Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain
| Autor: | James E. Grace, Brian Zambrowicz, Pradeep Vattikundala, Kenneth G. Carson, Jonathan Lippy, Clotilde Bourin, Alan Main, Alan Wilson, Sreenivasulu Naidu, Sandhya Mandlekar, Carolyn Diane Dzierba, Saravanan Elavazhagan, Walter Kostich, Gauri Shankar, Jeffrey M. Brown, Charles M. Conway, Charles F. Albright, Justin Vijay Louis, Yu-Wen Li, Vivek Sharma, Yanling Huang, Laszlo Kiss, Amr Nouraldeen, Susheel J. Nara, Martin A. Lewis, Ryan Westphal, Vinay K. Holenarsipur, Anand Balakrishnan, Amy Easton, Robert Zaczek, Jonathan C. Swaffield, Ted Molski, Rick L. Pieschl, Kevin Baker, Katerina Savelieva, Yingzhi Bi, Kenneth S. Santone, Linda J. Bristow, John E. Macor, Jianlin Feng, Guilan Ye, Joanne J. Bronson, Manish Lal Das, Reeba K. Vikramadithyan, Kevin O’Malley, Jason W. Allen, Brian D. Hamman, Michael Gulianello, Yifeng Lu, Thomas H. Lanthorn, Kimberley A. Lentz, Anoop Kumar, Manoj Dokania, Kumaran Dandapani, Rex Denton |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Nociception medicine.drug_class Stimulation Pharmacology Protein Serine-Threonine Kinases 03 medical and health sciences Drug Discovery and Translational Medicine Gene Knockout Techniques Mice 0302 clinical medicine Opioid receptor medicine Animals Humans Receptor Protein Kinase Inhibitors business.industry medicine.disease Electrophysiological Phenomena Rats 030104 developmental biology Peripheral neuropathy HEK293 Cells Phenotype Opioid Spinal Cord Neuropathic pain Knockout mouse Molecular Medicine Neuralgia business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | The Journal of Pharmacology and Experimental Therapeutics |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans. |
| Databáze: | OpenAIRE |
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