CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms
Abstract
In mouse the cannabinoid receptor 2 (CB2) agonists L768242 and (+)-AM1241, at doses of 30 mg/kg i.p. and 1 and 3 mg/kg i.v., respectively, reduced the second phase of nocifensive behaviors elicited by formalin intraplantar injection. This effect was counteracted by the selective CB2 antagonist SR144528 (1 mg/kg i.p.). In rat (+)-AM1241 (3 and 6 mg/kg i.v.) and L768242 (30 mg/kg i.p.) reduced allodynia elicited by L5-L6 spinal nerve ligation. SR144528 reverted these effects, supporting a CB2-mediated action. To clarify the mechanisms underlying these effects we investigated CB2 gene expression and function in the nervous system. CB2 mRNA was expressed in spinal cord and dorsal root ganglia (DRG) of both sham and neuropathic rats and was up-regulated in the ipsilateral spinal cord of neuropathic rats. Expression studies demonstrated the presence of CB2 mRNA in culture of spinal cord microglia. A biomarker, CGRP, was used to investigate modulation of DRG primary afferents by CB2 agonists. Both L768242 and (+)-AM1241 dose dependently (EC50 of 3.6 and 4.5 nM, respectively) reduced capsaicin-induced calcitonin gene-related peptide (CGRP) release. Coadministration of SR144528 resulted in a rightforward shift (pKB 8.1 and 8.2 for (+)-AM1241 and L768242, respectively) of the dose-response curve. Experiments on capsaicin-induced CGRP release in tissue from CB1-/- mice ruled out a CB1-mediated effect. These results confirm that CB2 is present in the central nervous system and suggest that CB2 agonists may elicit their analgesic effect by acting not only at non-neuronal peripheral sites but also at neural level, making CB2 an attractive target for chronic pain treatment.
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Upregulation of CB2 receptor immunoreactivity or mRNA is observed in sites implicated in nociceptive processing under conditions of induced neuropathy.
“However, an upregulation of CB2 receptor immunoreactivity or mRNA is observed in sites implicated in nociceptive processing under conditions of induced neuropathy.17, 18”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [17]
The CB2 agonist AM1241 suppresses both thermal hyperalgesia and mechanical allodynia following SNL in both rats and mice.
“The CB2 agonist AM1241 suppresses both thermal hyperalgesia and mechanical allodynia following SNL in both rats17, 44, 85 and mice44.”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [17]
CB2 mRNA was upregulated in the ipsilateral versus the contralateral spinal cord and dorsal root ganglion following SNL, and the presence of CB2 mRNA was confirmed in spinal cord microglial cells in culture.
“CB2 mRNA was also shown to be upregulated in the ipsilateral (versus the contralateral) spinal cord and DRG following SNL and the presence of CB2 mRNA was confirmed in spinal cord microglial cells in culture.17”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [17]
Cites
A new mathematical model for relative quantification in real-time RT-PCR
Pfaffl, M. W. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.9.e45 · Cited by 34,610 · see citing works
Quantitative assessment of tactile allodynia in the rat paw
Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M., & Yaksh, T. L. (1994) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(94)90144-9 · Cited by 7,740 · see citing works
Molecular characterization of a peripheral receptor for cannabinoids
Munro, S., Thomas, K. L., & Abu-Shaar, M. (1993) · Nature · doi:10.1038/365061a0 · Cited by 5,092 · see citing works
Structure of a cannabinoid receptor and functional expression of the cloned cDNA
Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C., & Bonner, T. I. (1990) · Nature · doi:10.1038/346561a0 · Cited by 5,011 · see citing works
Ho Kim, S., & Mo Chung, J. (1992) · Pain · doi:10.1016/0304-3959(92)90041-9 · Cited by 3,069 · see citing works
Cannabinoid receptor localization in brain.
Herkenham, M., Lynn, A. B., Little, M. D., Johnson, M. R., Melvin, L. S., de Costa, B. R., & Rice, K. C. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.5.1932 · Cited by 2,321 · see citing works
Galiègue, S., Mary, S., Marchand, J., Dussossoy, D., Carrière, D., Carayon, P., Bouaboula, M., Shire, D. J., Fur, G. L., & Casellas, P. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20780.x · Cited by 1,751 · see citing works
Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system
Tsou, K., Brown, S., Sañudo-Peña, M. C., Mackie, K., & Walker, J. M. (1998) · Neuroscience · doi:10.1016/s0306-4522(97)00436-3 · Cited by 1,586 · see citing works
Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice
Zimmer, A., Zimmer, A. M., Hohmann, A. G., Herkenham, M. A., & Bonner, T. I. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.10.5780 · Cited by 1,065 · see citing works
GLIA: A novel drug discovery target for clinical pain
Watkins, L. R., & Maier, S. F. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1251 · Cited by 674 · see citing works
Benito, C., Núñez, E., Tolón, R. M., Carrier, E. J., Rábano, A., Hillard, C. J., & Romero, J. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-35-11136.2003 · Cited by 624 · see citing works
HU-308: A specific agonist for CB 2 , a peripheral cannabinoid receptor
Hanus, L. O., Breuer, A., Tchilibon, S., Shiloah, S., Goldenberg, D., Horowitz, M., Pertwee, R. G., Ross, R. A., Mechoulam, R., & Fride, E. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.25.14228 · Cited by 574 · see citing works
Alzheimer's β-Amyloid Peptides Compete for Insulin Binding to the Insulin Receptor
Xie, L., Helmerhorst, E., Taddei, K., Plewright, B., van Bronswijk, W., & Martins, R. N. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-10-j0001.2002 · Cited by 542 · see citing works
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., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409888102 · Cited by 521 · see citing works
Ibrahim, M. M., Deng, H., Zvonok, A., Cockayne, D. A., Kwan, J., Mata, H. P., Vanderah, T. W., Lai, J., Porreca, F., Makriyannis, A., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834309100 · Cited by 491 · see citing works
Modulation of the cannabinoid CB 2 receptor in microglial cells in response to inflammatory stimuli
Maresz, K., Carrier, E. J., Ponomarev, E. D., Hillard, C. J., & Dittel, B. N. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03380.x · Cited by 483 · see citing works
Zhang, J., Hoffert, C., Vu, H. K., Groblewski, T., Ahmad, S., & O'Donnell, D. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02704.x · Cited by 419 · see citing works
Michaela, E., & Elphick, M. R. (2000) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(20000626)422:2 · Cited by 364 · see citing works
Hohmann, A. G., & Herkenham, M. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00524-7 · Cited by 301 · see citing works
Synthetic interstial fluid for isolated mammalian tissue
Bretag, A. H. (1969) · Life Sciences · doi:10.1016/0024-3205(69)90283-5 · Cited by 293 · see citing works
Valenzano, K. J., Tafesse, L., Lee, G., Harrison, J. E., Boulet, J. M., Gottshall, S. L., Mark, L., Pearson, M. S., Miller, W., Shan, S., et al. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.12.008 · Cited by 288 · see citing works
Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons
Wotherspoon, G., Fox, A., McIntyre, P., Colley, S., Bevan, S., & Winter, J. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.06.009 · Cited by 251 · see citing works
CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain
Clayton, N., Marshall, F. H., Bountra, C., & O'Shaughnessy, C. T. (2002) · Pain · doi:10.1016/s0304-3959(01)00454-7 · Cited by 247 · see citing works
Inhibition of Inflammatory Hyperalgesia by Activation of Peripheral CB2Cannabinoid Receptors
Quartilho, A., Mata, H. P., Ibrahim, M. M., Vanderah, T. W., Porreca, F., Makriyannis, A., & Malan, T. P. (2003) · Anesthesiology · doi:10.1097/00000542-200310000-00031 · Cited by 243 · see citing works
CB cannabinoid receptor agonists: pain relief without psychoactive effects?
MALANJR, T., IBRAHIM, M., LAI, J., Vanderah, T. W., Makriyannis, A., & Porreca, F. (2003) · Current Opinion in Pharmacology · doi:10.1016/s1471-4892(02)00004-8 · Cited by 223 · see citing works
Pre- and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord
Hohmann, A. G., Briley, E. M., & Herkenham, M. A. (1999) · Brain Research · doi:10.1016/s0006-8993(98)01321-3 · Cited by 183 · see citing works
Ahluwalia, J., Urbán, L., Bevan, S., & Nagy, I. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02703.x · Cited by 181 · see citing works
Nackley, A. G., Makriyannis, A., & Hohmann, A. G. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00126-x · Cited by 176 · see citing works
Ross, R. A., Coutts, A. A., McFarlane, S. M., Anavi-Goffer, S., Irving, A. J., Pertwee, R. G., MacEwan, D. J., & Scott, R. H. (2001) · Neuropharmacology · doi:10.1016/s0028-3908(00)00135-0 · Cited by 172 · see citing works
Elmes, S. J. R., Jhaveri, M. D., Smart, D., Kendall, D. A., & Chapman, V. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03690.x · Cited by 160 · see citing works
Gardell, L. R., Vanderah, T. W., Gardell, S. E., Wang, R., Ossipov, M. H., Lai, J., & Porreca, F. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-23-08370.2003 · Cited by 158 · see citing works
Sagar, D. R., Kelly, S., Millns, P. J., O'Shaughnessey, C. T., Kendall, D. A., & Chapman, V. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04206.x · Cited by 154 · see citing works
Hansson, P. T., & Dickenson, A. H. (2004) · Pain · doi:10.1016/j.pain.2004.10.007 · Cited by 121 · see citing works
Salio, C., Fischer, J., Franzoni, M. F., & Conrath, M. (2002) · Neuroscience · doi:10.1016/s0306-4522(01)00584-x · Cited by 120 · see citing works
Nackley, A. G., Zvonok, A. M., Makriyannis, A., & Hohmann, A. G. (2004) · Journal of Neurophysiology · doi:10.1152/jn.00886.2003 · Cited by 111 · see citing works
Inhibition of pain responses by activation of CB2 cannabinoid receptors
Malan, T. P., Ibrahim, M. M., Vanderah, T. W., Makriyannis, A., & Porreca, F. (2002) · Chemistry and Physics of Lipids · doi:10.1016/s0009-3084(02)00155-x · Cited by 99 · see citing works
Bernardini, N., Neuhuber, W., Reeh, P. W., & Sauer, S. K. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.03.017 · Cited by 93 · see citing works
Self-citationMuscarinic M2 Receptors on Peripheral Nerve Endings: A Molecular Target of Antinociception
Bernardini, N., Roza, C., Sauer, S. K., Gomeza, J., Wess, J., & Reeh, P. W. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-12-j0002.2002 · Cited by 85 · see citing works
Self-citationChange of dorsal horn neurochemistry in a mouse model of neuropathic cancer pain
Shimoyama, M., Tatsuoka, H., Ohtori, S., Tanaka, K., & Shimoyama, N. (2005) · Pain · doi:10.1016/j.pain.2004.12.018 · Cited by 56 · see citing works
Stimulation of calcitonin gene-related peptide synthesis and release
Deng, P.-Y., Ye, F., Cai, W.-J., Tan, G., Hu, C., Deng, H., & Li, Y. (2004) · Journal of Hypertension · doi:10.1097/00004872-200409000-00028 · Cited by 49 · see citing works
Schicho, R., Donnerer, J., Liebmann, I., et al. (2005) · Brain Research · doi:10.1016/j.brainres.2005.01.050 · Cited by 41 · see citing works
Brooks, J. W., Thompson, S., Rice, A. S. C., et al. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2004.09.014 · Cited by 13 · see citing works
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Racz, I., Nadal, X., Alferink, J., Baños, J. E., Rehnelt, J., Martín, M., Pintado, B., Gutierrez-Adan, A., Sanguino, E., Manzanares, J., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3400-08.2008 · Cited by 195 · see citing works
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- Authors
- Beltramo, M., Bernardini, N., Bertorelli, R., Campanella, M., Nicolussi, E., Fredduzzi, S., & Reggiani, A.
- Corresponding author
- Beltramo, M.
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2006-03
- Volume
- 23
- Issue
- 6
- Pages
- 1530-1538
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W1578820780
- Cited by
- 290
- References
- 42
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 9 · 2022: 7 · 2021: 15 · 2020: 15 · 2019: 14 · 2018: 7 · 2017: 20 · 2016: 9 · 2015: 4 · 2014: 12 · 2013: 20 · 2012: 17
- FWCI
- 18.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- CB2 receptor, CB2 receptor agonist, antihyperalgesia, neuropathic pain, allodynia, formalin test, spinal nerve ligation, spinal cord microglia, dorsal root ganglia, calcitonin gene-related peptide, CB1 receptor, chronic pain management
- MeSH terms
- Analgesics, Animals, Capsaicin, Cells, Cultured, Formaldehyde, Hyperalgesia, Ligation, Male, Nervous System Physiological Phenomena, Pain Measurement, RNA, Sciatic Nerve, Spinal Cord, Spinal Nerves, Transcription, Genetic, Calcitonin Gene-Related Peptide, Rats, Sprague-Dawley, Microglia, DNA Primers, DNA, Complementary, Reverse Transcriptase Polymerase Chain Reaction, Receptor, Cannabinoid, CB2, Mice, Rats
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