Cannabinoid receptors and the endocannabinoid system: Signaling and function in the central nervous system

International Journal of Molecular Sciences

Volumn 19, Issue 3, 2018, Pages

  Zou, Shenglong ^a   Kumar, Ujendra ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

Cannabinoid; Central nervous system; Endocannabinoid; Receptor; Signaling

Indexed keywords

CANNABINOID 1 RECEPTOR; CANNABINOID 2 RECEPTOR; CANNABINOID RECEPTOR; ENDOCANNABINOID; CANNABINOID RECEPTOR AGONIST;

ALZHEIMER DISEASE; CENTRAL NERVOUS SYSTEM; DRUG DESIGN; EXCITOTOXICITY; HUMAN; HUNTINGTON CHOREA; NEUROPROTECTION; NEUROTRANSMISSION; NONHUMAN; PARKINSON DISEASE; PATHOPHYSIOLOGY; PERIPHERAL NERVOUS SYSTEM; PI3K/AKT SIGNALING; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; DRUG EFFECT; GENETICS; METABOLISM;

ANIMALS; CANNABINOID RECEPTOR AGONISTS; CENTRAL NERVOUS SYSTEM; ENDOCANNABINOIDS; HUMANS; RECEPTORS, CANNABINOID; SIGNAL TRANSDUCTION;

EID: 85044120205     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms19030833     Document Type: Review

References (197)

1. Mechoulam, R. The Pharmacohistory of Cannabis sativa, in Cannabis as Therapeutic Agent; CRC Press: Boca Raton, FL, USA, 1986.
2. Iversen, L. The Science of Marijuana; Oxford University Press: Oxford, UK, 2000.
3. Pacher, P.; Batkai, S.; Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 2006, 58, 389–462.
4. Gaoni, Y.; Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 1964, 86, 1646–1647.
5. Matsuda, L.A.; Lolait, S.J.; Brownstein, M.J.; Young, A.C.; Bonner, T.I. Structure of a cannabinoid receptor and functional expression of the cloned cdna. Nature 1990, 346, 561–564.
6. Devane, W.A.; Dysarz, F.A., 3rd; Johnson, M.R.; Melvin, L.S.; Howlett, A.C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 1988, 34, 605–613.
7. 2. Pharmacol. Rev. 2010, 62, 588–631.
8. Munro, S.; Thomas, K.L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993, 365, 61–65.
9. Kano, M.; Ohno-Shosaku, T.; Hashimotodani, Y.; Uchigashima, M.; Watanabe, M. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 2009, 89, 309–380.
10. Howlett, A.C.; Barth, F.; Bonner, T.I.; Cabral, G.; Casellas, P.; Devane, W.A.; Felder, C.C.; Herkenham, M.; Mackie, K.; Martin, B.R.; et al. International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 2002, 54, 161–202.
11. Sugiura, T.; Kondo, S.; Sukagawa, A.; Nakane, S.; Shinoda, A.; Itoh, K.; Yamashita, A.; Waku, K. 2-arachidonoylgylcerol—A possible endogenous cannabinoid receptor-ligand in brain. Biochem. Biophys. Res. Commun. 1995, 215, 89–97.
12. Mechoulam, R.; Benshabat, S.; Hanus, L.; Ligumsky, M.; Kaminski, N.E.; Schatz, A.R.; Gopher, A.; Almog, S.; Martin, B.R.; Compton, D.R.; et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 1995, 50, 83–90.
13. Devane, W.A.; Hanus, L.; Breuer, A.; Pertwee, R.G.; Stevenson, L.A.; Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger, A.; Mechoulam, R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992, 258, 1946–1949.
14. Izzo, A.A.; Borrelli, F.; Capasso, R.; di Marzo, V.; Mechoulam, R. Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 2009, 30, 515–527.
15. Hill, A.J.; Williams, C.M.; Whalley, B.J.; Stephens, G.J. Phytocannabinoids as novel therapeutic agents in cns disorders. Pharmacol. Ther. 2012, 133, 79–97.
16. Mechoulam, R.; Sumariwalla, P.F.; Feldmann, M.; Gallily, R. Cannabinoids in models of chronic inflammatory conditions. Phytochem. Rev. 2005, 4, 11–18.
17. Patil, K.R.; Goyal, S.N.; Sharma, C.; Patil, C.R.; Ojha, S. Phytocannabinoids for cancer therapeutics: Recent updates and future prospects. Curr. Med. Chem. 2015, 22, 3472–3501.
18. Pertwee, R.G. Cannabinoid pharmacology: The first 66 years. Br. J. Pharmacol. 2006, 147, S163–S171.
19. Schacht, J.P.; Hutchison, K.E.; Filbey, F.M. Associations between cannabinoid receptor-1 (CNR1) variation and hippocampus and amygdala volumes in heavy cannabis users. Neuropsychopharmacology 2012, 37, 2368–2376.
20. Hartman, C.A.; Hopfer, C.J.; Haberstick, B.; Rhee, S.H.; Crowley, T.J.; Corley, R.P.; Hewitt, J.K.; Ehringer, M.A. The association between cannabinoid receptor 1 gene (CNR1) and cannabis dependence symptoms in adolescents and young adults. Drug Alcohol Depend. 2009, 104, 11–16.
21. Agrawal, A.; Lynskey, M.T. Candidate genes for cannabis use disorders: Findings, challenges and directions. Addiction 2009, 104, 518–532.
22. Hua, T.; Vemuri, K.; Pu, M.; Qu, L.; Han, G.W.; Wu, Y.; Zhao, S.; Shui, W.; Li, S.; Korde, A.; et al. Crystal structure of the human cannabinoid receptor CB1. Cell 2016, 167, 750–762.
23. Shao, Z.; Yin, J.; Chapman, K.; Grzemska, M.; Clark, L.; Wang, J.; Rosenbaum, D.M. High-resolution crystal structure of the human CB1cannabinoid receptor. Nature 2016, 540, 602–606.
24. Hua, T.; Vemuri, K.; Nikas, S.P.; Laprairie, R.B.; Wu, Y.; Qu, L.; Pu, M.; Korde, A.; Jiang, S.; Ho, J.H.; et al. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature 2017, 547, 468–471.
25. Ryberg, E.; Vu, H.K.; Larsson, N.; Groblewski, T.; Hjorth, S.; Elebring, T.; Sjorgren, S.; Greasley, P.J. Identification and characterisation of a novel splice variant of the human CB1receptor. FEBS Lett. 2005, 579, 259–264.
26. Shire, D.; Carillon, C.; Kaghad, M.; Calandra, B.; Rinaldicarmona, M.; Lefur, G.; Caput, D.; Ferrara, P. An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J. Biol. Chem. 1995, 270, 3726–3731.
27. Gonzalez-Mariscal, I.; Krzysik-Walker, S.M.; Doyle, M.E.; Liu, Q.R.; Cimbro, R.; Calvo, S.S.C.; Ghosh, S.; Ciesla, L.; Moaddel, R.; Carlson, O.D.; et al. Human CB1 receptor isoforms, present in hepatocytes and β-cells, are involved in regulating metabolism. Sci. Rep. 2016, 6, 33302.
28. Straiker, A.; Wager-Miller, J.; Hutchens, J.; Mackie, K. Differential signalling in human cannabinoid CB1 receptors and their splice variants in autaptic hippocampal neurones. Br. J. Pharmacol. 2012, 165, 2660–2671.
29. Xiao, J.C.; Jewell, J.P.; Lin, L.S.; Hagmann, W.K.; Fong, T.M.; Shen, C.P. Similar in vitro pharmacology of human cannabinoid CB1 receptor variants expressed in cho cells. Brain Res. 2008, 1238, 36–43.
30. Zhang, H.Y.; Bi, G.H.; Li, X.; Li, J.; Qu, H.; Zhang, S.J.; Li, C.Y.; Onaivi, E.S.; Gardner, E.L.; Xi, Z.X.; et al. Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats. Neuropsychopharmacology 2015, 40, 1037–1051.
31. Liu, Q.R.; Pan, C.H.; Hishimoto, A.; Li, C.Y.; Xi, Z.X.; Llorente-Berzal, A.; Viveros, M.P.; Ishiguro, H.; Arinami, T.; Onaivi, E.S.; et al. Species differences in cannabinoid receptor 2 (CNR2 gene): Identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands. Genes Brain Behav. 2009, 8, 519–530.
32. Di Marzo, V.; de Petrocellis, L. Why do cannabinoid receptors have more than one endogenous ligand? Philos. Trans. R. Soc. B 2012, 367, 3216–3228.
33. Castillo, P.E.; Younts, T.J.; Chavez, A.E.; Hashimotodani, Y. Endocannabinoid signaling and synaptic function. Neuron 2012, 76, 70–81.
34. Katona, I.; Freund, T.F. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat. Med. 2008, 14, 923–930.
35. Murataeva, N.; Straiker, A.; Mackie, K. Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br. J. Pharmacol. 2014, 171, 1379–1391.
36. Huang, H.; McIntosh, A.L.; Martin, G.G.; Landrock, D.; Chung, S.; Landrock, K.K.; Dangott, L.J.; Li, S.R.; Kier, A.B.; Schroeder, F. Fabp1: A novel hepatic endocannabinoid and cannabinoid binding protein. Biochemistry 2016, 55, 5243–5255.
37. Blankman, J.L.; Simon, G.M.; Cravatt, B.F. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem. Biol. 2007, 14, 1347–1356.
38. Rouzer, C.A.; Marnett, L.J. Endocannabinoid oxygenation by cyclooxygenases, lipoxygenases, and cytochromes p450: Cross-talk between the eicosanoid and endocannabinoid signaling pathways. Chem. Rev. 2011, 111, 5899–5921.
39. Maccarrone, M.; Rossi, S.; Bari, M.; de Chiara, V.; Fezza, F.; Musella, A.; Gasperi, V.; Prosperetti, C.; Bernardi, G.; Finazzi-Agro, A.; et al. Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum. Nat. Neurosci. 2008, 11, 152–159.
40. Ohno-Shosaku, T.; Kano, M. Endocannabinoid-mediated retrograde modulation of synaptic transmission. Curr. Opin. Neurobiol. 2014, 29, 1–8.
41. Khlaifia, A.; Farah, H.; Gackiere, F.; Tell, F. Anandamide, cannabinoid type 1 receptor, and nmda receptor activation mediate non-hebbian presynaptically expressed long-term depression at the first central synapse for visceral afferent fibers. J. Neurosci. 2013, 33, 12627–12637.
42. Puente, N.; Cui, Y.H.; Lassalle, O.; Lafourcade, M.; Georges, F.; Venance, L.; Grandes, P.; Manzoni, O.J. Polymodal activation of the endocannabinoid system in the extended amygdala. Nat. Neurosci. 2011, 14, 1542–1567.
43. Chavez, A.E.; Chiu, C.Q.; Castillo, P.E. Trpv1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nat. Neurosci. 2010, 13, 1511–1599.
44. Grueter, B.A.; Brasnjo, G.; Malenka, R.C. Postsynaptic trpv1 triggers cell type-specific long-term depression in the nucleus accumbens. Nat. Neurosci. 2010, 13, 1519–1525.
45. Lerner, T.N.; Kreitzer, A.C. Rgs4 is required for dopaminergic control of striatal ltd and susceptibility to parkinsonian motor deficits. Neuron 2012, 73, 347–359.
46. Schlosburg, J.E.; Blankman, J.L.; Long, J.Z.; Nomura, D.K.; Pan, B.; Kinsey, S.G.; Nguyen, P.T.; Ramesh, D.; Booker, L.; Burston, J.J.; et al. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat. Neurosci. 2010, 13, 1113–1119.
47. Marinelli, S.; Pacioni, S.; Bisogno, T.; di Marzo, V.; Prince, D.A.; Huguenard, J.R.; Bacci, A. The endocannabinoid 2-arachidonoylglycerol is responsible for the slow self-inhibition in neocortical interneurons. J. Neurosci. 2008, 28, 13532–13541.
48. Min, R.; Testa-Silva, G.; Heistek, T.S.; Canto, C.B.; Lodder, J.C.; Bisogno, T.; di Marzo, V.; Brussaard, A.B.; Burnashev, N.; Mansvelder, H.D. Diacylglycerol lipase is not involved in depolarization-induced suppression of inhibition at unitary inhibitory connections in mouse hippocampus. J. Neurosci. 2010, 30, 2710–2715.
49. Marinelli, S.; Pacioni, S.; Cannich, A.; Marsicano, G.; Bacci, A. Self-modulation of neocortical pyramidal neurons by endocannabinoids. Nat. Neurosci. 2009, 12, 1488–1490.
50. Bacci, A.; Huguenard, J.R.; Prince, D.A. Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 2004, 431, 312–316.
51. Han, J.; Kesner, P.; Metna-Laurent, M.; Duan, T.T.; Xu, L.; Georges, F.; Koehl, M.; Abrous, D.N.; Mendizabal-Zubiaga, J.; Grandes, P.; et al. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal ltd. Cell 2012, 148, 1039–1050.
52. Navarrete, M.; Araque, A. Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. Neuron 2010, 68, 113–126.
53. Navarrete, M.; Araque, A. Endocannabinoids mediate neuron-astrocyte communication. Neuron 2008, 57, 883–893.
54. Stella, N. Endocannabinoid signaling in microglial cells. Neuropharmacology 2009, 56, 244–253.
55. Dhopeshwarkar, A.; Mackie, K. CB2 cannabinoid receptors as a therapeutic target-what does the future hold? Mol. Pharmacol. 2014, 86, 430–437.
56. 2: A cannabinoid receptor with an identity crisis. Br. J. Pharmacol. 2010, 160, 467–479.
57. Gong, J.P.; Onaivi, E.S.; Ishiguro, H.; Liu, Q.R.; Tagliaferro, P.A.; Brusco, A.; Uhl, G.R. Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain Res. 2006, 1071, 10–23.
58. Den Boon, F.S.; Chameau, P.; Schaafsma-Zhao, Q.; van Aken, W.; Bari, M.; Oddi, S.; Kruse, C.G.; Maccarrone, M.; Wadman, W.J.; Werkman, T.R. Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors. Proc. Natl. Acad. Sci. USA 2012, 109, 3534–3539.
59. Mackie, K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb. Exp. Pharmacol. 2005, 299–325.
60. Katona, I.; Sperlagh, B.; Sik, A.; Kafalvi, A.; Vizi, E.S.; Mackie, K.; Freund, T.F. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 1999, 19, 4544–4558.
61. Tsou, K.; Brown, S.; Sanudo-Pena, M.C.; Mackie, K.; Walker, J.M. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 1998, 83, 393–411.
62. Maroso, M.; Szabo, G.G.; Kim, H.K.; Alexander, A.; Bui, A.D.; Lee, S.H.; Lutz, B.; Soltesz, I. Cannabinoid control of learning and memory through hcn channels. Neuron 2016, 89, 1059–1073.
63. Maccarrone, M.; Bab, R.; Biro, T.; Cabral, G.A.; Dey, S.K.; di Marzo, V.; Konje, J.C.; Kunos, G.; Mechoulam, R.; Pacher, P.; et al. Endocannabinoid signaling at the periphery: 50 years after thc. Trends Pharmacol. Sci. 2015, 36, 277–296.
64. Tam, J.; Trembovler, V.; di Marzo, V.; Petrosino, S.; Leo, G.; Alexandrovich, A.; Regev, E.; Casap, N.; Shteyer, A.; Ledent, C.; et al. The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling. FASEB J. 2008, 22, 285–294.
65. Clapper, J.R.; Moreno-Sanz, G.; Russo, R.; Guijarro, A.; Vacondio, F.; Duranti, A.; Tontini, A.; Sanchini, S.; Sciolino, N.R.; Spradley, J.M.; et al. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat. Neurosci. 2010, 13, 1265–1270.
66. Price, T.J.; Helesic, G.; Parghi, D.; Hargreaves, K.M.; Flores, C.M. The neuronal distribution of cannabinoid receptor type 1 in the trigeminal ganglion of the rat. Neuroscience 2003, 120, 155–162.
67. Veress, G.; Meszar, Z.; Muszil, D.; Avelino, A.; Matesz, K.; Mackie, K.; Nagy, I. Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons. Brain Struct. Funct. 2013, 218, 733–750.
68. Izzo, A.A.; Sharkey, K.A. Cannabinoids and the gut: New developments and emerging concepts. Pharmacol. Ther. 2010, 126, 21–38.
69. Miller, L.K.; Devi, L.A. The highs and lows of cannabinoid receptor expression in disease: Mechanisms and their therapeutic implications. Pharmacol. Rev. 2011, 63, 461–470.
70. Montecucco, F.; di Marzo, V. At the heart of the matter: The endocannabinoid system in cardiovascular function and dysfunction. Trends Pharmacol. Sci. 2012, 33, 331–340.
71. Rozenfeld, R. Type I cannabinoid receptor trafficking: All roads lead to lysosome. Traffic 2011, 12, 12–18.
72. Leterrier, C.; Bonnard, D.; Carrel, D.; Rossier, J.; Lenkei, Z. Constitutive endocytic cycle of the CB1 cannabinoid receptor. J. Biol. Chem. 2004, 279, 36013–36021.
73. Grimsey, N.L.; Graham, E.S.; Dragunow, M.; Glass, M. Cannabinoid receptor 1 trafficking and the role of the intracellular pool: Implications for therapeutics. Biochem. Pharmacol. 2010, 80, 1050–1062.
74. Rozenfeld, R.; Devi, L.A. Regulation of CB1 cannabinoid receptor trafficking by the adaptor protein ap-3. FASEB J. 2008, 22, 2311–2322.
75. 1) receptors are activated by anandamide. J. Biol. Chem. 2011, 286, 29166–29174.
76. Martin, B.R. Cellular effects of cannabinoids. Pharmacol. Rev. 1986, 38, 45–74.
77. Benard, G.; Massa, F.; Puente, N.; Lourenco, J.; Bellocchio, L.; Soria-Gomez, E.; Matias, I.; Delamarre, A.; Metna-Laurent, M.; Cannich, A.; et al. Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat. Neurosci. 2012, 15, 558–564.
78. Hebert-Chatelain, E.; Reguero, L.; Puente, N.; Lutz, B.; Chaouloff, F.; Rossignol, R.; Piazza, P.V.; Benard, G.; Grandes, P.; Marsicano, G. Cannabinoid control of brain bioenergetics: Exploring the subcellular localization of the CB1 receptor. Mol. Metab. 2014, 3, 495–504.
79. Hebert-Chatelain, E.; Reguero, L.; Puente, N.; Lutz, B.; Chaouloff, F.; Rossignol, R.; Piazza, P.V.; Benard, G.; Grandes, P.; Marsicano, G. Studying mitochondrial CB1 receptors: Yes we can. Mol. Metab. 2014, 3, 339.
80. Morozov, Y.M.; Horvath, T.L.; Rakic, P. A tale of two methods: Identifying neuronal CB1 receptors. Mol. Metab. 2014, 3, 338.
81. Koch, M.; Varela, L.; Kim, J.G.; Kim, J.D.; Hernandez-Nuno, F.; Simonds, S.E.; Castorena, C.M.; Vianna, C.R.; Elmquist, J.K.; Morozov, Y.M.; et al. Hypothalamic pomc neurons promote cannabinoid-induced feeding. Nature 2015, 519, 45–50.
82. Ma, L.; Jia, J.; Niu, W.; Jiang, T.; Zhai, Q.; Yang, L.; Bai, F.; Wang, Q.; Xiong, L. Mitochondrial CB1 receptor is involved in acea-induced protective effects on neurons and mitochondrial functions. Sci. Rep. 2015, 5, 12440.
83. Hebert-Chatelain, E.; Desprez, T.; Serrat, R.; Bellocchio, L.; Soria-Gomez, E.; Busquets-Garcia, A.; Pagano Zottola, A.C.; Delamarre, A.; Cannich, A.; Vincent, P.; et al. A cannabinoid link between mitochondria and memory. Nature 2016, 539, 555–559.
84. Sheng, Z.H.; Cai, Q. Mitochondrial transport in neurons: Impact on synaptic homeostasis and neurodegeneration. Nat. Rev. Neurosci. 2012, 13, 77–93.
85. Mattson, M.P.; Gleichmann, M.; Cheng, A. Mitochondria in neuroplasticity and neurological disorders. Neuron 2008, 60, 748–766.
86. Thibault, K.; Carrel, D.; Bonnard, D.; Gallatz, K.; Simon, A.; Biard, M.; Pezet, S.; Palkovits, M.; Lenkei, Z. Activation-dependent subcellular distribution patterns of CB1 cannabinoid receptors in the rat forebrain. Cereb. Cortex 2013, 23, 2581–2591.
87. Brailoiu, G.C.; Deliu, E.; Marcu, J.; Hoffman, N.E.; Console-Bram, L.; Zhao, P.; Madesh, M.; Abood, M.E.; Brailoiu, E. Differential activation of intracellular versus plasmalemmal CB2 cannabinoid receptors. Biochemistry 2014, 53, 4990–4999.
88. Demuth, D.G.; Molleman, A. Cannabinoid signalling. Life Sci. 2006, 78, 549–563.
89. Rhee, M.H.; Bayewitch, M.; Avidor-Reiss, T.; Levy, R.; Vogel, Z. Cannabinoid receptor activation differentially regulates the various adenylyl cyclase isozymes. J. Neurochem. 1998, 71, 1525–1534.
90. Maneuf, Y.P.; Brotchie, J.M. Paradoxical action of the cannabinoid win 55,212–2 in stimulated and basal cyclic amp accumulation in rat globus pallidus slices. Br. J. Pharmacol. 1997, 120, 1397–1398.
91. Glass, M.; Felder, C.C. Concurrent stimulation of cannabinoid CB1 and dopamine d2 receptors augments camp accumulation in striatal neurons: Evidence for a gs linkage to the CB1 receptor. J. Neurosci. 1997, 17, 5327–5333.
92. Bonhaus, D.W.; Chang, L.K.; Kwan, J.; Martin, G.R. Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: Evidence for agonist-specific trafficking of intracellular responses. J. Pharmacol. Exp. Ther. 1998, 287, 884–888.
93. Lauckner, J.E.; Hille, B.; Mackie, K. The cannabinoid agonist win55,212–2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc. Natl. Acad. Sci. USA 2005, 102, 19144–19149.
94. Turu, G.; Hunyady, L. Signal transduction of the CB1 cannabinoid receptor. J. Mol. Endocrinol. 2010, 44, 75–85.
95. Brown, S.P.; Safo, P.K.; Regehr, W.G. Endocannabinoids inhibit transmission at granule cell to purkinje cell synapses by modulating three types of presynaptic calcium channels. J. Neurosci. 2004, 24, 5623–5631.
96. Twitchell, W.; Brown, S.; Mackie, K. Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J. Neurophysiol. 1997, 78, 43–50.
97. Mackie, K.; Devane, W.A.; Hille, B. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma-cells. Mol. Pharmacol. 1993, 44, 498–503.
98. Mackie, K.; Hille, B. Cannabinoids inhibit N-type calcium channels in neuroblastoma glioma-cells. Proc. Natl. Acad. Sci. USA 1992, 89, 3825–3829.
99. Gergely, G.S.; Nora, L.; Noemi, H.; Tibor, A.; Zoltan, N.; Norbert, H. Presynaptic calcium channel inhibition underlies CB1 cannabinoid receptor-mediated suppression of gaba release. J. Neurosci. 2014, 34, 7958–7963.
100. Fisyunov, A.; Tsintsadze, V.; Min, R.; Burnashev, N.; Lozovaya, N. Cannabinoids modulate the P-type high-voltage-activated calcium currents in purkinje neurons. J. Neurophysiol. 2006, 96, 1267–1277.
101. Mackie, K.; Lai, Y.; Westenbroek, R.; Mitchell, R. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in att20 cells transfected with rat-brain cannabinoid receptor. J. Neurosci. 1995, 15, 6552–6561.
102. Guo, J.; Ikeda, S.R. Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons. Mol. Pharmacol. 2004, 65, 665–674.
103. Robbe, D.; Alonso, G.; Duchamp, F.; Bockaert, J.; Manzoni, O.J. Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens. J. Neurosci. 2001, 21, 109–116.
104. Howlett, A.C.; Blume, L.C.; Dalton, G.D. CB1 cannabinoid receptors and their associated proteins. Curr. Med. Chem. 2010, 17, 1382–1393.
105. Galve-Roperh, I.; Rueda, D.; del Pulgar, T.G.; Velasco, G.; Guzman, M. Mechanism of extracellular signal-regulated kinase activation by the CB1 cannabinoid receptor. Mol. Pharmacol. 2002, 62, 1385–1392.
106. Flores-Otero, J.; Ahn, K.H.; Delgado-Peraza, F.; Mackie, K.; Kendall, D.A.; Yudowski, G.A. Ligand-specific endocytic dwell times control functional selectivity of the cannabinoid receptor 1. Nat. Commun. 2014, 5, 4589.
107. Bouaboula, M.; Poinotchazel, C.; Bourrie, B.; Canat, X.; Calandra, B.; Rinaldicarmona, M.; Lefur, G.; Casellas, P. Activation of mitogen-activated protein-kinases by stimulation of the central cannabinoid receptor CB1. Biochem. J. 1995, 312, 637–641.
108. Derkinderen, P.; Ledent, C.; Parmentier, M.; Girault, J.A. Cannabinoids activate p38 mitogen-activated protein kinases through CB1 receptors in hippocampus. J. Neurochem. 2001, 77, 957–960.
109. Rueda, D.; Galve-Roperh, I.; Haro, A.; Guzman, M. The CB1 cannabinoid receptor is coupled to the activation of c-jun N-terminal kinase. Mol. Pharmacol. 2000, 58, 814–820.
110. Liu, J.; Gao, B.; Mirshahi, F.; Sanyal, A.J.; Khanolkar, A.D.; Makriyannis, A.; Kunos, G. Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem. J. 2000, 346, 835–840.
111. o/i-coupled cannabinoid receptor-mediated neurite outgrowth involves rap regulation of src and stat3. J. Biol. Chem. 2005, 280, 33426–33434.
112. McCudden, C.R.; Hains, M.D.; Kimple, R.J.; Siderovski, D.P.; Willard, F.S. G-protein signaling: Back to the future. Cell. Mol. Life Sci. 2005, 62, 551–577.
113. Kouznetsova, M.; Kelley, B.; Shen, M.X.; Thayer, S.A. Desensitization of cannabinoid-mediated presynaptic inhibition of neurotransmission between rat hippocampal neurons in culture. Mol. Pharmacol. 2002, 61, 477–485.
114. Jin, W.Z.; Brown, S.; Roche, J.P.; Hsieh, C.; Celver, J.P.; Kovoor, A.; Chavkin, C.; Mackie, K. Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization. J. Neurosci. 1999, 19, 3773–3780.
115. Daigle, T.L.; Kearn, C.S.; Mackie, K. Rapid CB1 cannabinoid receptor desensitization defines the time course of erk1/2 map kinase signaling. Neuropharmacology 2008, 54, 36–44.
116. Nguyen, P.T.; Schmid, C.L.; Raehal, K.M.; Selley, D.E.; Bohn, L.M.; Sim-Selley, L.J. Beta-arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region-dependent manner. Biol. Psychiatry 2012, 71, 714–724.
117. −/− mice. Behav. Pharmacol. 2008, 19, 298–307.
118. Ahn, K.H.; Mahmoud, M.M.; Shim, J.Y.; Kendall, D.A. Distinct roles of beta-arrestin 1 and beta-arrestin 2 in org27569-induced biased signaling and internalization of the cannabinoid receptor 1 (CB1). J. Biol. Chem. 2013, 288, 9790–9800.
119. Gomez del Pulgar, T.; Velasco, G.; Guzman, M. The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem. J. 2000, 347, 369–373.
120. Gomez, O.; Sanchez-Rodriguez, A.; Le, M.Q.U.; Sanchez-Caro, C.; Molina-Holgado, F.; Molina-Holgado, E. Cannabinoid receptor agonists modulate oligodendrocyte differentiation by activating pi3k/akt and the mammalian target of rapamycin (mtor) pathways. Br. J. Pharmacol. 2011, 163, 1520–1532.
121. Molina-Holgado, E.; Vela, J.M.; Arevalo-Martin, A.; Almazan, G.; Molina-Holgado, F.; Borrell, J.; Guaza, C. Cannabinoids promote oligodendrocyte progenitor survival: Involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/akt signaling. J. Neurosci. 2002, 22, 9742–9753.
122. Molina-Holgado, F.; Pinteaux, E.; Heenan, L.; Moore, J.D.; Rothwell, N.J.; Gibson, R.M. Neuroprotective effects of the synthetic cannabinoid hu-210 in primary cortical neurons are mediated by phosphatidylinositol 3-kinase/akt signaling. Mol. Cell. Neurosci. 2005, 28, 189–194.
123. Ozaita, A.; Puighermanal, E.; Maldonado, R. Regulation of pi3k/akt/gsk-3 pathway by cannabinoids in the brain. J. Neurochem. 2007, 102, 1105–1114.
124. Blazquez, C.; Chiarlone, A.; Bellocchio, L.; Resel, E.; Pruunsild, P.; Garcia-Rincon, D.; Sendtner, M.; Timmusk, T.; Lutz, B.; Galve-Roperh, I.; et al. The CB1 cannabinoid receptor signals striatal neuroprotection via a pi3k/akt/mtorc1/bdnf pathway. Cell. Death Differ. 2015, 22, 1618–1629.
125. Lopez-Cardona, A.P.; Perez-Cerezales, S.; Fernandez-Gonzalez, R.; Laguna-Barraza, R.; Pericuesta, E.; Agirregoitia, N.; Gutierrez-Adan, A.; Agirregoitia, E. CB1 cannabinoid receptor drives oocyte maturation and embryo development via pi3k/akt and mapk pathways. FASEB J. 2017, 31, 3372–3382.
126. Di Marzo, V.; Stella, N.; Zimmer, A. Endocannabinoid signalling and the deteriorating brain. Nat. Rev. Neurosci. 2015, 16, 30–42.
127. Iversen, L. Cannabis and the brain. Brain 2003, 126, 1252–1270.
128. Di Marzo, V. Targeting the endocannabinoid system: To enhance or reduce? Nat. Rev. Drug Discov. 2008, 7, 438–455.
129. Gerdeman, G.; Lovinger, D.M. CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J. Neurophysiol. 2001, 85, 468–471.
130. Chiarlone, A.; Bellocchio, L.; Blazquez, C.; Resel, E.; Soria-Gomez, E.; Cannich, A.; Ferrero, J.J.; Sagredo, O.; Benito, C.; Romero, J.; et al. A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc. Natl. Acad Sci. USA 2014, 111, 8257–8262.
131. Marsicano, G.; Goodenough, S.; Monory, K.; Hermann, H.; Eder, M.; Cannich, A.; Azad, S.C.; Cascio, M.G.; Gutierrez, S.O.; van der Stelt, M.; et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 2003, 302, 84–88.
132. Zoppi, S.; Nievas, B.G.P.; Madrigal, J.L.M.; Manzanares, J.; Leza, J.C.; Garcia-Bueno, B. Regulatory role of cannabinoid receptor 1 in stress-induced excitotoxicity and neuroinflammation. Neuropsychopharmacology 2011, 36, 805–818.
133. Blazquez, C.; Chiarlone, A.; Sagredo, O.; Aguado, T.; Pazos, M.R.; Resel, E.; Palazuelos, J.; Julien, B.; Salazar, M.; Borner, C.; et al. Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in huntington’s disease. Brain 2011, 134, 119–136.
134. Kim, S.H.; Won, S.J.; Mao, X.O.; Jin, K.; Greenberg, D.A. Molecular mechanisms of cannabinoid protection from neuronal excitotoxicity. Mol. Pharmacol. 2006, 69, 691–696.
135. Khaspekov, L.G.; Verca, M.S.B.; Frumkina, L.E.; Hermann, H.; Marsicano, G.; Lutz, B. Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity. Eur. J. Neurosci. 2004, 19, 1691–1698.
136. Sanchez-Blazquez, P.; Rodriguez-Munoz, M.; Vicente-Sanchez, A.; Garzon, J. Cannabinoid receptors couple to nmda receptors to reduce the production of no and the mobilization of zinc induced by glutamate. Antioxid. Redox Signal. 2013, 19, 1766–1782.
137. Vicente-Sanchez, A.; Sanchez-Blazquez, P.; Rodriguez-Munoz, M.; Garzon, J. Hint1 protein cooperates with cannabinoid 1 receptor to negatively regulate glutamate nmda receptor activity. Mol. Brain 2013, 6, 42.
138. Brotchie, J.M. CB1 cannabinoid receptor signalling in parkinson’s disease. Curr. Opin. Pharmacol. 2003, 3, 54–61.
139. Waksman, Y.; Olson, J.M.; Carlisle, S.J.; Cabral, G.A. The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. J. Pharmacol. Exp. Ther. 1999, 288, 1357–1366.
140. Milton, N.G.N. Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide. Neurosci. Lett. 2002, 332, 127–130.
141. Benito, C.; Nunez, E.; Tolon, R.M.; Carrier, E.J.; Rabano, A.; Hillard, C.J.; Romero, J. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in alzheimer’s disease brains. J. Neurosci. 2003, 23, 11136–11141.
142. 35S]guanylyl-5′-O-(thio)-triphosphate binding in the basal ganglia of aged rats. Neuroscience 1998, 84, 1075–1083.
143. Westlake, T.M.; Howlett, A.C.; Bonner, T.I.; Matsuda, L.A.; Herkenham, M. Cannabinoid receptor-binding and messenger-RNA expression in human brain—An in-vitro receptor autoradiography and in-situ hybridization histochemistry study of normal aged and alzheimers brains. Neuroscience 1994, 63, 637–652.
144. Ramirez, B.G.; Blazquez, C.; Gomez del Pulgar, T.; Guzman, M.; de Ceballos, M.L. Prevention of alzheimer’s disease pathology by cannabinoids: Neuroprotection mediated by blockade of microglial activation. J. Neurosci. 2005, 25, 1904–1913.
145. Haghani, M.; Shabani, M.; Javan, M.; Motamedi, F.; Janahmadi, M. CB1 cannabinoid receptor activation rescues amyloid beta-induced alterations in behaviour and intrinsic electrophysiological properties of rat hippocampal ca1 pyramidal neurones. Cell. Physiol. Biochem. 2012, 29, 391–406.
146. Aso, E.; Palomer, E.; Juves, S.; Maldonado, R.; Munoz, F.J.; Ferrer, I. CB1 agonist acea protects neurons and reduces the cognitive impairment of AβPP/PS1 mice. J. Alzheimers Dis. 2012, 30, 439–459.
147. Van der Stelt, M.; Mazzola, C.; Esposito, G.; Matias, I.; Petrosino, S.; de Filippis, D.; Micale, V.; Steardo, L.; Drago, F.; Iuvone, T.; et al. Endocannabinoids and beta-amyloid-induced neurotoxicity in vivo: Effect of pharmacological elevation of endocannabinoid levels. Cell. Mol. Life Sci. 2006, 63, 1410–1424.
148. Glass, M.; Faull, R.L.M.; Dragunow, M. Loss of cannabinoid receptors in the substantia-nigra in huntingtons-disease. Neuroscience 1993, 56, 523–527.
149. A receptor alterations in the human basal ganglia in huntington’s disease. Neuroscience 2000, 97, 505–519.
150. Horne, E.A.; Coy, J.; Swinney, K.; Fung, S.; Cherry, A.E.T.; Marrs, W.R.; Naydenov, A.V.; Lin, Y.H.; Sun, X.C.; Keene, C.D.; et al. Downregulation of cannabinoid receptor 1 from neuropeptide y interneurons in the basal ganglia of patients with huntington’s disease and mouse models. Eur. J. Neurosci. 2013, 37, 429–440.
151. Glass, M.; Van Dellen, A.; Blakemore, C.; Hannan, A.J.; Faull, R.L.M. Delayed onset of huntington’s disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors. Neuroscience 2004, 123, 207–212.
152. Mievis, S.; Blum, D.; Ledent, C. Worsening of huntington disease phenotype in CB1 receptor knockout mice. Neurobiol. Dis. 2011, 42, 524–529.
153. Naydenov, A.V.; Sepers, M.D.; Swinney, K.; Raymond, L.A.; Palmiter, R.D.; Stella, N. Genetic rescue of CB1 receptors on medium spiny neurons prevents loss of excitatory striatal synapses but not motor impairment in hd mice. Neurobiol. Dis. 2014, 71, 140–150.
154. Dowie, M.J.; Howard, M.L.; Nicholson, L.F.B.; Faull, R.L.M.; Hannan, A.J.; Glass, M. Behavioural and molecular consequences of chronic cannabinoid treatment in huntington’s disease transgenic mice. Neuroscience 2010, 170, 324–336.
155. Ellison, J.M.; Gelwan, E.; Ogletree, J. Complex partial seizure symptoms affected by marijuana abuse. J. Clin. Psychiatry 1990, 51, 439–440.
156. Consroe, P.F.; Wood, G.C.; Buchsbaum, H. Anticonvulsant nature of marihuana smoking. JAMA 1975, 234, 306–307.
157. Keeler, M.H.; Reifler, C.B. Grand mal convulsions subsequent to marijuana use—Case report. Dis. Nerv. Syst. 1967, 28, 474–475.
158. Clement, A.B.; Hawkins, E.G.; Lichtman, A.H.; Cravatt, B.F. Increased seizure susceptibility and proconvulsant activity of anandamide in mice lacking fatty acid amide hydrolase. J. Neurosci. 2003, 23, 3916–3923.
159. Wallace, M.J.; Martin, B.R.; DeLorenzo, R.J. Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. Eur. J. Pharmacol. 2002, 452, 295–301.
160. Chen, K.; Neu, A.; Howard, A.L.; Foldy, C.; Echegoyen, J.; Hilgenberg, L.; Smith, M.; Mackie, K.; Soltesz, I. Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures. J. Neurosci. 2007, 27, 46–58.
161. Chen, K.; Ratzliff, A.; Hilgenberg, L.; Gulyas, A.; Freund, T.F.; Smith, M.; Dinh, T.P.; Piomelli, D.; Mackie, K.; Soltesz, I. Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron 2003, 39, 599–611.
162. Bhaskaran, M.D.; Smith, B.N. Cannabinoid-mediated inhibition of recurrent excitatory circuitry in the dentate gyrus in a mouse model of temporal lobe epilepsy. PLoS ONE 2010, 5, e10683.
163. Falenski, K.W.; Blair, R.E.; Sim-Selley, L.J.; Martin, B.R.; DeLorenzo, R.J. Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy. Neuroscience 2007, 146, 1232–1244.
164. Wallace, M.J.; Blair, R.E.; Falenski, K.W.; Martin, B.R.; DeLorenzo, R.J. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J. Pharmacol. Exp. Ther. 2003, 307, 129–137.
165. Falenski, K.W.; Carter, D.S.; Harrison, A.J.; Martin, B.R.; Blair, R.E.; DeLorenzo, R.J. Temporal characterization of changes in hippocampal cannabinoid CB1 receptor expression following pilocarpine-induced status epilepticus. Brain Res. 2009, 1262, 64–72.
166. Di Marzo, V.; Matias, I. Endocannabinoid control of food intake and energy balance. Nat. Neurosci. 2005, 8, 585–589.
167. Kirkham, T.C.; Williams, C.M.; Fezza, F.; di Marzo, V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: Stimulation of eating by 2-arachidonoyl glycerol. Br. J. Pharmacol. 2002, 136, 550–557.
168. Bellocchio, L.; Lafenetre, P.; Cannich, A.; Cota, D.; Puente, N.; Grandes, P.; Chaouloff, F.; Piazza, P.V.; Marsicano, G. Bimodal control of stimulated food intake by the endocannabinoid system. Nat. Neurosci. 2010, 13, 281–283.
169. Soria-Gomez, E.; Bellocchio, L.; Reguero, L.; Lepousez, G.; Martin, C.; Bendahmane, M.; Ruehle, S.; Remmers, F.; Desprez, T.; Matias, I.; et al. The endocannabinoid system controls food intake via olfactory processes. Nat. Neurosci. 2014, 17, 407–415.
170. Moreira, F.A.; Crippa, J.A. The psychiatric side-effects of rimonabant. Rev. Bras. Psiquiatr. 2009, 31, 145–153.
171. Koch, M. Cannabinoid receptor signaling in central regulation of feeding behavior: A mini-review. Front. Neurosci. 2017, 11, 293.
172. Fine, P.G.; Rosenfeld, M.J. The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides Med. J. 2013, 4, e0022.
173. Donvito, G.; Nass, S.R.; Wilkerson, J.L.; Curry, Z.A.; Schurman, L.D.; Kinsey, S.G.; Lichtman, A.H. The endogenous cannabinoid system: A budding source of targets for treating inflammatory and neuropathic pain. Neuropsychopharmacology 2017, 43, 52–79.
174. Akopian, A.N.; Ruparel, N.B.; Jeske, N.A.; Patwardhan, A.; Hargreaves, K.M. Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia. Trends Pharmacol. Sci. 2009, 30, 79–84.
175. Jhaveri, M.D.; Sagar, D.R.; Elmes, S.J.R.; Kendall, D.A.; Chapman, V. Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain. Mol. Neurobiol. 2007, 36, 26–35.
176. Russo, E.B. Cannabinoids in the management of difficult to treat pain. Ther. Clin. Risk Manag. 2008, 4, 245–259.
177. Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.; Denovan-Wright, E.M. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br. J. Pharmacol. 2015, 172, 4790–4805.
178. Hall, W.; Christie, M.J.; Currow, D. Cannabinoids and cancer: Causation, remediation, and palliation. Lancet Oncol. 2005, 6, 35–42.
179. Guzman, M. Cannabinoids: Potential anticancer agents. Nat. Rev. Cancer 2003, 3, 745–755.
180. Velasco, G.; Sanchez, C.; Guzman, M. Towards the use of cannabinoids as antitumour agents. Nat. Rev. Cancer 2012, 12, 436–444.
181. Pisanti, S.; Picardi, P.; D’Alessandro, A.; Laezza, C.; Bifulco, M. The endocannabinoid signaling system in cancer. Trends Pharmacol. Sci. 2013, 34, 273–282.
182. Sanchez, C.; de Ceballos, M.L.; del Pulgar, T.G.; Rueda, D.; Corbacho, C.; Velasco, G.; Galve-Roperh, I.; Huffman, J.W.; Cajal, S.R.Y.; Guzman, M. Inhibition of glioma growth in vivo by selective activation of the CB2 cannabinoid receptor. Cancer Res. 2001, 61, 5784–5789.
183. 9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through cdc2 regulation. Cancer Res. 2006, 66, 6615–6621.
184. Hart, S.; Fischer, O.M.; Ullrich, A. Cannabinoids induce cancer cell proliferation via tumor necrosis factor alpha-converting enzyme (tace/adam17)-mediated transactivation of the epidermal growth factor receptor. Cancer Res. 2004, 64, 1943–1950.
185. Abramowicz, M.; Zuccotti, G.; Pflomm, J.M. Cannabis and cannabinoids. JAMA 2016, 316, 2424–2425.
186. Volkow, N.D.; Swanson, J.M.; Evins, A.E.; DeLisi, L.E.; Meier, M.H.; Gonzalez, R.; Bloomfield, M.A.P.; Curran, H.V.; Baler, R. Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: A review. JAMA Psychiatry 2016, 73, 292–297.
187. Bauer, M.; Chicca, A.; Tamborrini, M.; Eisen, D.; Lerner, R.; Lutz, B.; Poetz, O.; Pluschke, G.; Gertsch, J. Identification and quantification of a new family of peptide endocannabinoids (pepcans) showing negative allosteric modulation at CB1 receptors. J. Biol. Chem. 2012, 287, 36944–36967.
188. Pamplona, F.A.; Ferreira, J.; Menezes de Lima, O., Jr.; Duarte, F.S.; Bento, A.F.; Forner, S.; Villarinho, J.G.; Bellocchio, L.; Wotjak, C.T.; Lerner, R.; et al. Anti-inflammatory lipoxin a4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proc. Natl. Acad. Sci. USA 2012, 109, 21134–21139.
189. Ignatowska-Jankowska, B.M.; Baillie, G.L.; Kinsey, S.; Crowe, M.; Ghosh, S.; Owens, R.A.; Damaj, I.M.; Poklis, J.; Wiley, J.L.; Zanda, M.; et al. A cannabinoid CB1 receptor-positive allosteric modulator reduces neuropathic pain in the mouse with no psychoactive effects. Neuropsychopharmacology 2015, 40, 2948–2959.
190. Khurana, L.; Mackie, K.; Piomelli, D.; Kendall, D.A. Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities. Neuropharmacology 2017, 124, 3–12.
191. Hudson, B.D.; Hebert, T.E.; Kelly, M.E.M. Ligand- and heterodimer-directed signaling of the CB1 cannabinoid receptor. Mol. Pharmacol. 2010, 77, 1–9.
192. Fujita, W.; Gomes, I.; Dove, L.S.; Prohaska, D.; McIntyre, G.; Devi, L.A. Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers. Biochem. Pharmacol. 2014, 92, 448–456.
193. Keating, G.M. Eluxadoline: A review in diarrhoea-predominant irritable bowel syndrome. Drugs 2017, 77, 1009–1016.
194. Culler, M.D. Somatostatin-dopamine chimeras: A novel approach to treatment of neuroendocrine tumors. Horm Metab. Res. 2011, 43, 854–857.
195. Perrey, D.A.; Gilmour, B.P.; Thomas, B.F.; Zhang, Y.A. Toward the development of bivalent ligand probes of cannabinoid CB1 and orexin ox1 receptor heterodimers. ACS Med. Chem. Lett. 2014, 5, 634–638.
196. Glass, M.; Govindpani, K.; Furkert, D.P.; Hurst, D.P.; Reggio, P.H.; Flanagan, J.U. One for the price of two…Are bivalent ligands targeting cannabinoid receptor dimers capable of simultaneously binding to both receptors? Trends Pharmacol. Sci. 2016, 37, 353–363.
197. Van Esbroeck, A.C.M.; Janssen, A.P.A.; Cognetta, A.B., 3rd; Ogasawara, D.; Shpak, G.; van der Kroeg, M.; Kantae, V.; Baggelaar, M.P.; de Vrij, F.M.S.; Deng, H.; et al. Activity-based protein profiling reveals off-target proteins of the faah inhibitor bia 10–2474. Science 2017, 356, 1084–1087.