1-(2′,4′-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihy droindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice

Neurobiology of Disease

Volumn 37, Issue 1, 2010, Pages 177-185

  Luongo, L ^a   Palazzo, E ^a   Tambaro, S ^b   Giordano, C ^a   Gatta, L ^a   Scafuro, M A ^a   Rossi, F sca ^a   Lazzari, P ^b   Pani, L ^b,d   de Novellis, V ^a   Malcangio, M ^c   Maione, S ^a  

^a SECOND UNIVERSITY OF NAPLES   (Italy)

^b Neuroscience PharmaNess SCARL   (Italy)

^c KING'S COLLEGE LONDON   (United Kingdom)

^d CNR   (Italy)

Author keywords

CB2receptor; Endocannabinoids; Microglia; Neuropathic pain

Indexed keywords

1 (2',4' DICHLOROPHENYL) 6 METHYL N CYCLOHEXYLAMINE 1,4 DIHYDROINDENO[1,2 C]PYRAZOLE 3 CARBOXAMIDE; CANNABINOID 2 RECEPTOR; CANNABINOID RECEPTOR AGONIST; MESSENGER RNA; NESS 400; UNCLASSIFIED DRUG; 1 (2',4' DICHLOROPHENYL) 6 METHYL N CYCLOHEXYLAMINE 1,4 DIHYDROINDENO(1,2 C)PYRAZOLE 3 CARBOXAMIDE; 1-(2',4'-DICHLOROPHENYL)-6-METHYL-N-CYCLOHEXYLAMINE-1,4-DIHYDROINDENO(1,2-C)PYRAZOLE-3 CARBOXAMIDE; ANALGESIC AGENT; CYTOKINE; INDENE DERIVATIVE; PYRAZOLE DERIVATIVE;

ALLODYNIA; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ASTROCYTOSIS; CELL ACTIVATION; CELL COUNT; CELL PROLIFERATION; CELL TYPE; CHRONIC DRUG ADMINISTRATION; CONTROLLED STUDY; DRUG MECHANISM; GENE EXPRESSION; HYPERALGESIA; HYPERTROPHY; MALE; MICROGLIA; MOUSE; NERVE CELL PLASTICITY; NERVE INJURY; NEUROPATHIC PAIN; NONHUMAN; PAIN THRESHOLD; PRIORITY JOURNAL; PROTEIN EXPRESSION; RECEPTOR UPREGULATION; SPINAL CORD DORSAL HORN; ANIMAL; ASTROCYTE; C57BL MOUSE; DRUG EFFECT; DRUG POTENTIATION; GLIOSIS; METABOLISM; NERVOUS SYSTEM INJURY; PAIN; PATHOPHYSIOLOGY; PHYSIOLOGY; SPINAL CORD; STIMULATION; TEMPERATURE; TIME;

ANALGESICS; ANIMALS; ASTROCYTES; CELL COUNT; CYTOKINES; GLIOSIS; HYPERALGESIA; INDENES; MALE; MICE; MICE, INBRED C57BL; MICROGLIA; PAIN; PAIN THRESHOLD; PHYSICAL STIMULATION; PYRAZOLES; RECEPTOR, CANNABINOID, CB2; RNA, MESSENGER; SPINAL CORD; TEMPERATURE; TIME FACTORS; TRAUMA, NERVOUS SYSTEM;

EID: 70450221675     PISSN: 09699961     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.nbd.2009.09.021     Document Type: Article

References (74)

1. Barclay J., Clark A.K., Ganju P., Gentry C., Patel S., Wotherspoon G., Buxton F., Song C., Ullah J., Winter J., Fox A., Bevan S., and Malcangio M. Role of the cysteine protease cathepsin S in neuropathic hyperalgesia. Pain 130 3 (2007) 225-234
2. Beggs S., and Salter M.W. Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury. Brain Behav. Immun. 21 5 (2007) 624-633
3. Beltramo M., Bernardini N., Bertorelli R., Campanella M., Nicolussi E., Fredduzzi S., and Reggiani A. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur. J. Neurosci. 23 6 (2006) 1530-1538
4. Bonica J.J. Pain-basic principles of management. Northwest Med. 69 8 (1970) 567-568
5. Calignano A., La Rana G., Giuffrida A., and Piomelli D. Control of pain initiation by endogenous cannabinoids. Nature 394 (1998) 277-281
6. Carrier E.J., Kearn C.S., Barkmeier A.J., Breese N.M., Yang W., Nithipatikom K., Pfister S.L., Campbell W.B., and Hillard C.J. Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol. Pharmacol. 65 4 (2004) 999-1007
7. Casu M.A., Porcella A., Ruiu S., Saba P., Marchese G., Carai M.A., Reali R., Gessa G.L., and Pani L. Differential distribution of functional cannabinoid CB1 receptors in the mouse gastroenteric tract. Eur. J. Pharmacol. 10 459(1) (2003) 97-105
8. Cheng Y., and Hitchcock S.A. Targeting cannabinoid agonists for inflammatory and neuropathic pain. Expert Opin. Investig. Drugs 16 7 (2007) 951-965 Review
9. Clark A.K., Gentry C., Bradbury E.J., McMahon S.B., and Malcangio M. Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur. J. Pain 11 2 (2007) 223-230
10. Clark A.K., Yip P.K., Grist J., Gentry C., Staniland A.A., Marchand F., Dehvari M., Wotherspoon G., Winter J., Ullah J., Bevan S., and Malcangio M. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. U. S. A. 19 104(25) (2007) 10655-10660
11. Clayton N., Marshall F.H., Bountra C., and O'Shaughnessy C.T. CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain 96 (2002) 253-260
12. Colburn R.W., Rickman A.J., and DeLeo J.A. The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp. Neurol. 157 (1999) 289-304
13. Correa F., Mestre L., Docagne F., and Guaza C. Activation of cannabinoid CB2 receptor negatively regulates IL-12p40 production in murine macrophages: role of IL-10 and ERK1/2 kinase signaling. Br. J. Pharmacol. 145 4 (2005 Jun.) 441-448
14. Costa B., Trovato A.E., Colleoni M., Giagnoni G., Zarini E., and Croci T. Effect of the cannabinoid CB1 receptor antagonist, SR141716, on nociceptive response and nerve demyelination in rodents with chronic constriction injury of the sciatic nerve. Pain 116 1-2 (2005) 52-61
15. Coull J.A., Beggs S., Boudreau D., Boivin D., Tsuda M., Inoue K., Gravel C., Salter M.W., and De Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 15 438 (2005) 1017-1021
16. Coyle D.E. Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynic behavior. Glia 23 (1998) 75-83
17. Di Marzo V. Endocannabinoids and other fatty acid derivates with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim. Biophys. Acta 1392 (1998) 153-175
18. Decosterd I., and Woolf C.J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87 2 (2000) 149-158
19. Franklin A., and Stella N. Arachidonylcyclopropylamide increases microglial cell migration through cannabinoid CB2 and abnormal-cannabidiol-sensitive receptors. Eur. J. Pharmacol. 8 474(2-3) (2003) 195-198
20. Galderisi U., Di Bernardo G., Cipollaro M., Peluso G., Cascino A., Cotrufo R., and Melone M.A. Differentiation and apoptosis of neuroblastoma cells: role of N-myc gene product. J. Cell. Biochem. 73 1 (1999) 97-105
21. Garcia-Ovejero D., Arevalo-Martin A., Petrosino S., Docagne F., Hagen C., Bisogno T., Watanabe M., Guaza C., Di Marzo V., and Molina-Holgado E. The endocannabinoid system is modulated in response to spinal cord injury in rats. Neurobiol. Dis 33 1 (2009) 57-71
22. Garden G.A., and Möller T. Microglia biology in health and disease. J. Neuroimmune Pharmacol. 1 2 (2006) 127-137 Review
23. Goya P., Jagerovic N., Hernandez-Folgado L., and Martin M.I. Cannabinoids and neuropathic pain. Mini Rev. Med. Chem 3 7 (2003) 765-772
24. Guindon J., Desroches J., Dani M., and Beaulieu P. Pre-emptive antinociceptive effects of a synthetic cannabinoid in a model of neuropathic pain. Eur. J. Pharmacol. 568 1-3 (2007) 173-176
25. Hains B.C., and Waxman S.G. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J. Neurosci 26 16 (2006) 4308-4317
26. Hald A., Nedergaard S., Hansen R.R., Ding M., and Heegaard A.M. Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain. Eur. J. Pain 13 2 (2008 May 20) 138-145
27. Hanus L., Breuer A., Tchilibon S., Shiloah S., Goldenberg D., Horowitz M., Pertwee R.G., Ross R.A., Mechoulam R., and Fride E. HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 14,228-14,233
28. Ibrahim M.M., Deng H., Zvonok A., Cockayne D.A., Kwan J., Mata H.P., Vanderah T.W., Lai J., Porreca F., Makriyannis A., and Malan Jr. T.P. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc. Natl. Acad. Sci. U. S. A. 100 18 (2003) 10529-10533
29. Ibrahim M.M., Porreca F., Lai J., Albrecht P.J., Rice F.L., Khodorova A., Davar G., Makriyannis A., Vanderah T.W., Mata H.P., and Malan Jr. T.P. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc. Natl. Acad. Sci. U. S. A. 22 102(8) (2005) 3093-3098
30. Jhaveri M.D., Sagar D.R., Elmes S.J., Kendall D.A., and Chapman V. Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain. Mol. Neurobiol. 36 1 (2007) 26-35 Review
31. Ji R.R., and Suter M.R. p38 MAPK, microglial signaling, and neuropathic pain. Mol. Pain 3 1 (2007) 33
32. John G.R., Chen L., Rivieccio M.A., Melendez-Vasquez C.V., Hartley A., and Brosnan C.F. Interleukin-1beta induces a reactive astroglial phenotype via deactivation of the Rho GTPase-Rock axis. J. Neurosci. 24 11 (2004) 2837-2845
33. Kigerl K.A., McGaughy V.M., and Popovich P.G. Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury. J. Comp. Neurol. 494 4 (2006) 578-594
34. Kreutzberg G.W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19 8 (1996) 312-318 Review
35. Lange J.H., and Kruse C.G. Keynote review: Medicinal chemistry strategies to CB1 cannabinoid receptor antagonists. Drug Discov. Today 15 10(10) (2005) 693-702 Review
36. La Rana G., Russo R., Campolongo P., Bortolato M., Mangieri R.A., Cuomo V., Iacono A., Raso G.M., Meli R., Piomelli D., and Calignano A. Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]. J. Pharmacol. Exp. Ther. 317 3 (2006) 1365-1371
37. Leichsenring A., Andriske M., Bäcker I., Stichel C.C., and Lübbert H. Analgesic and antiinflammatory effects of cannabinoid receptor agonists in a rat model of neuropathic pain. Naunyn-Schmiedeberg's Arch. Pharmacol. 379 6 (2009) 627-636
38. Maione S., Bisogno T., de Novellis V., Palazzo E., Cristino L., Valenti M., Petrosino S., Guglielmotti V., Rossi F., and Di Marzo V. Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors. J. Pharmacol. Exp. Ther. 316 3 (2006) 969-982
39. Maresz K., Carrier E.J., Ponomarev E.D., Hillard C.J., and Dittel B.N. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J. Neurochem. 95 2 (2005) 437-445
40. Matsuda L.A., Lolait S.J., Brownstein M.J., Young A.C., and Bonner T.I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 9 346(6284) (1990) 561-564
41. Metz A.E., Yau H.J., Centeno M.V., Apkarian A.V., and Martina M. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain. Proc. Natl. Acad. Sci. U. S. A. 106 7 (2009) 2423-2428
42. Millan M.J. The induction of pain: an integrative review. Prog. Neurobiol. 57 1 (1999) 1-164 Review
43. Milligan E.D., and Watkins L.R. Pathological and protective roles of glia in chronic pain. Nat. Rev., Neurosci. 10 1 (2009) 23-36 Review
44. Milligan E.D., Sloane E.M., and Watkins L.R. Glia in pathological pain: a role for fractalkine. J. Neuroimmunol. (2008) 9
45. Moss A., Beggs S., Vega-Avelaira D., Costigan M., Hathway G.J., Salter M.W., and Fitzgerald M. Spinal microglia and neuropathic pain in young rats. Pain 128 3 (2007) 215-224
46. Munro S., Thomas K.L., and Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365 6441 (1993) 61-65
47. Murineddu G., Lazzari P., Ruiu S., Sanna A., Loriga G., Manca I., Falzoi M., Dessì C., Curzu M.M., Chelucci G., Pani L., and Pinna G.A. Tricyclic pyrazoles. 4. Synthesis and biological evaluation of analogues of the robust and selective CB2 cannabinoid ligand 1-(2′,4′-dichlorophenyl)-6-methyl-N-piperidin-1-yl-1,4-dihyd roindeno[1,2-c]pyrazole-3-carboxamide. J. Med. Chem. 49 25 (2006) 7502-7512
48. Palazzo E., de Novellis V., Petrosino S., Marabese I., Vita D., Giordano C., Di Marzo V., Mangoni G.S., Rossi F., and Maione S. Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system. Eur. J. Neurosci. 24 7 (2006) 2011-2020
49. Panikashvili D., Simeonidou C., Ben-Shabat S., Hanus L., Breuer A., Mechoulam R., and Shohami E. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature. 413 6855 (2001) 527-531
50. Pertwee R.G. Cannabinoid receptors and pain. Prog. Neurobiol. 63 5 (2001) 569-611 Review
51. Petrosino S., Palazzo E., de Novellis V., Bisogno T., Rossi F., Maione S., and Di Marzo V. Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. Neuropharmacology 52 2 (2007) 415-422
52. Popovich P.G., Wei P., and Stokes B.T. Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J. Comp. Neurol. 377 3 (1997) 443-464
53. Porcella A., Marchese G., Casu M.A., Rocchitta A., Lai M.L., Gessa G.L., and Pani L. Evidence for functional CB1 cannabinoid receptor expressed in the rat thyroid. Eur. J. Endocrinol. 147 2 (2002) 255-261 Erratum in: Eur J Endocrinol 2002; 147(3):434
54. Racz I., Nadal X., Alferink J., Baños J.E., Rehnelt J., Martín M., Pintado B., Gutierrez-Adan A., Sanguino E., Manzanares J., Zimmer A., and Maldonado R. Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain. J. Neurosci. 28 46 (2008) 12125-12135
55. Racz I., Nadal X., Alferink J., Baños J.E., Rehnelt J., Martín M., Pintado B., Gutierrez-Adan A., Sanguino E., Bellora N., Manzanares J., Zimmer A., and Maldonado R. Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain. J. Neurosci. 28 46 (2008) 12136-12145
56. Romero-Sandoval A., and Eisenach J.C. Spinal cannabinoid receptor type 2 activation reduces hypersensitivity and spinal cord glial activation after paw incision. Anesthesiology 106 4 (2007) 787-794
57. Romero-Sandoval A., Nutile-McMenemy N., and DeLeo J.A. Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury. Anesthesiology 108 4 (2008) 722-734
58. Sheng W.S., Hu S., Min X., Cabral G.A., Lokensgard J.R., and Peterson P.K. Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1beta-stimulated human astrocytes. Glia 49 2 (2005) 211-219
59. Scholz J., and Woolf C.J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 10 11 (2007) 1361-1368
60. Schreiber K.L., Beitz A.J., and Wilcox G.L. Activation of spinal microglia in a murine model of peripheral inflammation-induced, long-lasting contralateral allodynia. Neurosci. Lett. 440 1 (2008) 63-67
61. Stella N. Endocannabinoid signaling in microglial cells. Neuropharmacology 56 Suppl. 1 (2009) 244-253 Review
62. Stuesse S.L., Cruce W.L., Lovell J.A., McBurney D.L., and Crisp T. Microglial proliferation in the spinal cord of aged rats with a sciatic nerve injury. Neurosci. Lett. 23 287(2) (2000) 121-124
63. Tanga F.Y., Raghavendra V., and DeLeo J.A. Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem. Int. 45 (2004) 397-407
64. Tóth Z.E., and Mezey E. Simultaneous visualization of multiple antigens with tyramide signal amplification using antibodies from the same species. J. Histochem. Cytochem. 55 6 (2007) 545-554
65. Tsuda M., Inoue K., and Salter M.W. Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia. Trends Neurosci. 28 2 (2005) 101-107 Review
66. Valenzano K.J., Tafesse L., Lee G., Harrison J.E., Boulet J.M., Gottshall S.L., Mark L., Pearson M.S., Miller W., Shan S., Rabadi L., Rotshteyn Y., Chaffer S.M., Turchin P.I., Elsemore D.A., Toth M., Koetzner L., and Whiteside G.T. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48 5 (2005) 658-672
67. Viscomi M.T., Oddi S., Latini L., Pasquariello N., Florenzano F., Bernardi G., Molinari M., and Maccarrone M. Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J. Neurosci. 29 14 (2009) 4564-4570
68. Wake H., Moorhouse A.J., Jinno S., Kohsaka S., and Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29 13 (2009) 3974-3980
69. Walter L., Franklin A., Witting A., Wade C., Xie Y., Kunos G., Mackie K., and Stella N. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J. Neurosci. 23 4 (2003) 1398-1405
70. Whiteside G.T., Gottshall S.L., Boulet J.M., Chaffer S.M., Harrison J.E., Pearson M.S., Turchin P.I., Mark L., Garrison A.E., and Valenzano K.J. A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833. Eur. J. Pharmacol. 28 528(1-3) (2005) 65-72
71. Wotherspoon G., Fox A., McIntyre P., Colley S., Bevan S., and Winter J. Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons. Neuroscience 135 1 (2005) 235-245
72. Yamamoto W., Mikami T., and Iwamura H. Involvement of central cannabinoid CB2 receptor in reducing mechanical allodynia in a mouse model of neuropathic pain. Eur. J. Pharmacol. 583 1 (2008) 56-61
73. Zhang J., Hoffert C., Vu H.K., Groblewski T., Ahmad S., and O'Donnell D. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur. J. Neurosci. 17 12 (2003) 2750-2754
74. Zhuo M. Cortical excitation and chronic pain. Trends Neurosci. 31 4 (2008) 199-207