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Central and peripheral sites of action for CB 2 receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats
Open accessAbstract
BACKGROUND AND PURPOSE Cannabinoid CB 2 receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory and neuropathic pain. However, mechanisms underlying CB 2 ‐mediated analgesic effects remain largely unknown. The present study was conducted to elucidate the CB 2 receptor expression in ‘pain relevant’ tissues and the potential sites of action of CB 2 agonism in rats. EXPERIMENTAL APPROACH Expression of cannabinoid receptor mRNA was evaluated by quantitative RT‐PCR in dorsal root ganglia (DRGs), spinal cords, paws and several brain regions of sham, chronic inflammatory pain (CFA) and neuropathic pain (spinal nerve ligation, SNL) rats. The sites of CB 2 mediated antinociception were evaluated in vivo following intra‐DRG, intrathecal (i.t.) or intraplantar (i.paw) administration of potent CB 2 ‐selective agonists A‐836339 and AM1241. KEY RESULTS CB 2 receptor gene expression was significantly up‐regulated in DRGs (SNL and CFA), spinal cords (SNL) or paws (CFA) ipsilateral to injury under inflammatory and neuropathic pain conditions. Systemic A‐836339 and AM1241 produced dose‐dependent efficacy in both inflammatory and neuropathic pain models. Local administration of CB 2 agonists also produced significant analgesic effects in SNL (intra‐DRG and i.t.) and CFA (intra‐DRG) pain models. In contrast to A‐836339, i.paw administration of AM‐1241 dose‐relatedly reversed the CFA‐induced thermal hyperalgesia, suggesting that different mechanisms may be contributing to its in vivo properties. CONCLUSIONS AND IMPLICATIONS These results demonstrate that both DRG and spinal cord are important sites contributing to CB 2 receptor‐mediated analgesia and that the changes in CB 2 receptor expression play a crucial role for the sites of action in regulating pain perception.
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“CFA administration into a ventral footpad leads to upregulation of CB 2 receptors, but not CB 2 receptor mRNA in dorsal root ganglia or ipsilateral paw tissue of rats, suggesting that these receptors play an integral role in the endocannabinoid modulation of chronic inflammatory pain (Hsieh et al, 2011).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Hsieh et al, 2011
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“Acute administration of CB 2 receptor agonists reduces CFA-induced mechanical and thermal hyperalgesia (Hsieh et al, 2011;Valenzano et al, 2005;Yao et al, 2008Yao et al, , 2009)).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Hsieh et al, 2011
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Curto-Reyes, V., Boto, T., Hidalgo, A., Menéndez, L., & Baamonde, A. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.06.057 · Cited by 24
Recent Development of CB2 Selective and Peripheral CB1/CB2 Cannabinoid Receptor Ligands
Nevalainen, T. (2013) · Current Medicinal Chemistry · doi:10.2174/09298673113206660296 · Cited by 23
“the phenyl morpholinyl analogue 8 developed by BoehringerIngelheim [24], a 2,2,3,3-tetramethylcyclopropyl)-methanone derivative A-836339 (9), from Abbott Laboratories [25, 26], and a pyridine-based compound 10 synthesized by Adolor Corporation [27] (Fig.”
BackgroundFeng, Z., Pearce, L. V., Zhang, Y., Xing, C., Herold, B. K. A., Ma, S., Hu, Z., Turcios, N. A., Yang, P., Tong, Q., et al. (2016) · The AAPS Journal · doi:10.1208/s12248-016-9888-z · Cited by 23
“For example, CB2 [49] and TRPV1 [50] are potential therapeutic targets for analgesic activity.”
Advances in the Treatment of Chronic Pain by Targeting GPCRs
Che, T. (2020) · Biochemistry · doi:10.1021/acs.biochem.0c00644 · Cited by 21
Effects of inflammatory pain on CB1 receptor in the midbrain periaqueductal gray
Wilson‐Poe, A. R., Wiese, B. M., Kibaly, C., Lueptow, L. M., Garcia, J. J., Anand, P., Cahill, C. M., & Morón, J. A. (2021) · PAIN Reports · doi:10.1097/pr9.0000000000000897 · Cited by 20
“function of CB2 receptors in the dorsal root ganglion, as well as rostral ventromedial medulla (RVM), which is the downstream target of the PAG in the descending pain pathway.(17,21) Other stress-”
BackgroundBosier, B., Doyen, P. J., Brolet, A., Muccioli, G. G., Ahmed, E., Desmet, N., Hermans, E., & Deumens, R. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13324 · Cited by 20
Amalraj, A., Jacob, J., C., K. V. A., & Gopi, S. (2020) · ACS Omega · doi:10.1021/acsomega.0c03456 · Cited by 20
Wilkerson, J. L., & Milligan, E. D. (2011) · ISRN Anesthesiology · doi:10.5402/2011/593894 · Cited by 20
“As before, the actions of A-836339 at these sites were due primarily to the CB2R, and not μ-opioid receptor agonism [167] (Table 1).”
BackgroundMethodInfluentialConsiderations for Cannabinoids in Perioperative Care by Anesthesiologists
Laudański, K., & Wain, J. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030558 · Cited by 22
Fabbro, L. D., Filho, C. B., Souza, L. C., Savegnago, L., Alves, D. A. C., Schneider, P. H., de Salles, H. D., & Jessé, C. R. (2012) · Brain Research · doi:10.1016/j.brainres.2012.08.008 · Cited by 19
“In models of chronic pain, several studies have suggested possible up-regulation of both cannabinoid receptors in different areas of the central nervous system (Amaya et al., 2006; Fernández-Ruiz et al., 2008; Hsieh et al., 2011).”
The endocannabinoid system as a therapeutic target in neuropathic pain: a review
Quintero, J.-M., Díaz, L. E., Galve‐Roperh, I., Bustos, R., Leon, M.-X., Beltran, S., & Dodd, S. (2024) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2024.2407824 · Cited by 18
“This suggests that CB2R agonists may relieve pain by acting on both peripheral DRG sites and central levels [105].”
Pinna, G., Loriga, G., Lazzari, P., Ruiu, S., Falzoi, M., Frau, S., Pau, A., Murineddu, G., Asproni, B., & Pinna, G. A. (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.05.055 · Cited by 17
Progress in the mechanisms of pain associated with neurodegenerative diseases
Tian, Z., Zhang, Q., Wang, L., Li, M., Li, T., Wang, Y., Cao, Z., Jiang, X., & Luo, P. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102579 · Cited by 18
Sałaga, M., Zatorski, H., Zielińska, M., Mosińska, P., Timmermans, J., Kordek, R., Storr, M., & Fichna, J. (2017) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-017-1402-3 · Cited by 15
Guenther, K. G., Xu, Z., Romero, J., Hillard, C. J., Mackie, K., & Hohmann, A. G. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109601 · Cited by 13
Cannabinoid CB2 receptor‐mediated analgesia: mechanism‐based insights and therapeutic potential
Guenther, K. G., & Hohmann, A. G. (2025) · British Journal of Pharmacology · doi:10.1111/bph.70116 · Cited by 12
“However, increases were only seen in one study that used rats (Hsieh et al., 2011), but not in another study using mice (Negrete et al., 2011).”
InfluentialEfficacy of cannabinoids in fibromyalgia: a literature review
Anaya, H. J. M., Ortiz, M. P. T., Valencia, D. H. F., & Ribero, O. F. G. (2021) · Colombian Journal of Anesthesiology · doi:10.5554/22562087.e980 · Cited by 16
“(47,48) While the preclinical trials did not focus on specific diseases such as fibromyalgia, they do focus on a set of symptoms and signs present in chronic pain diseases.”
BackgroundHu, S., Cheng, G., Zhou, H., Zhang, Q., Zhang, Q., Wang, Y., Shen, Y., Lian, C.-X., Ma, X., Zhang, Q., et al. (2022) · Molecules · doi:10.3390/molecules27030702 · Cited by 13
“CB2R was also reported to be involved in the regulation of inflammation, anti-cancer, anti-fibrotic, and nerve system disease [10,13].”
BackgroundNelson, D. W., Frost, J. M., Tietje, K. R., Florjancic, A. S., Ryther, K. B., Carroll, W. A., Dart, M. J., Daza, A. V., Hooker, B. A., Grayson, G. K., et al. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.01.121 · Cited by 11
Self-citationPET Imaging of Endocannabinoid System
Horti, A. G., Raymont, V., & Terry, G. E. (2014) · Springer eBooks · doi:10.1007/978-3-642-42014-6_11 · Cited by 11
Antinociceptive effects of JWH015 in female and male rats
Craft, R. M., Greene, N. Z., & Wakley, A. A. (2017) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000337 · Cited by 11
“In animal studies, both CB1 and CB2 receptors have been shown to mediate the antinociceptive effects of a range of cannabinoids; however, CB2 receptors appear to be more involved in cannabinoid antinociception against chronic than acute pain, perhaps because CB2 receptors are upregulated during inflammation and nerve…”
BackgroundBagher, A. M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26094430 · Cited by 14
“All drugs and reagents were stored at − 20 ◦ C and thawed to room temperature before use.”
In vivo inflammation imaging using a CB2R-targeted near infrared fluorescent probe.
Zhang, S., Shao, P., Ling, X., Yang, L., Hou, W., Thorne, S. H., Beaino, W., Anderson, C. J., Ding, Y., & Bai, M. (2015) · Europe PMC (PubMed Central) · Cited by 10
Fennel Essential Oil as a Complementary Therapy in the Management of Diabetes
Ștefănescu, R., Ősz, B.-E., Pintea, A., Zöld, E. L., Tero-Vescan, A., Vari, C.-E., Fulop, E., Blaș, I., & Vancea, S. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15122657 · Cited by 9
The Development of Cannabinoids as Therapeutic Agents in the United States
Murray, C. H., Gannon, B. M., Winsauer, P. J., Cooper, Z. D., & Delatte, M. S. (2024) · Pharmacological Reviews · doi:10.1124/pharmrev.123.001121 · Cited by 10
The Endocannabinoid System as a Therapeutic Target in Diabetic Peripheral Neuropathic Pain
Bagher, A. M. (2021) · Journal of Microscopy and Ultrastructure · doi:10.4103/jmau.jmau_97_20 · Cited by 9
“CB2Rs are found in immune cells, which are unregulated in neuropathic pain conditions.[50-52] Microglia play an essential role in neuropathic pain, as reactive microglia interact with neurons and are involved in neuropathic pain’s pathophysiology.”
BackgroundCampeau, L., Füllhase, C., Sawada, N., Gratzke, C., Hedlund, P., Howlett, A. C., & Andersson, K. (2013) · Neurourology and Urodynamics · doi:10.1002/nau.22454 · Cited by 9
“Spinal cord and dorsal root ganglia CB2R expression was significantly up-regulated in inflammatory and neuropathic pain conditions in rats, and may help mediate analgesic effects.(6) CB2R have also been localized in sensory and cholinergic bladder nerves of rats.”
BackgroundThe Effects of Cannabinoids on Ischemic Stroke-Associated Neuroinflammation: A Systematic Review
Alraddadi, E. A., Aljuhani, F. F., Alsamiri, G. Y., Hafez, S. Y., Alselami, G. I., Almarghalani, D. A., & Alamri, F. F. (2025) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-025-10171-z · Cited by 9
“AM1241, a synthetic CB2R agonist, has been extensively studied for its effects on neuropathic pain (Wilkerson et al. 2012; Hsieh et al. 2011), and hepatic and myocardial fibrosis (Ali et al. 2021; Li et al. 2016).”
Cannabinoids For the Treatment of Neuropathic Pain: Are They Safe and Effective?
Gutierrez, T., & Hohmann, A. G. (2011) · Future Neurology · doi:10.2217/fnl.11.6 · Cited by 8
Zhu, Q., Zhu, Y., & Wang, W. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.01.058 · Cited by 8
Metadata
- Authors
- Hsieh, G. C., Pai, M., Chandran, P., Hooker, B. A., Zhu, C. Z., Salyers, A. K., Wensink, E. J., Zhan, C., Carroll, W. A., Dart, M. J., Yao, B. B., Honore, P., & Meyer, M. D.
- Affiliations
- Abbott (United States) (US)
- Corresponding author
- Hsieh, Gin C
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2010-12-14
- Volume
- 162
- Issue
- 2
- Pages
- 428-440
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC3031063
- OpenAlex
- W1594786713
- Cited by
- 139
- References
- 58
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 8 · 2023: 8 · 2022: 8 · 2021: 11 · 2020: 8 · 2019: 4 · 2018: 6 · 2017: 7 · 2016: 8 · 2015: 7 · 2014: 12 · 2013: 19 · 2012: 9
- FWCI
- 10.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- CB2 receptor, cannabinoid analgesia, neuropathic pain, inflammatory pain, dorsal root ganglia, spinal cord, AM1241, intrathecal administration, receptor gene expression, thermal hyperalgesia, spinal nerve ligation, complete Freund's adjuvant
- MeSH terms
- Analgesia, Analgesics, Animals, Brain, Cannabinoids, Disease Models, Animal, Ganglia, Spinal, Inflammation, Male, Neuralgia, Pain, RNA, Messenger, Spinal Cord, Thiazoles, Rats, Sprague-Dawley, Opioid Peptides, Receptor, Cannabinoid, CB2, Rats, Pain Perception
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