Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Kostich, W. and Hamman, B. D. and Li, Y.-W. and Naidu, S. and Dandapani, K. and Feng, J. and Easton, A. and Bourin, C. and Baker, K. and Allen, J. and Savelieva, K. and Louis, J. V. and Dokania, M. and Elavazhagan, S. and Vattikundala, P. and Sharma, V. and Das, M. L. and Shankar, G. and Kumar, A. and Holenarsipur, V. K. and Gulianello, M. and Molski, T. and Brown, J. M. and Lewis, M. and Huang, Y. and Lu, Y. and Pieschl, R. and OMalley, K. and Lippy, J. and Nouraldeen, A. and Lanthorn, T. H. and Ye, G. and Wilson, A. and Balakrishnan, A. and Denton, R. and Grace, J. E. and Lentz, K. A. and Santone, K. S. and Bi, Y. and Main, A. and Swaffield, J. and Carson, K. and Mandlekar, S. and Vikramadithyan, R. K. and Nara, S. J. and Dzierba, C. and Bronson, J. and Macor, J. E. and Zaczek, R. and Westphal, R. and Kiss, L. and Bristow, L. and Conway, C. M. and Zambrowicz, B. and Albright, C. F. (2016) Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain. Journal of Pharmacology and Experimental Therapeutics, 358 (3). pp. 371-386. ISSN 1521-0103


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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 a2 adrenergic and opioid receptors. These studies showed that a2 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 a2 adrenergic signaling, a pathway known to be antinociceptive in humans.

Item Type: Article
Subjects: Pharmaceutical Sciences
Divisions: College of Pharmacy > Pharmaceutical Sciences
Depositing User: Dr Justin Louis
Date Deposited: 01 May 2017 09:35
Last Modified: 01 May 2017 09:35

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