Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes

Current Neuropharmacology

Volumn 4, Issue 3, 2006, Pages 239-257

  Manzanares, J ^a   Julian, M D ^a   Carrascosa, A ^b  

^a MIGUEL HERNÁNDEZ UNIVERSITY   (Spain)

^b HOSPITAL UNIVERSITARIO 12 DE OCTUBRE   (Spain)

Author keywords

Analgesia; Cannabidiol; Cannabinoid receptor; Cannabis; Endocannabinoid; Inflammatory pain; Neuropathic pain; Tetrahydrocannabinol

Indexed keywords

1 (2,4 DICHLOROPHENYL) 5 (4 IODOPHENYL) 4 METHYL N (1 PIPERIDYL) 1H PYRAZOLE 3 CARBOXAMIDE; 2,3 DIHYDRO 5 METHYL 3 (MORPHOLINOMETHYL) 6 (1 NAPHTHOYL)PYRROLO[1,2,3 DE][1,4]BENZOXAZINE; 4 (1,1 DIMETHYLHEPTYL) 1',2',3',4',5',6' HEXAHYDRO 2,3' DIHYDROXY 6' (3 HYDROXYPROPYL)BIPHENYL; AJULEMIC ACID; ALPHA 2 ADRENERGIC RECEPTOR; ANANDAMIDE; BENZYLSULFONYL FLUORIDE; CANNABIDIOL; CANNABINOID; CANNABINOID DERIVATIVE; CANNABINOID RECEPTOR; CANNABINOID RECEPTOR AGONIST; CANNABINOID RECEPTOR ANTAGONIST; CANNABIS; CYCLOOXYGENASE 2 INHIBITOR; DEXANABINOL; DIAZEPAM; DRONABINOL; ENDOCANNABINOID; LEVONANTRADOL; MORPHINE; MU OPIATE RECEPTOR; N (4 HYDROXYPHENYL)ARACHIDONAMIDE; NABILONE; NALTREXONE; NONSTEROID ANTIINFLAMMATORY AGENT; RIMONABANT; TETRAHYDROCANNABINOL; UNINDEXED DRUG; VANILLOID RECEPTOR 1;

ANALGESIA; ANTIINFLAMMATORY ACTIVITY; ANTINOCICEPTION; ANXIETY DISORDER; ATAXIA; BRAIN INJURY; CANCER PAIN; CARDIOVASCULAR DISEASE; CATALEPSY; CHRONIC PAIN; CLINICAL TRIAL; CONCENTRATION LOSS; CONFUSION; DEPOLARIZATION; DEPRESSION; DIZZINESS; DROWSINESS; DRUG CONTRAINDICATION; DRUG EFFICACY; DRUG INDICATION; DRUG INDUCED HEADACHE; DRUG POTENCY; DRUG POTENTIATION; DRUG SAFETY; DYSPHORIA; ELECTROSTIMULATION; ENZYME DEGRADATION; EUPHORIA; FATIGUE; FIBROMYALGIA; GABAERGIC TRANSMISSION; HALLUCINATION; HUMAN; HYPERALGESIA; HYPOTENSION; INTERMETHOD COMPARISON; LETHAL DOSE; MIGRAINE; NAUSEA; NERVOUSNESS; NEUROPATHIC PAIN; NEUROTRANSMISSION; NEUROTRANSMITTER RELEASE; NOCICEPTION; NONHUMAN; PAIN THRESHOLD; PATHOPHYSIOLOGY; PHANTOM PAIN; POSTOPERATIVE PAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; RECEPTOR BINDING; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; SOMNOLENCE; SPASTICITY; SPINAL CORD DORSAL HORN; TOOTH EXTRACTION; UNSTEADINESS; XEROSTOMIA;

EID: 33747314445     PISSN: 1570159X     EISSN: None     Source Type: Journal    
DOI: 10.2174/157015906778019527     Document Type: Review

References (179)

1. Ahluwalia, J., Urban, L., Capogna, M., Bevan, S., Nagy, I. (2000) Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons. Neuroscience, 100, 685-688.
2. Anthony, J., Warner, L., Kessler, R. (1994) Comparative epidemiology of dependence on tobacco, alcohol, controlled substance and inhalants: basic findings from the National Comorbidity Survey. Exp. Clin. Psychopharmacol., 2, 244-268.
3. Ates, M., Hamza, M., Seidel, K., Kotalla, C.E., Ledent, C., Guhring, H. (2003) Intrathecally applied flurbiprofen produces an endocannabinoid-dependent antinociception in the rat formalin test. Eur. J. Neurosci., 17, 597-604.
4. Barinaga, M. (2001) How cannabinoids work in the brain. Science, 291, 2530-2531.
5. Behbehani, M.M. (1995) Functional characteristics of the midbrain periaqueductal gray. Prog. Neurobiol., 46, 575-605.
6. Berman, J.S., Symonds, C., Birch, R. (2004) Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain, 112, 299-306.
7. Boger, D.L., Miyauchi, H., Du, W., Hardouin, C., Fecik, R.A., Cheng, H., Hwang, I., Hedrick, M.P., Leung, D., Acevedo, O., Guimaraes, C.R., Jorgensen, W.L., Cravatt, B.F. (2005) Discovery of a potent, selective, and efficacious class of reversible alphaketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics. J. Med. Chem., 48, 1849-1856.
8. Breivogel, C.S., Griffin, G., Di Marzo, V., Martin, B.R. (2001) Evidence for a new G-protein-coupled cannabinoid receptor in mouse brain. Mol. Pharmacol., 60, 155-163.
9. Brenneisen, R., Egli, A., ElSohly, M.A., Henn, V., Spiess, Y. (1996) The effect of orally and rectally administered Δ9- tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J. Clin. Pharmacol. Ther., 34, 446-452.
10. Bridges, D., Ahmad, K., Rice, A.S. (2001) The synthetic cannabinoid WIN 55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Br. J. Pharmacol., 113, 586-594.
11. Bridges, D., Rice, A.S., Egertova, M., Elphick, M.R., Winter, J., Michael, G.J. (2003) Localisation of cannabinoid receptor 1 in rat dorsal root ganglion using in situ hybridisation and immunohisto-chemistry. Neuroscience, 119, 803-812.
12. British Medical Association (1997) Therapeutic Uses of Cannabis. London, Harwood Academic Publishers.
13. Buckley, N.E., McCoy, K.L., Mezey, E., Bonner, T, Zimmer, A., Felder, C.C., Glass, M., Zimmer, A. (2000) Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur. J. Pharmacol., 396, 141-149.
14. Buggy, D.J., Toogood, L., Maric, S., Sharpe, P., Lambert, D.G., Rowbotham, D.J. (2003) Lack of analgesic efficacy of oral delta-9- tetrahydrocannabinol in postoperative pain. Pain, 106, 169-172.
15. Burstein, S.H., Karst, M., Schneider, U., Zurier, R.B. (2004) Ajulemic acid: A novel cannabinoid produces analgesia without a "high". Life Sci., 75, 1513-1522.
16. Cadas, H., di Tomaso, E., Piomelli, D. (1997) Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci, 17, 1226-1242.
17. Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D., Julius, D. (1997) The capsaicin receptor, a heat-activated ion channel in the pain pathway. Nature, 389, 816-824.
18. Chapman, V. (1999) The cannabinoid CB1 receptor antagonist, SR141716A, selectively facilitates nociceptive responses of dorsal horn neurones in the rat. Br. J. Pharmacol., 127, 1765-1767.
19. Chieng, B., Christie, M.J. (1994) Inhibition by opioids acting on mu-receptors of GABAergic and glutamatergic postsynaptic potentials in single rat periaqueductal gray neurones in vitro. Br. J. Pharmacol., 113, 303-309.
20. Clark, W.C., Janal, M.N., Zeidenberg, P., Nahas, G.G. (1981). Effects of moderate and high doses of marihuana on thermal pain: A sensory decision theory analysis. J. Clin. Pharmacol., 21 (8-9 Suppl.), 299S-310S.
21. Clark, A.J., Ware, M.A., Yazer, E., Murray, T.J., Lynch, M.E. (2004) Patterns of cannabis use among patients with multiple sclerosis. Neurology, 62, 2098-2100.
22. Compton, D.R., Aceto, M.D., Lowe, J., Martin, B.R, (1996) In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A), inhibition of delta 9-tetrahydocannabinol-induced responses and apparent agonist activity. J. Pharmacol. Exp. Ther., 277, 586-594.
23. Consroe, P., Musty, R., Rein, J., Tillery, W., Pertwee, R. (1997) The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur. Neurol. 38, 44-48.
24. Cook, S.A., Welch, S.P., Lichtman, A.H., Martin, B.R. (1995) Evaluation of cAMP involvement in cannabinoid-induced antinociception. Life Sci., 56, 2049-2056.
25. Corchero, J., Avila, M.A., Fuentes, J.A., Manzanares, J. (1997) Delta 9-tetrahydrocannabinol increases prodynorphin and proenkephalin gene expression in the spinal cord of the rat. Life Sci., 61, L39-L43.
26. Corchero, J., Manzanares, J., Fuentes, J.A. (2004) Cannabinoid/opioid crosstalk in the central nervous system. Crit. Rev. Neurobiol., 16, 159-172.
27. Cravatt, B.F., Demarest, K., Patricelli, M.P., Bracey, M.H., Giang, D.K., Martin, B.R., Lichtman, A.H. (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl. Acad. Sci. USA, 98, 9371-9376.
28. Deutsch, D.G., Lin, S., Hill, W.A., Morse, K.L., Salehani, D., Arreaza, G., Omeir, R.L., Makriyannis, A. (1997) Fatty acid sulfonyl fluorides inhibit anandamide metabolism and bind to the cannabinoid receptor. Biochem. Biophys. Res. Commun., 231, 217-221.
29. Devane, W.A., Dysarz, F.A. 3rd, Johnson, M.R., Melvin, L.S., Howlett, A.C. (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol., 34, 605-613.
30. Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.A., Griffin, G., Gibson, D, Mandelbaum, A, Etinger, A, Mechoulam, R. (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 258, 1946-1949.
31. Di Marzo, V., Breivogel, C.S., Tao, Q., Bridgen, D.T., Razdan, R.K., Zimmer, A.M., Zimmer, A., Martin, B.R. (2000) Levels, metabolism, and pharmacological activity of anandamide in CB1 cannabinoid receptor knockout mice, evidence for non-CB1, non-CB2 receptor-mediated actions of anandamide in mouse brain. J Neurochem., 75, 2434-2444.
32. Di Marzo, V., Fontana, A., Cadas, H., Schinelli, S., Cimino, G., Schwartz, J.C., Piomelli, D. (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature, 372, 686-691.
33. Edsall, S.A., Knapp, R.J., Vanderab, T.W., Roeske, W.R., Consroe, P., Yamamura, H.I. (1996) Antisense oligodeoxynucleotide treatment to the brain cannabinoid receptor inhibits antinociception. Neuroreport, 7, 593-596.
34. Elphick, M.R., Egertova, M. (2001) The neurobiology and evolution of cannabinoid signalling. Philos. Trans. R. Soc. Lond. B. Biol. Sci., 356, 381-408.
35. Farquhar-Smith, W.P., Egertova, M., Bradbury, E.J., McMahon, S.B., Rice, A.S., Elphick, M.R. (2000) Cannabinoid CB(1) receptor expression in rat spinal cord. Mol. Cell. Neurosci., 15, 510-521.
36. Fimiani, C., Liberty, T., Aquirre, A.J., Amin, I., Ali, N., Stefano, G.B. (1999) Opiate, cannabinoid, and eicosanoid signaling converges on common intracellular pathways nitric oxide coupling. Prostaglandins Other Lipid Mediat, 57, 23-34.
37. Fowler, C.J. (2004) Possible involvement of the endocannabinoid system in the actions of three clinically used drugs. Trends Pharmacol. Sci., 25, 59-61.
38. Fox, A., Kesingland, A., Gentrym C., McNair, K., Patel, S., Urban, L., James, I. (2001) The role of central and peripheral Cannabinoid 1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain, 92, 91-100.
39. Freund, T.F., Katona, I., Piomelli, D. (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev., 83, 1017-1066.
40. Fride, E., Feigin, C., Ponde, D.E., Breuer, A., Hanus, L., Arshavsky, N., Mechoulam, R. (2004) (+)-Cannabidiol analogues which bind cannabinoid receptors but exert peripheral activity only. Eur. J. Pharmacol., 506, 179-188.
41. Fuentes, J.A., Ruiz-Gayo, M., Manzanares, J., Vela, G., Reche, I., Corchero, J. (1999) Cannabinoids as potential new analgesics. Life Sciences, 65, 675-685.
42. Gaoni, Y., Mechoulam, R. (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc., 86, 1646-1467.
43. Giang, D.K., Cravatt, B.F. (1997) Molecular characterization of human and mouse fatty acid amide hydrolases. Proc. Natl. Acad. Sci. USA, 94, 2238-2242.
44. Giuffrida, A., Beltramo., M., Piomelli, D. (2001) Mechanisms of endocannabinoid inactivation, biochemistry and pharmacology. J. Pharmacol. Exp. Ther., 298, 7-14.
45. Gopez, J.J., Yue, H., Vasudevan, R., Malik, A.S., Fogelsanger, L.N., Lewis, S., Panikashvili, D., Shohami, E., Jansen, S.A., Narayan, R.K., Strauss, K.I. (2005) Functional outcomes, provides neuroprotection, and reduces inflammation in a rat model of traumatic brain injury. Neurosurgery, 56, 590-604.
46. Greenwald, M.K., Stitzer, M.L. (2000) Antinociceptive, subjective and behavioral effects of smoked marijuana in humans. Drug Alcohol Depend., 59, 261-275.
47. Grinspoon, L., Bakalar, J.B. (1997) Marihuana, the forbidden medicine. New Haven: Yale University Press.
48. Grudt, T.J., Henderson, G. (1998) Glycine and GABAA receptor-mediated synaptic transmission in rat substantia gelatinosa, inhibition by mu-opioid and GABAB agonists. J Physiol., 507, 473-483.
49. Grudt, T.J., Williams, J.T (1994) mu-Opioid agonists inhibit spinal trigeminal substantia gelatinosa neurons in guinea pig and rat. J. Neurosci, 14, 1646-1654.
50. Guhring, H., Hamza, M., Sergejeva, M., Ates, M., Kotalla, C.E., Ledent, C., Brune, K. (2002) A role for endocannabinoids in indomethacin-induced spinal antinociception. Eur. J. Pharmacol., 454, 153-163.
51. Hajos, N., Ledent, C., Freund, T.F. (2001) Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience, 106, 1-4.
52. Hanus, L., Abu-Lafi, S., Fride, E., Breuer, A., Shalev, D.E., Kustanovich, I., Vogel, Z., Mechoulam, R. (2001) 2-Arachidonyl glyceryl ether, a novel endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl. Acad. Sci., 98, 3662-3665.
53. Herkenham, M., Lynn, A.B., Johnson, M.R., Melvin, L.S., de Costa, B.R., Rice, K.C. (1991) Characterization and localization of cannabinoid receptors in rat brain, a quantitative in vitro autoradio-graphic study. J. Neurosci, 11, 563-583.
54. Herzberg, U., Eliav, E., Bennett, G.J., Kopin, I.J. (1997) The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neurosci. Lett., 221, 157-160.
55. Hill, S.Y., Schwin, R., Goodwin, D.W., Powell, B.J. (1974) Marihuana and pain. J. Pharmacol. Exp. Ther., 188, 415-418.
56. Hohman, A.G., Walker, J.M. (1999) Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat. J. Neurophysiol., 81, 575-585.
57. Hohmann, A.G, Herkenham, M. (1998) Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin. Neurosci. Lett., 252, 13-16.
58. Hohmann, A.G., Herkenham, M. (1999) Cannabinoid receptors undergo axonal flow in sensory nerves. Neuroscience, 92, 1171-1175.
59. Hohmann, A.G., Herkenham, M. (1999) Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia, a double-label in situ hybridization study. Neuroscience, 90, 923-931.
60. Hohmann, A.G., Tsou, K., Walker, J.M. (1998) Cannabinoid modulation of wide dynamic range neurons in the lumbar dorsal horn of the rat by spinally administered WIN55,212-2. Neurosci. Lett., 257, 119-122.
61. Holt, S., Fowler, C.J. (2003) Anandamide metabolism by fatty acidamide hydrolase in intact C6 glioma cells. Increased sensitivity to inhibition by ibuprofen and flurbiprofen upon reduction of extra- but not intracellular pH. Naunyn Schmiedebergs Arch. Pharmacol., 367, 237-244.
62. Howlett, A.C. (2002) The cannabinoid receptors. Prostaglandins Other Lipid Mediat., 68-69, 619-631.
63. Howlett, A.C. (2004) Efficacy in CB1 receptor-mediated signal transduction. Br. J. Pharmacol., 142, 1209-1218.
64. Howlett, A.C., Johnson, M.R., Melvin, L.S., Milne, G.M. (1988) Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. Mol. Pharmacol., 33, 297-302.
65. Huang, S.M., Bisogno, T., Trevisani, M., Al-Hayani, A., De Petrocellis, L., Fezza, F., Tognetto, M., Petros, T.J., Krey, J.F., Chu, C.J., Miller, J.D., Davies, S.N., Geppetti, P., Walker, J.M., Di Marzo, V. (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc. Natl. Acad Sci. USA, 99, 8400-8405.
66. Ibrahim, M.M., Deng, H., Zvonok, A., Cockayne, D.A., Kwan, J., Mata, H.P., Bandera, T.W., Lai, J., Porreca, F., Makriyannis, A., Malan, T.P. Jr. (2003) Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc. Natl. Acad. Sci. USA, 100, 10529-10533.
67. 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., Malan, T.P. Jr. (2005) CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc. Natl. Acad Sci. USA, 102, 3093-3098.
68. Iversen, L. (2003) Cannabis and the brain. Brain, 126, 1252-1270.
69. Iversen, L.L., Chapman, V. (2002) Cannabinoids, a real prospect for pain relief? Curr. Opin. Pharmacol., 2, 50-55.
70. Jain, A.K., Ryan, J.R., McMahon, F.G., Smith, G. (1981) Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J. Clin. Pharmacol., 21 (8-9 Suppl.), 320S-326S.
71. Jarai, Z., Wagner, J.A., Varga, K., Lake, K.D., Compton, D.R., Martin, B.R., Zimmer, A.M., Bonner, T.I. (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc. Natl. Acad. Sci. USA, 96, 14136-14141.
72. Jennings, E.A., Vaughan, C.W., Christie, M.J. (2001) Cannabinoid actions on rat superficial medullary dorsal horn neurons in vitro. J. Physiol., 534, 805-812.
73. Jochimsen, P.R., Lawton, R.L., VerSteeg, K., Noyes, R. Jr. (1978) Effect of benzopyranoperidine, a delta-9-THC congener, on pain. Clin. Pharmacol. Ther., 24, 223-227.
74. Jones, R.T. (1978) Behavioral tolerance: lessons learned from cannabis research. NIDA Res. Monogr., 18, 118-126.
75. Jones, R.T. (1987) Drug of abuse profile: cannabis. Clin. Chem. 33, 72B-81B.
76. Kamibayashi, T., Maze, M. (2000) Clinical uses of alpha2-adrenergic agonists. Anesthesiology, 93, 1345-1349.
77. Karst, M., Salim, K., Burstein, S., Conrad, L, Hoy, L., Schneider, U. (2003) Analgesic effect of the synthetic cannabinoid CT-3 on the chronic neuropathic pain. JAMA, 290, 1757-1762.
78. Katona, I., Rancz, E.A., Acsady, L., Ledent, C., Mackie, K., Hajos, N., Freund, T.F. (2001) Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J. Neurosci., 21, 9506-9518.
79. Katona, I., Sperlagh, B., Magloczky, Z., Santha, E., Kofalvi, A., Czirjak, S., Mackie, K., Vizi, E.S., Freund, T.F (2000) GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus. Neuroscience, 100, 797-804.
80. Khan, Z.P., Ferguson, C.N., Jones, R.M. (1999) Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia, 54, 146-165.
81. Kohno, T., Kumamoto, E., Higashi, H., Shimoji, K., Yoshimura, M. (1999) Actions of opioids on excitatory and inhibitory transmission in substantia gelatinosa of adult rat spinal cord. J. Physiol., 518, 803-813.
82. Kozak, K.R., Prusakiewicz, J.J., Rowlinson, S.W., Prudhomme, D.R., Marnett, L.J. (2003) Amino acid determinants in cyclooxy-genase-2 oxygenation of the endocannabinoid anandamide. Bio-chemistry, 42, 9041-9049.
83. Kozak, K.R., Rowlinson, S.W., Marnett, L.J. (2000) Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prosta-glandins by cyclooxygenase-2. J. Biol. Chem., 275, 33744-33749.
84. Kreitzer, A.C., Regehr, W.G. (2001) Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J. Neurosci., 21, RC174:1-5.
85. Kreitzer, A.C., Regehr, W.G. (2001) Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron, 29, 717-727.
86. Ledent, C., Valverde, O., Cossu, G., Petitet, F., Aubert, J-F., Beslot, F., Bohme, G.A., Imperato, A., Pedrazzini, T., Roques, B.P., Vassart, G., Fratta, W., Parmentier, M. (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science, 283, 401-404.
87. Lichtman, A.H., Cook, S.A., Martin, B.R. (1996) Investigation of brain sites mediating cannabinoid-induced antinociception in rats, evidence supporting periaqueductal gray involvement. J. Pharmacol. Exp. Ther., 276, 585-593.
88. Lichtman, A.H., Martin, B.R. (1991) Cannabinoid-induced antinociception is mediated by a spinal a2-noradrenergic mechanism. Brain Res., 559, 309-314.
89. Lichtman, A.H., Martin, B.R. (1991) Spinal and supraspinal components of cannabinoid-induced antinociception. J. Pharmacol. Exp. Ther., 258, 517-523.
90. Lim, G., Sung, B., Ji, R.R., Mao, J. (2003) Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats. Pain, 105, 275-283.
91. Lopez-Rodriguez, M.L., Viso, A., Ortega-Gutierrez, S., Lastres-Becker, I., Gonzalez, S., Fernandez-Ruiz, J.J., Ramos, J.A. (2001) Design, synthesis and biological evaluation of novel arachidonic acid derivatives as highly potent and selective endocannabinoid transporter inhibitors. J. Med. Chem., 44, 4505-4508.
92. Luo, C., Kumamoto, E., Furue, H., Chen, J., Yoshimura, M. (2002) Anandamide inhibits excitatory transmission to rat substantia gelatinosa neurones in a manner different from that of capsaicin. Neurosci. Lett., 321, 17-20.
93. Manning, B.H., Martin, W.J., Meng, I.D. (2003) The rodent amygdala contributes to the production of cannabinoid-induced antinociception. Neuroscience, 120, 1157-1170.
94. Manzanares, J., Corchero, J., Romero, J., Fernandez-Ruiz, J.J., Ramos, J.A., Fuentes, J.A. (1999) Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol. Sci., 20, 287-294.
95. Mao, J., Price, D.D., Lu, J., Keniston, L., Mayer, D.J. (2000) Two distinctive antinociceptive systems in rats with pathological pain. Neurosci. Lett., 280, 13-16.
96. Martin, B.R. (1985) Structural requirements for cannabinoid-induced antinociceptive activity in mice. Life Sci., 36, 1523-1530.
97. Martin, B.R., Lichtman, A.H. (1998) Cannabinoid transmission and pain perception. Neurobiol. Dis., 5, 447-461.
98. Martin, W.J., Coffin, P.O., Attias, E., Balinsky, M., Tsou, K., Walker, J.M. (1999) Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections. Brain Res., 822, 237-242.
99. Martin, W.J., Hohmann, A.G., Walker, J.M. (1996) Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist, correlation between electrophysiological and antinociceptive effects. J. Neurosci., 16, 6601-6611.
100. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., Bonner, T.I. (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346, 561-564.
101. Maurer, M., Henn, V., Dittrich, A., Hofmann, A.(1990) Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur. Arch. Psychiatry Clin. Neurosci., 240, 1-4.
102. Mechoulam, R. (2000) Looking back at Cannabis research. Curr. Pharm. Des., 6, 1313-1322.
103. Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N.E., Schatz, A.R., Gopher, A., Almog, S., Martin, B.R., Compton, D.R., Pertwee, R.G., Griffin, G., Bayewitch, M., Barg, J., Vogel, Z. (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol., 50, 83-90.
104. Meng, I.D., Manning, B.H., Martin, W.J., Fields, H.L. (1998) An analgesia circuit activated by cannabinoids. Nature, 395, 381-383.
105. Milstein, S.L., MacCannell, K., Karr, G., Clark, S. (1975) Marijuana-produced changes in pain tolerance. Experienced and non-experienced subjects. Int. Pharmacopsychiatry, 10, 177-182.
106. Morisset, V., Urban, L. (2001) Cannabinoid-induced presynaptic inhibition of glutamatergic EPSCs in substancia gelatinosa neurons of the spinal cord. J. Neurophysiol., 86, 40-48.
107. Mukhopadhyay, S., Chapnick, B.M., Howlett, A.C. (2002) Anandamide-induced vasorelaxation in rabbit aortic rings has two components, G protein dependent and independent. Am. J. Physiol. Heart Circ. Physiol., 282, H2046-H2054.
108. Munro, S., Thomas, K.L., Abu-Shaar, M. (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature, 365, 61-65.
109. Naef, M., Curatolo, M., Petersen-Felix, S., Arendt-Nielsen, L., Zbinden, A., Brenneisen, R. (2003) The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain, 105, 79-88.
110. Notcutt, W.G., Price, M., Chapman, G. (1997) Clinical experience with nabilone for chronic pain. Pharm. Sci., 3, 551-555.
111. Notcutt, W., Price, M., Miller, R., Newport, S., Phillips, C., Simmons, S., Sansom, C. (2004) Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies. Anaesthesia, 59, 440-452.
112. Noyes, R. Jr., Baram, D.A. (1974) Cannabis analgesia. Compr. Psychiatry, 15, 531-535.
113. Noyes, R. Jr., Brunk, S.F., Avery, D.H., Canter, A. (1975) The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin. Pharmacol. Ther., 18, 84-89.
114. Noyes, R. Jr., Brunk, S.F., Baram, D.A., Canter, A. (1975) Analgesic effect of delta-9 tetrahydrocannabinol. J. Clin. Pharmacol., 15, 139-143.
115. Ohno-Shosaku, T., Maejima, T., Kano, M. (2001) Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron, 29, 729-738.
116. Pertwee, R.G. (2001) Cannabinoid receptors and pain. Prog. Neurobiol., 63, 569-611.
117. Pertwee, R.G. (2002) Cannabinoids and multiple sclerosis. Pharmacol. Ther., 95, 165-174.
118. Piomelli, D., Beltramo, M., Giuffrida, A., Stella, N. (1998) Endogenous cannabinoid signaling. Neurobiol. Dis., 5, 462-473.
119. Piomelli, D., Beltramo, M., Glasnapp, S., Lin, S.Y., Goutopoulos, A., Xie, X.Q., Makriyannis, A. (1999) Structural determinants for recognition and translocation by the anandamide transporter. Proc. Natl. Acad. Sci. USA, 96, 5802-5807.
120. Porter, A.C., Felder, C.C. (2001) The endocannabinoid nervous system, unique opportunities for therapeutic intervention. Pharmacol. Ther., 90, 45-60.
121. Porter, A.C., Sauer, J.M., Knierman, M.D., Becker, G.W., Berna, M.J., Bao, J., Nomikos, G.G., Carter, P., Bymaster, F.P., Leese, A.B., Felder, C.C. (2002) Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J. Pharmacol Exp. Ther., 301, 1020-1024.
122. Price, T.J., Helesic, G., Parghi, D., Hargreaves, K.M., Flores, C.M. (2003) The neuronal distribution of cannabinoid receptor type 1 in the trigeminal ganglion of the rat. Neuroscience, 120, 155-162.
123. Pryce, G., Ahmed, Z., Hankey, D.J., Jackson, S.J., Croxford, J.L., Pocock, J.M., Ledent, C., Petzold, A., Thompson, A.J., Giovannoni, G., Cuzner, M.L., Baker, D. (2003) Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain, 126, 2191-2202.
124. Przewlocki, R., Przewlocka, B. (2001) Opioids in chronic pain. Eur. J. Pharmacol., 429, 79-91.
125. Pugh, G. Jr., Smith, P.B., Dombrowski, D.S., Welch, S.P. (1996) The role of endogenous opioids in enhancing the antinociception produced by the combination of delta 9-tetrahydrocannabinol and morphine in the spinal cord. J. Pharmacol. Exp. Ther., 279, 608-616.
126. Pugh, G., Abood, M.E., Welch, S.P. (1995) Antisense oligode-oxynucleotides to the k-1 receptor block the antinociceptive effects of D9-THC in the spinal cord. Brain Res., 689, 157-158.
127. Radbruch, L., Elsner, F. (2005) Emerging analgesics in cancer pain management. Expert Opin. Emerg. Drugs, 10, 151-171.
128. Raffa, R.B., Stone, D.J., Hipp, S.J. (1999) Differential cholera-toxin sensitivity of supraspinal antinociception induced by the cannabinoid agonists D9-THC, WIN 55,212-2 and anandamide in mice. Neurosci. Lett., 263, 29-32.
129. Raft, D., Gregg, J., Ghia, J., Harris, L. (1977) Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Psychological correlates of the analgesic response. Clin. Pharmacol. Ther., 21, 26-33.
130. Reichman, M., Nen, W., Hokin, L.E. (1988) Delta-9-tetrahydro-cannabinol increases arachidonic acid levels in guinea pig cerebral cortex slices. Mol. Pharmacol., 34, 823-828.
131. Rice, A.S., Farquhar-Smith, W.P., Nagy, I. (2002) Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot. Essent. Fatty Acids, 66, 243-256.
132. Richardson, J.D., Aanonsen, L., Hargreaves, K.M. (1997) SR 141716A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice. Eur. J. Pharmacol, 319, R3-R4.
133. Richardson, J.D., Aanonsen, L., Hargreaves, K.M. (1998) Anti-hyperalgesic effects of spinal cannabinoids. Eur. J. Pharmacol., 345, 145-153.
134. Richardson, J.D., Kilo, S., Hargreaves, K.M. (1998) Cannabinoids reduces hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain, 75, 111-119.
135. Robson, P. (2001) Therapeutic aspects of cannabis and cannabinoids. Br. J. Psychiatry, 178, 107-115.
136. Rosenberg, M.F., Anthony, J.C. (2001) Early clinical manifestations of cannabis dependence in a community sample. Drug Alcohol Depend. 64, 123-131.
137. Russo, E. (1998) Cannabis for migraine treatment: the once and future prescription? An historical and scientific review. Pain, 76, 3-8.
138. Russo, E.B. (2004) Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol. Lett., 25, 31-39.
139. Sanudo-Pena, M.C., Romero, J., Seale, G.E., Fernandez-Ruiz, J.J., Walker, J.M. (2000) Activational role of cannabinoids on movement. Eur. J. Pharmacol., 391, 269-274.
140. Sanudo-Pena, M.C., Strangman, N.M., Mackie, K., Walker, J.M., Tsou, K. (1999) CB1 receptor localization in rat spinal cord and roots, dorsal root ganglion, and peripheral nerve. Zhongguo Yao Li Xue Bao, 20, 1115-1120.
141. Schlicker, E., Kathmann, M. (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci., 22, 565-572.
142. Scott, D.A., Wright, C.E., Angus, J.A. (2004) Evidence that CB-1 and CB-2 cannabinoid receptors mediate antinociception in neuro-pathic pain in the rat. Pain, 109, 124-131.
143. Shen, M., Piser, T.M., Seybold, V.S, Thayer, S.A. (1996) Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J. Neurosci., 16, 4322-4324.
144. Shire, D., Carillon, C., Kaghad, M., Calandra, B., Rinaldi-Carmona, M., Le Fur, G., Caput, D., Ferrara, P. (1995) An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J. Biol. Chem., 270, 3726-3731.
145. Siegling, A., Hofmann, H.A., Denzer, D., Mauler, F., De Vry, J. (2001) Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain. Eur. J. Pharmacol., 415, R5-R7.
146. Small-Howard, A.L., Shimoda, L.M., Adra, C.N., Turner, H. (2005) Anti-inflammatory potential of CB1-mediated cAMP elevation in mast cells. Biochem. J., 388(pt 2), 465-73.
147. Smith, F.L., Fujimori, K., Lowe, J., Welch, S.P., (1998) Characterization of D9-tetrahydrocannabinol and anandamide antinociception in non-arthritic and arthritic rats. Pharmacol. Biochem. Behav., 60, 183-191.
148. Smith, P.B., Martin, B.R. (1992) Spinal mechanisms of delta 9- tetrahydrocannabinol-induced analgesia. Brain Res., 578, 8-12.
149. Smith, P.F. (2004) Medicinal cannabis extracts for the treatment of multiple sclerosis. Curr. Opin. Investig. Drugs, 5, 727-730.
150. Staquet, M., Gantt, C., Machin, D. (1978) Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clin. Pharmacol. Ther., 23, 397-401.
151. Stella, N., Schweitzer, P., Piomelli, D.A. (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature, 388, 773-778.
152. Strangman, N.M., Walker, J.M., (1999) The cannabinoid WIN 55,212-2 inhibits the activity-dependent facilitation of spinal nociceptive responses. J. Neurophysiol., 81, 472-477.
153. Swift, W., Hall, W., Tesson, M. (2001) Cannabis use and dependence among Australian adults: results from the National Survey of Mental Health and Wellbeing. Addiction, 96, 737-748.
154. Szabo, B., Wallmichrath, I., Mathonia, P., Pfreundtner, C. (2000) Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata. Neuroscience, 97, 89-97.
155. Takano, Y., Yaksh, T.L. (1992) Characterization of the pharmacology of intrathecally administered alpha-2 agonists and antagonists in rats. J. Pharmacol. Exp. Ther., 261, 764-772.
156. Tjolsen, A., Hole, K. (1997) Animal models of analgesia In: Dickenson, L., Bessing, J. Eds, The Pharmacology of Pain. Heidelberg, Springer. pp. 1-20.
157. Todd, A.J., Spike, R.C. (1993) The localization of classical transmitters and neuropeptides within neurons in laminae I-III of the mammalian spinal dorsal horn. Prog. Neurobiol., 41, 609-645.
158. Tramer, M.R., Carroll, D., Campbell, F.A., Reynolds, D.J., Moore, R.A., McQuay, H.J. (2001) Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ, 323, 16-21.
159. Tsou, K., Brown, M.C., Sanudo-Pena, M.C., Mackie, K., Walker, J.M. (1998) Immunohistochemical distrubution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience, 83, 393-411.
160. Valenzano, K.J., Tafessem, L., Lee, G., Harrison, J.E., Bouletm J.M., Gottshallm, S.L., Mark, L., Pearson, M.S., Miller, W., Shan, S., Rabadi, L., Rotshteyn, Y., Chafferm, S.M., Turchinm, P.I., Elsemore, D.A., Toth, M., Koetznerm, L., Whiteside, G.T. (2005) 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, 658-672.
161. Vaney, C., Heinzel-Gutenbrunner, M., Jobin, P., Tschopp, F., Gattlen, B., Hagen, U., Schnelle, M., Reif, M. (2004) Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult. Scler., 10, 417-424.
162. Vaughan, C.W., Connor, M., Bagley, E.E., Christie, M.J. (2000) Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol. Pharmacol., 57, 288-295.
163. Vaughan, C.W., McGregor, I.S., Christie, M.J. (1999) Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br. J. Pharmacol., 127, 935-940.
164. Wade, D.T., Makela, P., Robson, P., House, H., Bateman, C. (2004) 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., 10, 434-441.
165. Wade, D.T., Robson, P., House, H., Makela, P., Ara, J. (2003) A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin. Rehabil., 17, 21-29.
166. Walker, J.M., Hohmann, G., Martin, W. J., Strangman, N.M. (1999) The neurobiology of cannabinoid analgesia. Life Sci., 65, 665-673.
167. Walker, J.M., Huang, S.M., Strangman, N.M., Tsou, K., Sanudo-Pena, M.C. (1999) Pain modulation by release of the endogenous cannabinoid anandamide. Proc. Natl. Acad. Sci. USA, 96, 12198-12203.
168. Walker, J.M., Krey, J.F., Chu, C.J., Huang, S.M. (2002) Endocannabinoids and related fatty acid derivatives in pain modulation. Chem. Phys. Lipids, 121, 159-172.
169. Walter, L., Stella, N. (2004) Cannabinoids and neuroinflammation. Br. J. Pharmacol., 141, 775-785.
170. Ware, M.A., Doyle, C.R., Woods, R., Lynch, M.E., Clarck, A.J. (2003) Cannabis use for chronic non-cancer pain: results of a prospective survey. Pain, 102, 211-216.
171. Ware, M.A., Gamsa, A., Persson, J., Fitzcharles, M.A. (2002) Cannabis for chronic pain: case series and implications for clinicians. Pain Res. Manag., 7, 95-99.
172. Watson, S.J., Benson, J.A. Jr., Joy, J.E. (2000) Marijuana and medicine: assessing the science base: a summary of the 1999 Institute of Medicine report. Arch. Gen. Psychiatry, 57, 547-552.
173. Welch, S.P., Dunlow, L.D., Patrick, G.S., Razdan, R.K. (1995) Characterisation of anandamide-induced antinociception and cross-tolerance to delta 9-THC after intrathecal administration to mice: blockade of delta 9-THC-induced antinociception. J. Pharmacol. Exp. Ther., 273, 1235-1244.
174. Welch, S.P., Stevens, D.L. (1992) Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. J. Pharmacol. Exp. Ther. 262, 10-18.
175. Wilson, R.I., Nicoll, R.A. (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature, 410, 588-592.
176. Yaksh, T.L. (1985) Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol. Biochem. Behav., 22, 845-858.
177. Zeidenberg, P., Clark, W.C., Jaffe, J., Anderson, S.W., Chin, S., Malitz, S. (1973) Effect of oral administration of delta-9-tetrahydrocannabinol on memory, speech, and perception of thermal stimulation: results with four normal human volunteer subjects. Preliminary report. Comp. Psychiatry, 14, 549-556.
178. Zhang, J., Hoffert, C., Vu, H.K., Groblewski, T., Ahmad, S., O'Donnell, D. (2003) Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur. J. Neurosci., 17, 2750-2754.
179. Zimmer, A., Zimmer, A.M., Hohmann, A.G., Herkenham, M., Bonner, T.I. (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA, 96, 5780-5785.