US 2015O125441A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0125441 A1 Wang et al. (43) Pub. Date: May 7, 2015 (54) METHODS OF TREATING DEPRESSION AND Publication Classification PAIN (51) Int. Cl. (71) Applicant: NEW YORK UNIVERSITY, New A613 L/453 (2006.01) York, NY (US) A6II 45/06 (2006.01) A613 L/405 (2006.01) (72) Inventors: Jing Wang, New York, NY (US); (52) U.S. Cl. Edward Ziff, New York, NY (US) CPC ........... A6 IK3I/453 (2013.01); A61 K3I/4015 (2013.01); A61K 45/06 (2013.01) (73) Assignee: New York University, New York, NY (57) ABSTRACT (US) The present invention provides methods of treating and phar maceutical compositions useful for treating a mood disorder (21) Appl. No.: 14/401,202 or depressive symptoms associated with pain, inducing anal gesia and treating pain in a Subject by administering a phar (22) PCT Filed: May 24, 2013 maceutically effective amount of an agent capable of one or more of increasing GluA1 level, expression, concentration, or 86) PCT NO. PCT/US2013/042572 biological1ological activity,activitV. iincreasing calciumlci permeableble AMPA O. S371 (c)(1) amino-3-hydroxy-5-methylisoxazole-4-propionic acid) (2) Date: s Nov. 14, 2014 receptor (CPAR) level, expression, concentration, or biologi e - rs cal activity or potentiating a CPAR current. The agent may be an AMPA potentiator or ampakine. The agent may increase O O AMPA receptor currents by slowing the deactivation of open Related U.S. Application Data channels and may be, for instance, 2-pyrrolidinone, 4-2- (60) Provisional application No. 61/750,504, filed on Jan. (phenylsulfonylamino)ethylthio-2,6-difluorophenoxyaceta 9, 2013, provisional application No. 61/651,107, filed mide (PEPA) or LY451646. The agent may also be a protein, on May 24, 2012. RNA or DNA product. Patent Application Publication May 7, 2015 Sheet 1 of 11 US 201S/O125441 A1 FIG. 1A FIG. 1B FIG. 1C FIG. 1D Sham sham a A SN A SN 15 3.0 p<0.01 p<0.001 2.5 5 10 20 ss s 3 s 5 p<0.01 p<0.01 6. is 0 0.0 O s Baseline POD3 POD 14. Baseline POD 3 POD 14 POD 3 POD 14 POD 3 POD 14 gd FIG. 1E FIG. 1F FIG. 1 G FIG. 1H COe shell Core Shell O POD 3 POD14 POD3 POD14 Patent Application Publication May 7, 2015 Sheet 2 of 11 US 201S/O125441 A1 FIG. 2A FIG. 2B FIG. 2C FIG. 2D a fair pool 50pA 50pA n as 25mS 25ms 2 2 FIG. 2E FIG. 2F 31 NASPM NASPM 50pA 5OOA O fBaseline E. fBaseliné E. Sham SN Wm -70 mV Wm= -70 mV. p<0.001 FIG. 2 FIG. 2G 40 FIG. 2H400 EPSC arra N. BC 15 BC 12 30 N 300 N. 2 00 100 a. NAC Core =- Baseline NASPM Baseline NASPM Patent Application Publication May 7, 2015 Sheet 3 of 11 US 201S/O125441 A1 FIG. 3A -14 days 0 days 14 days FIG. 3C FIG. 3D FIG. 3E aSaline th s - s c 3 4. a NASPM as 9 S a B.S9 5O O S S as s s 2. S. 2 1 1 Es 9 S 3 85 O 12345678:10 c 2 .S. 9 C. o 5O O O Ol's SNI+ SNI+ time (bins of 3min) ge Saline NASPM Saline NASPM r c FIG. 3B FIG. 3F FIG. 3G FIG. 3H NASPM SS p40.01 p<0.05 Bc 1.7 Bc15 BC 12 U. K. £5 0.6 Stratin 38 04 0.4 is 86 86 SN + Sham + Sham + s" Sham SN. " SalineSN + NASPM Saline NASPM Patent Application Publication May 7, 2015 Sheet 4 of 11 US 201S/O125441 A1 FIG. 4A -14 days 0 days 14 days FIG. 4B F G. 4C 3 12 O O SN + SNI + SNI + SN + Saline 2-pyrrolidinone Saline 2-pyrrolidinone FIG. 4D FIG. 4E p<0.05 2-pyrrolidinone O BC 1.2 BC 1.2 Striatu : 2 O SN + SN + Saline 2-pyrrolidinone NAC Core Patent Application Publication May 7, 2015 Sheet 5 of 11 US 201S/O125441 A1 FIG. 5 -- naive -o- SN -A- sham Surgery -- SNI uninjured leg 2.0 1.5 1.0 0.5 0.0 ==s CD CY) N CO : S r : ? -- naive -o- SN -Al Sham -- SNI uninjured leg Patent Application Publication May 7, 2015 Sheet 6 of 11 US 201S/O125441 A1 FIG. 6A 150 100 5 O Sham SN baseline POD 14 POD56 FIG. 6C — — — naive Sham SN O1 8O 3% 0. 6 % baseline POD 2 POD 7 naive SN 2 sham Patent Application Publication May 7, 2015 Sheet 7 of 11 US 201S/O125441 A1 FIG. 7A - 15 s s O S SS S 5 O O 6hr 24 hr 48 hr >7 d paW incision Control 1.00 3 5 0.75 SD 92 5 0.50 CD 3 0.25 d 0.00 POD 1 POD 2 POD 7 paW incision Control Patent Application Publication May 7, 2015 Sheet 8 of 11 US 201S/O125441 A1 FIG. 8A Hippocampus FIG. 8B 1.5 1.0 aO.O Sham SN Sham SN FIG. 8C Cerebellum GluA1 ::::::::::::::::::::::::::: ---, ... : :------ Tubulin 8 8- :::::::::::::: z z FIG. 8D 1 15 10 0.5 0.0 Sham SN Sham SN Patent Application Publication May 7, 2015 Sheet 9 of 11 US 201S/O125441 A1 FIG. 9A sham 20ms "20ms FIG. 9B 50 O Sham V (mV) -75 - 25 50 75 -50 -100 O SN 100 V (mV) -75 -50 -25 25 50 75 -100 -200 FIG. 9C Rectification Index 15 1.0 0.5 0.0 Sham SN Patent Application Publication May 7, 2015 Sheet 10 of 11 US 201S/O125441 A1 FIG 10A FIG. 1 OB mechanical SuCrose preference hypersensitivity "p-0.05 p=0.5 0.9 o o 0.6 0.3 1 0.0 O Saline NASPM Saline NASPM FIG 10C loCOmotion -H Saline g 1500 - A - NASPM E 1000 2 p=0.3 E 500 8 O O (3min bins) 0 1 2 3 4 5 6 789 10 FIG. 1 OD NAC Shell Patent Application Publication May 7, 2015 Sheet 11 of 11 US 201S/O125441 A1 FIG. 1 1A S. mechanical allodynia 15 DMSO CX546 3 10 s is 5 2 s O S 10 mg/kg 5 mg/kg 2.5 mg/kg Cold allodynia 3 DMSO ge 2 CX546 ; O 8 1 O 10 mg/kg 5 mg/kg 2.5 mg/kg forced Swim test 250 3. 200 > DMSO Es 150 CX546 2 100 E 50 O DMSO CX546 (10mg/kg) US 2015/O125441 A1 May 7, 2015 METHODS OF TREATING DEPRESSION AND cology 2011; Tokita, et al., Pharmacol Biochem Behav 2011; PAN Koike, et al., Behav Brain Res 2011; 224: 107-11). 0005. A key glutamate signaling mechanism is the traf FIELD OF THE INVENTION ficking of C-amino-3-hydroxy-5-methyl-4-isoxazolepropi 0001. The present invention relates generally to treating onic acid (AMPA) receptors (Ziff, Neuron 2007:53: 627-33). mood disorders such as depression, particularly those asso AMPA receptors bind glutamate to conduct excitatory post ciated with or Subsequent to pain, Such as chronic pain, induc synaptic currents, and they are tetramers formed by varying ing analgesia and treating pain. combinations of four subunits, GluA1, 2, 3 and 4. GluA1 and GluA2 are the most abundant subunits in the NAc. GluA2 BACKGROUND OF THE INVENTION lacking AMPA receptors form in the NAc when GluA1 expression is increased, and they are permeable to calcium 0002 Pain is a major public health issue, affecting a third (Greger, et al Trends Neurosci 2007:30: 407-16). These cal of Americans. Loss of function as the result of pain costs our cium permeable AMPA receptors (CPARs) can regulate cal healthcare system over 300 billion dollars annually. Pain is a cium-dependent synaptic plasticity. While GluA2 subunits common morbidity after Surgery, and most pain patients Suf constitutively traffic to synapses, GluA1 trafficking is activ fer from depressed mood (Scott, et al., J. Bone Joint Surg Br ity-dependent and hence may respond to rewards (Barry, et al. 2010:92: 1253-8: Edwards, et al., Pain Res Manag 2009; 14: Curr Opin Neurobiol 2002; 12: 279-86) or pain. Thus, tightly 307-11 Dworkin, et al., Clin J. Pain 1991; 7: 79–94; Romano controlled GluA1 trafficking promotes the formation of et al., Psychol Bull 1985: 97: 18-34 and Rieckmann, et al., CPARs in the NAc and provides synaptic plasticity to regulate Psychother Pschother Psychosom 2006: 75: 353-61). Pain behaviors (Conrad, et al., Nature 2008; 454: 118-21). GluA1 induced depression impairs rehabilitation and worsens Surgi has been shown to modulate depressive symptoms. For cal outcome. example, GluA1 knockout mice display vulnerability to 0003. Depression is also a common and debilitating affec depression (Chourbaji, et al., FASEB J 2008: 22: 3129-34), tive feature of chronic pain (Dworkin, et al., ClinJ Pain 1991; and decreased GluA1 levels in the NAc have been reported in 7: 79-94; Miller, et al., J Pain 2009; 10: 619-627). Current rats that exhibit depressive behavior (Toth, et al., J. Neuro analgesics focus on sensory pain symptoms, but drugs such as chem 2008: 107: 522-32), whereas increased GluA1 levels NSAIDs and opioids have significant side effects. Thus, bet are found in the NAc with antidepressant treatments (Tan, et terunderstanding of the regulation of depression in pain states al. Exp Brain Res 2006: 170: 448-56). Studies in chronic pain will result in new treatments that focus on the depressive or postoperative pain, however, have not examined the role of symptoms of pain to improve daily function.