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(12) United States Patent (10) Patent No.: US 8,501,740 B2 Gutstein (45) Date of Patent: Aug US00850.1740B2 (12) United States Patent (10) Patent No.: US 8,501,740 B2 Gutstein (45) Date of Patent: Aug. 6, 2013 (54) METHODS OF TREATMENT OF OPIOID FOREIGN PATENT DOCUMENTS TOLERANCE, PHYSICAL DEPENDENCE, WO WO O2/O58687 A2 * 8, 2002 PAN AND ADDCTION WITH INHIBITORS OF CERTAIN GROWTH FACTOR OTHER PUBLICATIONS RECEPTORS Polakiewicz et al. 1998, “A Mitogen-activated protein kinase path (75) Inventor: Howard Gutstein, Bellaire, TX (US) way is required for u-opioid receptor desensitization.” Journal of Biological Chemistry, vol. 273, No. 20, pp. 12402-12406.* (73) Assignee: Board of Regents, The University of Elliott et al. 1994, "The NMDA receptor antagonists, LY274614 and Texas System, Austin, TX (US) MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L- arginine ...” Pain, vol. 56, pp. 69-75.* (*) Notice: Subject to any disclaimer, the term of this Kolesnikov et al. 1993, “Blockade oftolerance to morphinebut not to patent is extended or adjusted under 35 k-opioids by a nitric oxide synthase inhibitor.” Proc. 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USPC .................... 514/252.18, 256; 544/242, 295, 544/364 (Continued) See application file for complete search history. Primary Examiner — Kara R McMillian (56) References Cited (74) Attorney, Agent, or Firm — Parker Highlander PLLC U.S. PATENT DOCUMENTS (57) ABSTRACT 6,667,293 B1 12/2003 Zhao et al. Methods of preventing the development and reversing or 6,894,051 B1 5/2005 Zimmermann et al. 7,034,013 B2 4/2006 Thompson et al. partially reversing opioid tolerance in a Subject are provided 7,115,587 B2 10/2006 Nerurkar et al. herein. Such methods include the step of administering to a 7,151,106 B2 12/2006 Hayry subject in need thereofatherapeutically effective amount of a 7,544,799 B2 6/2009 Zimmermann et al. PDGFR modulator or EGFR modulator alone or together 7,629,331 B2 12/2009 Pipkin et al. with an opiate analgesic. 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Sustained activation of ERK and downstream receptor signaling in Kolesnikov, Y.A., et al., Blockade ofTolerance to Morphinebut not to malignant glioma cells.” International Journal of Oncology, 38:555 Opioids by a Nitric Oxide Synthase Inhibitor, Proc Natl Acad Sci 569, 2011. USA, 1993, 90:5162-516. Chu et al., “BCR/ABL kinase inhibition by imatinib mesylate Kotecha, S.A., et al., A D2 class dopamine receptor transactivates a enhances MAP kinase activity in chronic myelogenous leukemia receptor tyrosine kinase to inhibit NMDA receptor transmission. CD34+ cells.” Blood, 103(8):3167-3174, 2004. Neuron, 2002. 35(6): p. 1111-22. Johnson et al., “Induction of heparin-binding EGF-like growth factor 20. Kumar A. et al., Structure and Clinical Relevance of the Epider and activation of EGF receptor in imatinib mesylate-treated mal Growth Factor Receptor in Human Cancer, JClin Oncol. Apr. 1, squamous carcinoma cells,” Journal of Cellular Physiology, 2008:26(10): 1742-51. 205:218-227, 2005. 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