxel selectively impairs reversal learning while sparing prior learning, new learning and episodic memory. Neurobiol Learn Mem 144:259-270|
|Carey, Lawrence M; Lee, Wan-Hung; Gutierrez, Tannia et al. (2017) Small molecule inhibitors of PSD95-nNOS protein-protein interactions suppress formalin-evoked Fos protein expression and nociceptive behavior in rats. Neuroscience 349:303-317|
|Li, Li-Li; Cisek, Katryna; Courtney, Michael J (2017) Efficient Binding of the NOS1AP C-Terminus to the nNOS PDZ Pocket Requires the Concerted Action of the PDZ Ligand Motif, the Internal ExF Site and Structural Integrity of an Independent Element. Front Mol Neurosci 10:58|
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