The present application """"""""Protein-protein interaction inhibitors as novel analgesics"""""""" addresses the critical need for efficacious analgesics lacking adverse side-effects. The NMDA receptor is involved in the maintenance of chronic pain and other pathological neuronal diseases. Dr. Lai, a co-principal investigator for this project, first showed that the small molecule inhibitor IC87201 disrupts the functional protein-protein interaction involving PDZ domains (neuronal nitric oxide synthase, nNOS and postsynaptic density protein 95, PSD95) required for NMDA receptor signaling. IC87201 also attenuated hyperalgesia in a rat model of neuropathic pain produced by traumatic nerve injury. However, whether nNOS-PSD95 inhibitors suppress nociceptive processing remains unknown. The objective of this application is to validate disruptors of nNOS-PSD95 protein-protein interactions as broad spectrum analgesics that suppress nociceptive processing using animal models of evoked and spontaneous pain. Persistent pain associated with central nervous system sensitization will be produced using inflammatory and toxic neuropathic insults. IC87201, one of the first small molecule protein-protein interaction disruptors, shows efficacy in several preclinical pain models. These findings support our hypothesis that disruption of signal compartmentalization represents an innovative approach to develop novel analgesics with fewer side-effects. The investigators, with extensive combined experience in drug discovery (Lai) and development of novel pain models (Hohmann) are well-positioned to conduct the proposed work. We will conduct experiments proposed under two Specific Aims: (1) To evaluate antinociceptive efficacy of small molecule inhibitors of nNOS-PSD95 on both inflammation-evoked behavioral hypersensitivities and neuronal activation;(2) To assess the efficacy of small molecule inhibitors of nNOS-PSD95 in suppressing spontaneous neuropathic pain using a conditioned place preference approach. Completion of this project is expected to validate the use of nNOS-PSD95 inhibitors as a new class of broad-spectrum analgesics. These studies are expected to validate the disruption of signal compartmentation as an innovative and feasible approach to drug development. The development of effective pharmacotherapies with novel chemical structures that possess limited side-effect profiles and minimal abuse liability is expected to drive down health care costs and alleviate suffering in patients.
Inadequate treatment of pain results in significant socioeconomic costs in medical costs and lost productivity. This proposal seeks to validate small molecule inhibitors that specifically disrupt a major neuronal signaling pathway implicated in pathological pain. These studies will assess the ability of these inhibitors to suppress both nociceptive processing and ongoing spontaneous pain using models of inflammation and nerve injury.
|Deng, Liting; Lee, Wan-Hung; Xu, Zhili et al. (2016) Prophylactic treatment with the tricyclic antidepressant desipramine prevents development of paclitaxel-induced neuropathic pain through activation of endogenous analgesic systems. Pharmacol Res 114:75-89|
|Smith, Alexandra E; Xu, Zhili; Lai, Yvonne Y et al. (2016) Source memory in rats is impaired by an NMDA receptor antagonist but not by PSD95-nNOS protein-protein interaction inhibitors. Behav Brain Res 305:23-9|
|Carey, Lawrence M; Slivicki, Richard A; Leishman, Emma et al. (2016) A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase. Mol Pain 12:|
|Slivicki, Richard A; Ali, Yousuf O; Lu, Hui-Chen et al. (2016) Impact of Genetic Reduction of NMNAT2 on Chemotherapy-Induced Losses in Cell Viability In Vitro and Peripheral Neuropathy In Vivo. PLoS One 11:e0147620|
|Deng, Liting; Cornett, Benjamin L; Mackie, Ken et al. (2015) CB1 Knockout Mice Unveil Sustained CB2-Mediated Antiallodynic Effects of the Mixed CB1/CB2 Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain. Mol Pharmacol 88:64-74|
|Lee, Wan-Hung; Xu, Zhili; Ashpole, Nicole M et al. (2015) Small molecule inhibitors of PSD95-nNOS protein-protein interactions as novel analgesics. Neuropharmacology 97:464-75|
|Deng, Liting; Guindon, JosÃ©e; Cornett, Benjamin L et al. (2015) Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biol Psychiatry 77:475-87|
|Marcus, David J; Zee, Michael; Hughes, Alex et al. (2015) Tolerance to the antinociceptive effects of chronic morphine requires c-Jun N-terminal kinase. Mol Pain 11:34|
|Guindon, JosÃ©e; Deng, Liting; Fan, Baochang et al. (2014) Optimization of a cisplatin model of chemotherapy-induced peripheral neuropathy in mice: use of vitamin C and sodium bicarbonate pretreatments to reduce nephrotoxicity and improve animal health status. Mol Pain 10:56|
|Rahn, Elizabeth J; Deng, Liting; Thakur, Ganesh A et al. (2014) Prophylactic cannabinoid administration blocks the development of paclitaxel-induced neuropathic nociception during analgesic treatment and following cessation of drug delivery. Mol Pain 10:27|