The Role and Clinical Implications of the Endocannabinoid System in Pain Processing
References
1. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci.
2003;4:873-884.
2. Hohmann AG, Rice AS. Cannabinoids. In: McMahon S, Koltzenburg M, Tracey I, Turk DC, eds. Wall & Melzack’s Textbook of Pain. 6th ed. Philadelphia, PA: Saunders; 2008.
3. Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561-564.
4. Gerard CM, Mollereau C, Vassart G, et al. Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J. 1991;279(pt 1):129-134.
5. Howlett AC. The cannabinoid receptors. Prostaglandins Other Lipid Mediat. 2002;68/69:619- 631.
6. Howlett AC, Champion TM, Wilken GH, et al. Stereochemical effects of 11-OH-delta 8- tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor. Neuropharmacology. 1990;29:161-165.
7. Mackie K, Lai Y, Westenbroek R, et al. 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.
8. McAllister SD, Griffin G, Satin LS, et al. Cannabinoid receptors can activate and inhibit G protein-coupled inwardly rectifying potassium channels in a xenopus oocyte expression system. J Pharmacol Exp Ther. 1999;291:618-626.
9. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in the brain.
Proc Natl Acad Sci U S A. 1990;87:1932-1936.
10. Matsuda LA, Bonner TI, Lolait SJ. Localization of cannabinoid receptor mRNA in rat brain.
J Comp Neurol. 1993;327:535-550.
11. Felder CC, Glass M. Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol. 1998;38:179-200.
12. Rinaldi-Carmona M, Barth F, Heaulme M, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994;350:240-244.
13. Compton DR, Aceto MD, Lowe J, et al. In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of delta 9-tetrahydrocannabinol-induced responses and apparent agonist activity. J Pharmacol Exp Ther. 1996;277:586-594.
14. Katona I, Sperlagh B, Sik A, et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci. 1999;19:4544-4558.
15. Huang CC, Lo SW, Hsu KS. Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons. J Physiol. 2001;532:731-748.
16. Szabo B, Schlicker E. Effects of cannabinoids on neurotransmission. Handb Exp Pharmacol.
2005:327-365.
17. Klein TW, Newton C, Larsen K, et al. The cannabinoid system and immune modulation. J Leukoc Biol. 2003;74:486-496.
18. Cabral GA, Marciano-Cabral F. Cannabinoid receptors in microglia of the central nervous system: immune functional relevance. J Leukoc Biol. 2005;78:1192-1197.
19. Van Sickle MD, Duncan M, Kingsley PJ, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310:329-332.
20. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61-65.
21. Beltramo M, Bernardini N, Bertorelli R, et al. CB2 receptor-mediated antihyperalgesia:
possible direct involvement of neural mechanisms. Eur J Neurosci. 2006;23:1530-1538.
22. Walczak JS, Pichette V, Leblond F, et al. Characterization of chronic constriction of the saphenous nerve, a model of neuropathic pain in mice showing rapid molecular and electrophysiological changes. J Neurosci Res. 2006;83:1310-1322.
23. Wotherspoon G, Fox A, McIntyre P, et al. Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons. Neuroscience. 2005;135:235-245.
24. Zhang J, Hoffert C, Vu HK, et al. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci.
2003;17:2750-2754.
25. Racz I, Nadal X, Alferink J, et al. Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain. J Neurosci.
2008;28:12125-12135.
26. Guindon J, Hohmann AG. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol. 2008;153:319-334.
27. Deng L, Guindon J, Cornett BL, et al. Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent
withdrawal. Biol Psychiatry. 2015;77:475-487.
28. Deng L, Cornett BL, Mackie K, et al. CB1 knockout mice unveil sustained CB2-mediated antiallodynic effects of the mixed CB1CB2 agonist CP55,940 in a mouse model of paclitaxel-induced neuropathic pain. Mol Pharmacol. 2015;88:64-74.
29. Di Marzo V, Fontana A. Anandamide, an endogenous cannabinomimetic eicosanoid: “killing two birds with one stone.” Prostaglandins Leukot Essent Fatty Acids. 1995;53:1-11.
30. Ahn K, McKinney MK, Cravatt BF. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev. 2008;108:1687-1707.
31. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946-1949.
32. Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-
monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50:83-90.
33. Sugiura T, Kondo S, Sukagawa A, et al. 2-Arachidonoyglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215:89-97.
34. Gonsiorek W, Lunn C, Fan X, et al. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol
Pharmacol. 2000;57:1045-1050.
35. Ahn K, Johnson DS, Mileni M, et al. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem Biol. 2009;16:411-420.
36. Long JZ, Li W, Booker L, et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 2009;5:37-44.
37. Jhaveri MD, Richardson D, Robinson I, et al. Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of
inflammatory pain. Neuropharmacology. 2008;55:85-93.
38. Ross RA. Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol. 2003;140:790-801.
39. Cravatt BF, Giang DK, Mayfield SP, et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384:83-87.
40. Gulyas AI, Cravatt BF, Bracey MH, et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci. 2004;20:441-458.
41. Cravatt BF, Prospero-Garcia O, Siuzdak G, et al. Chemical characterization of a family of brain lipids that induce sleep. Science. 1995;268:1506-1509.
42. Blankman JL, Simon GM, Cravatt BF. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol. 2007;14:1347- 1356.
43. Sugiura T, Kobayashi Y, Oka S, et al. Biosynthesis and degradation of anandamide and 2- arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent Fatty Acids. 2002;66:173-192.
44. Vaughan CW, Christie MJ. Retrograde signalling by endocannabinoids. Handb Exp Pharmacol. 2005:367-383.
45. Schlosburg JE, Kinsey SG, Lichtman AH. Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation. AAPS J. 2009;11:39-44.
46. Petrosino S, Palazzo E, de Novellis V, et al. Changes in spinal and supraspinal
endocannabinoid levels in neuropathic rats. Neuropharmacology. 2007;52:415-422.
47. Falenski KW, Thorpe AJ, Schlosburg JE, et al. FAAH-- mice display differential tolerance, dependence, and cannabinoid receptor adaptation after delta 9-tetrahydrocannabinol and anandamide administration. Neuropsychopharmacology. 2010;35:1775-1787.
48. Schlosburg JE, Blankman JL, Long JZ, et al. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci.
2010;13:1113-1119.
49. Burston JJ, Woodhams SG. Endocannabinoid system and pain: an introduction. Proc Nutr Soc. 2014;73:106-117.
50. Jean-Gilles L, Feng S, Tench CR, et al. Plasma endocannabinoid levels in multiple sclerosis.
J Neurol Sci. 2009;287:212-215.
51. Ramesh D, D’Agata A, Starkweather A, et al. Contribution of endocannabinoid gene expression and genotype on low back pain susceptibility and chronicity [published online ahead of print May 5, 2017]. Clin J Pain. doi:10.1097/AJP.0000000000000508.
52. Rani Sagar D, Burston JJ, Woodhams SG, et al. Dynamic changes to the endocannabinoid system in models of chronic pain. Philos Trans R Soc Lond B Biol Sci. 2012;367:3300- 3311.
53. Starowicz K, Przewlocka B. Modulation of neuropathic-pain-related behaviour by the spinal endocannabinoidendovanilloid system. Philos Trans R Soc Lond B Biol Sci.
2012;367:3286-3299.
54. Walker JM, Hohmann AG, Martin WJ, et al. The neurobiology of cannabinoid analgesia.
Life Sci. 1999;65:665-673.
55. Richardson JD, Aanonsen L, Hargreaves KM. SR 141716A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice. Eur J Pharmacol. 1997;319:R3- R4.
56. Chapman V. The cannabinoid CB1 receptor antagonist, SR141716A, selectively facilitates nociceptive responses of dorsal horn neurones in the rat. Br J Pharmacol.
1999;127:1765-1767.
57. Lim G, Sung B, Ji RR, Mao J. Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats.
Pain. 2003;105:275-283.
58. Martin WJ, Patrick SL, Coffin PO, et al. An examination of the central sites of action of cannabinoid-induced antinociception in the rat. Life Sci. 1995;56:2103-2109.
59. Walker JM, Huang SM, Strangman NM, et al. Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci U S A. 1999;96:12198-12203.
60. Rea K, Roche M, Finn DP. Supraspinal modulation of pain by cannabinoids: the role of GABA and glutamate. Br J Pharmacol. 2007;152:633-648.
61. Lee MC, Ploner M, Wiech K, et al. Amygdala activity contributes to the dissociative effect of cannabis on pain perception. Pain. 2013;154:124-134.
62. Cooper ZD, Comer SD, Haney M. Comparison of the analgesic effects of dronabinol and smoked marijuana in daily marijuana smokers. Neuropsychopharmacology.
2013;38(10):1984-1992.
63. Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology.
2007;107:785-796.
64. Lynch ME, Ware MA. Cannabinoids for the treatment of chronic non-cancer pain: an
updated systematic review of randomized controlled trials. J Neuroimmune Pharmacol.
2015;10:293-301.
65. Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol. 2011;72:735-744.
66. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313:2456-2473.
67. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68:515-521.
68. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9:506-521.
69. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34:672- 680.
70. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182:E694-E701.
71. Corey-Bloom J, Wolfson T, Gamst A, et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ. 2012;184:1143-1150.
72. Wallace MS, Marcotte TD, Umlauf A, et al. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain. 2015;16:616-627.
73. Wilsey B, Marcotte T, Deutsch R, et al. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013;14:136-148.
74. Wilsey BL, Deutsch R, Samara E, et al. A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis. J Pain Res. 2016;9:587-598.
75. Zajicek JP, Hobart JC, Slade A, et al. Multiple sclerosis and extract of cannabis: results of the MUSEC trial. J Neurol Neurosurg Psychiatry. 2012;83:1125-1132.
76. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008;9:254-264.
77. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ.
2004;329:253.
78. Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.
Pain. 2007;133:210-220.
79. Rog DJ, Nurmikko TJ, Friede T, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005;65:812-819.
80. Blake DR, Robson P, Ho M, et al. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology. 2006;45:50-52.
81. Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004;112:299-306.
82. Wade DT, Makela P, Robson P, et al. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler. 2004;10:434-441.
83. Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 “N of 1” studies. Anaesthesia. 2004;59:440-452.
84. Wade DT, Robson P, House H, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003;17:21-29.
85. Selvarajah D, Gandhi R, Emery CJ, et al. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic
neuropathy: depression is a major confounding factor. Diabetes Care. 2010;33:128-130.
86. Langford RM, Mares J, Novotna A, et al. A double-blind, randomized, placebo-controlled, parallel-group study of THCCBD oromucosal spray in combination with the existing
treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J Neurol. 2013;260:984-997.
87. Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage. 2014;47:166-173.
88. Serpell M, Ratcliffe S, Hovorka J, et al. A double-blind, randomized, placebo-controlled, parallel group study of THCCBD spray in peripheral neuropathic pain treatment. Eur J Pain. 2014;18:999-1012.
89. Wissel J, Haydn T, Muller J, et al. Low dose treatment with the synthetic cannabinoid
Nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. J Neurol. 2006;253:1337-1341.
90. Pinsger M, Schimetta W, Volc D, et al. Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain---a randomized controlled trial. Wien Klin Wochenschr. 2006;118:327-335.
91. Frank B, Serpell MG, Hughes J, et al. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ. 2008;336:199-201.
92. Skrabek RQ, Galimova L, Ethans K, et al. Nabilone for the treatment of pain in fibromyalgia.
J Pain. 2008;9:164-173.
93. Ware MA, Fitzcharles MA, Joseph L, et al. The effects of nabilone on sleep in fibromyalgia:
results of a randomized controlled trial. Anesth Analg. 2010;110:604-610.
94. Pini LA, Guerzoni S, Cainazzo MM, et al. Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. J Headache Pain. 2012;13:677-684.
95. Toth C, Mawani S, Brady S, et al. An enriched-enrolment, randomized withdrawal, flexible- dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain.
2012;153:2073-2082.
96. Turcotte D, Doupe M, Torabi M, et al. Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Pain Med.
2015;16:149-159.
97. Huggins JP, Smart TS, Langman S, et al. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain. 2012;153:1837-1846.
98. Li GL, Winter H, Arends R, et al. Assessment of the pharmacology and tolerability of PF- 04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects.
Br J Clin Pharmacol. 2012;73(5):706-16.
99. Kerbrat A, Ferre JC, Fillatre P, et al. Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. N Engl J Med. 2016;375:1717-1725.
100. van Esbroeck ACM, Janssen APA, Cognetta AB, 3rd, et al. Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science 2017;356:1084- 1087.
101. Anand P, Whiteside G, Fowler CJ, et al. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res Rev. 2009;60:255-266.
102. Mulvihill MM, Nomura DK. Therapeutic potential of monoacylglycerol lipase inhibitors.
Life Sci. 2013;92:492-497.
103. Agarwal N, Pacher P, Tegeder I, et al. Cannabinoids mediate analgesia largely via
peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci. 2007;10:870-879.
104. Rolke R, Magerl W, Campbell KA, et al. Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur J Pain. 2006;10:77-88.
105. Grim TW, Ghosh S, Hsu KL, et al. Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models.
Pharmacol Biochem Behav. 2014;124:405-411.
106. Crowe MS, Leishman E, Banks ML, et al. Combined inhibition of monoacylglycerol lipase and cyclooxygenases synergistically reduces neuropathic pain in mice. Br J Pharmacol.
2015;172:1700-1712.
107. Welch SP. Interaction of the cannabinoid and opioid systems in the modulation of nociception. Int Rev Psychiatry. 2009;21:143-151.
108. Ramesh D, Ross GR, Schlosburg JE, et al. Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice. J Pharmacol Exp Ther. 2011;339:173-185.
109. Savage SR, Romero-Sandoval A, Schatman M, et al. Cannabis in pain treatment: clinical and research considerations. J Pain. 2016;17:654-668.
110. NCSL NCoSL. State Medical Marijuana Laws. http:www.ncsl.orgresearchhealthstate- medical-marijuana-laws.aspx. Accessed June 29, 2017.
111. Ilgen MA, Bohnert K, Kleinberg F, et al. Characteristics of adults seeking medical marijuana certification. Drug Alcohol Depend. 2013;132:654-659.
112. Bonn-Miller MO, Boden MT, Bucossi MM, et al. Self-reported cannabis use characteristics, patterns and helpfulness among medical cannabis users. Am J Drug Alcohol Abuse.
2013;40:23-30.