Central and peripheral sites of action for CB 2 receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats

Hsieh, Gin C; Pai, Madhavi; Chandran, Prasant; Hooker, Bradley A; Zhu, Chang Z; Salyers, Anita K; Wensink, Erica J; Zhan, CenChen; Carroll, William A; Dart, Michael J; Yao, Betty B; Honore, Prisca; Meyer, Michael D

doi:10.1111/j.1476-5381.2010.01046.x

Cited by 142Cannabis and Cannabinoid ResearchPain Mechanisms and TreatmentsIon Channels and Receptors

Central and peripheral sites of action for CB 2 receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats

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Hsieh, Gin C, Pai, Madhavi, Chandran, Prasant, Hooker, Bradley A, Zhu, Chang Z, Salyers, Anita K, Wensink, Erica J, Zhan, CenChen +5 more·2011·British Journal of Pharmacology

DOI 10.1111/j.1476-5381.2010.01046.xPMC PMC3031063

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Abstract

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 CB2 receptors, but not CB2 receptor mRNA in dorsal root ganglia or ipsilateral paw tissue of rats.
“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
Acute administration of CB2 receptor agonists reduces CFA-induced mechanical and thermal hyperalgesia.
“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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Grenald, S. A., Young, M. A., Wang, Y., Ossipov, M. H., Ibrahim, M. M., Largent-Milnes, T. M., & Vanderah, T. W. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.12.008 · Cited by 97 · see citing works
Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and Its Putative Receptors GPR18 and GPR55
Alba, R. G., Barragán‐Iglesias, P., González‐Hernández, A., Valdez-Moráles, E. E., Granados‐Soto, V., Condés‐Lara, M., Rodríguez, M. G., & Marichal‐Cancino, B. A. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01496 · Cited by 94 · see citing works
“Notably, nerve injury and inflammation upregulate expression of CB2 receptors in neurons and microglia (Beltramo et al., 2006; Rahn and Hohmann, 2009; Sagar et al., 2009; Hsieh et al., 2011).”
Background
Validating Antibodies to the Cannabinoid CB2 Receptor
Marchalant, Y., Brownjohn, P. W., Bonnet, A., Kleffmann, T., & Ashton, J. C. (2014) · Journal of Histochemistry & Cytochemistry · doi:10.1369/0022155414530995 · Cited by 91 · see citing works
“The spinal cord has also been identified as a possible site for CB2 expression (Beltramo et al. 2006; Hsieh et al. 2011), with western blot analysis commonly used to quantify expression (Brownjohn and Ashton 2012; Curto-Reyes et al.”
Background
The endocannabinoid system mediates aerobic exercise-induced antinociception in rats
Galdino, G. S., Romero, T. R. L., Silva, J. F. P., de Aguiar, D. C., de Paula, A. M., Cruz, J. S., Parrella, C., Piscitelli, F., Duarte, I. D. G., Marzo, V. D., et al. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.09.022 · Cited by 88 · see citing works
A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid
Hashiesh, H. M., Sharma, C., Goyal, S. N., Sadek, B. S., Jha, N. K., Kaabi, J. A., & Ojha, S. K. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111639 · Cited by 90 · see citing works
Topical analgesics for neuropathic pain: Preclinical exploration, clinical validation, future development
Sawynok, J. (2013) · European Journal of Pain · doi:10.1002/j.1532-2149.2013.00400.x · Cited by 79 · see citing works
“CB2 receptors are not normally detected in DRGs, but, following nerve injury, they are observed on central and peripheral aspects of sensory neurons, and CB2 mRNA in DRGs is up-regulated (Wotherspoon et al., 2005; Hsieh et al., 2011).”
Background
Cannabinoid CB2receptor attenuates morphine‐induced inflammatory responses in activated microglial cells
Merighi, S., Gessi, S., Varani, K., Fazzi, D., Mirandola, P., & Borea, P. A. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01948.x · Cited by 79 · see citing works
“It is known that the anti-inflammatory properties of CB receptor agonists are expressed through the activation of CB2 receptors (Klein and Newton, 2007; Romero-Sandoval et al., 2009; Correa et al., 2010; Hsieh et al., 2011).”
Background
Acute resistance exercise induces antinociception by activation of the endocannabinoid system in rats
Galdino, G., Romero, T., Pinho da Silva, J. F., Aguiar, D., de Paula, A. M., Cruz, J., Parrella, C., Piscitelli, F., Duarte, I., Di Marzo, V., et al. (2014) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000000340 · Cited by 72 · see citing works
Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain
Gutierrez, T., Crystal, J. D., Zvonok, A. M., Makriyannis, A., & Hohmann, A. G. (2011) · Pain · doi:10.1016/j.pain.2011.03.038 · Cited by 71 · see citing works
Cannabis and pain: a scoping review
Pantoja‐Ruiz, C., Restrepo-Jiménez, P., Castañeda‐Cardona, C., Ferreirós, A., & Rosselli, D. (2021) · Brazilian Journal of Anesthesiology (English Edition) · doi:10.1016/j.bjane.2021.06.018 · Cited by 76 · see citing works
Cannabinoid CB2 Agonist AM1710 Differentially Suppresses Distinct Pathological Pain States and Attenuates Morphine Tolerance and Withdrawal
Li, A.-L., Lin, X., Dhopeshwarkar, A., Thomaz, A. C., Carey, L. M., Liu, Y., Nikas, S. P., Makriyannis, A., Mackie, K., & Hohmann, A. G. (2018) · Molecular Pharmacology · doi:10.1124/mol.118.113233 · Cited by 69 · see citing works
“, 2017), AM1241 (Hsieh et al., 2011; Gao et al., 2016), A836339 (Yao et al.”
Influential
Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction
Hedlund, P. (2013) · Neurourology and Urodynamics · doi:10.1002/nau.22442 · Cited by 69 · see citing works
“Other studies have reported similar distributions for CB2 mRNA or protein in the rat lower lumbar DRG or spinal dorsal horn.(42,43) In a study by Merriam et al.”
Result
Nociceptor plasticity: A closer look
Pace, M. C., Passavanti, M. B., Nardis, L. D., Bosco, F., Sansone, P., Pota, V., Barbarisi, M., Palagiano, A., Iannotti, F. A., Panza, E., et al. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25993 · Cited by 67 · see citing works
“Also, the gene expression of CB2 receptors was assessed in these pathological models, and it was found up-regulated in DRG (both in inflammatory and neuropathic settings), spinal cord (neuropathic model only) and paws (inflammation model only) (Hsieh et al., 2011).”
Background
Endocannabinoid system and pain: an introduction
Burston, J. J., & Woodhams, S. G. (2013) · Proceedings of The Nutrition Society · doi:10.1017/s0029665113003650 · Cited by 65 · see citing works
Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models
Vincenzi, F., Targa, M., Corciulo, C., Tabrizi, M. A., Merighi, S., Gessi, S., Saponaro, G., Baraldi, P. G., Borea, P. A., & Varani, K. (2013) · Pain · doi:10.1016/j.pain.2013.02.007 · Cited by 63 · see citing works
“CB2 receptors are well expressed in DRG neurons, as confirmed by previous works that reported CB2 mRNA expression [7,29].”
Background
CB1 Knockout Mice Unveil Sustained CB2-Mediated Antiallodynic Effects of the Mixed CB1/CB2 Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain
Deng, L., Cornett, B., Mackie, K., & Hohmann, A. G. (2015) · Molecular Pharmacology · doi:10.1124/mol.115.098483 · Cited by 60 · see citing works
“CB2 receptors by CB2 agonists, after acute or chronic administration, suppresses neuropathic pain (Yamamoto et al., 2008; Hsieh et al., 2011; Landry et al., 2012; Deng et al., 2015).”
Background
Spinal cannabinoid CB2 receptors as a target for neuropathic pain: an investigation using chronic constriction injury
Brownjohn, P. W., & Ashton, J. C. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.12.028 · Cited by 57 · see citing works
Cannabinoid Agonists Inhibit Neuropathic Pain Induced by Brachial Plexus Avulsion in Mice by Affecting Glial Cells and MAP Kinases
Paszcuk, A. F., Dutra, R. C., Silva, K. A. B. S., Quintão, N. L. M., Campos, M. M., & Calixto, J. Β. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024034 · Cited by 58 · see citing works
“As cannabinoid receptors play an important role in neuropathic pain [4,6], we further evaluated the expression of both cannabinoid receptors after BPA in mice.”
BackgroundInfluential
Retracted:Cannabinoid CB2receptors modulate ERK‐1/2 kinase signalling and NO release in microglial cells stimulated with bacterial lipopolysaccharide
Merighi, S., Gessi, S., Varani, K., Simioni, C., Fazzi, D., Mirandola, P., & Borea, P. A. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01673.x · Cited by 52 · see citing works
“Activation of CB2 receptors has anti-inflammatory effects (Klein and Newton, 2007; Romero-Sandoval et al., 2009; Correa et al., 2010; Hsieh et al., 2011).”
Background
Retracted
CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain
Khasabova, I. A., Gielissen, J. M., Chandiramani, A., Harding-Rose, C., Odeh, D. A., Simone, D. A., & Seybold, V. S. (2011) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e3283474a6d · Cited by 53 · see citing works
“Although some components of CB2 receptor-mediated analgesia are mediated through actions on the central nervous system following systemic injection (Hohmann et al., 2005; Yamamoto et al., 2008b; Curto-Reyes et al., 2010; Hsieh et al., 2010), the antihyperalgesic effect of AM1241 in this study was mediated locally.”
Influential
Bilateral Changes of Cannabinoid Receptor Type 2 Protein and mRNA in the Dorsal Root Ganglia of a Rat Neuropathic Pain Model
Svíženská, I. H., Brázda, V., Klusáková, I., & Dubový, P. (2013) · Journal of Histochemistry & Cytochemistry · doi:10.1369/0022155413491269 · Cited by 52 · see citing works
“One of the strongest pain management strategies may be to administer CB2R-selective agonists that inhibit tactile and thermal hypersensitivity in neuropathic pain models and avoid unwanted central nervous system (CNS) effects (Ibrahim et al. 2003; Hsieh et al. 2011).”
BackgroundMethodResult
Immunofluorescent spectral analysis reveals the intrathecal cannabinoid agonist, AM1241, produces spinal anti‐inflammatory cytokine responses in neuropathic rats exhibiting relief from allodynia
Wilkerson, J. L., Gentry, K. R., Dengler, E. C., Wallace, J. A., Kerwin, A. A., Kuhn, M. N., Zvonok, A. M., Thakur, G. A., Makriyannis, A., & Milligan, E. D. (2012) · Brain and Behavior · doi:10.1002/brb3.44 · Cited by 51 · see citing works
“…widely characterized cannabinoid agonist that controls hyperalgesia (exaggerated nociceptive thresholds) and allodynia following intraperitoneal (i.p.) (Ibrahim et al. 2006; Rahn et al. 2008), intravenous (i.v.) (Beltramo et al. 2006), intra-DRG, or intrathecal (i.t.) (Hsieh et al. 2011) injection.”
BackgroundInfluential
The central cannabinoid receptor type-2 (CB2) and chronic pain
Shang, Y.-C., & Tang, Y. (2016) · International Journal of Neuroscience · doi:10.1080/00207454.2016.1257992 · Cited by 51 · see citing works
Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain
Hossain, M. Z., Ando, H., Unno, S., & Kitagawa, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041423 · Cited by 52 · see citing works
“Additionally, spinal nerve ligation injury increased CB2 receptor immunoreactivity in nerve sections proximal, but not distal, to the site of ligation [105].”
Background
Neuroprotection and reduction of glial reaction by cannabidiol treatment after sciatic nerve transection in neonatal rats
Perez, M., Ulian-Benitez, S., Cartarozzi, L. P., Bel, E. A. D., Guimarães, F. S., & de Oliveira, A. L. R. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12341 · Cited by 49 · see citing works
“Also, CB2 receptor has recently been shown in DRG neurons by Hsieh et al. (2011).”
Background
Anti-nociceptive interactions between opioids and a cannabinoid receptor 2 agonist in inflammatory pain
Yuill, M. B., Hale, D. E., Guindon, J., & Morgan, D. J. (2017) · Molecular Pain · doi:10.1177/1744806917728227 · Cited by 49 · see citing works
Cannabinoids in the descending pain modulatory circuit: Role in inflammation
Bouchet, C. A., & Ingram, S. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107495 · Cited by 51 · see citing works
Activation of CB2 receptors as a potential therapeutic target for migraine: evaluation in an animal model
Greco, R., Mangione, A. S., Sandrini, G., Nappi, G., & Tassorelli, C. (2014) · The Journal of Headache and Pain · doi:10.1186/1129-2377-15-14 · Cited by 46 · see citing works
Effects of gonadal hormones on the peripheral cannabinoid receptor 1 (CB1R) system under a myositis condition in rats
Niu, K. Y., Zhang, Y., & Ro, J. Y. (2012) · Pain · doi:10.1016/j.pain.2012.07.037 · Cited by 45 · see citing works
“Although we did not systematically investigate this in the present study, CB2R expressed in primary sensory neurons also mediate analgesic activity in chronic inflammatory and neuropathic pain conditions [24].”
Background
Is There Any Clinically Relevant Cannabinoid-Induced Analgesia?
Kraft, B. (2012) · Pharmacology · doi:10.1159/000337376 · Cited by 44 · see citing works
NMP-7 Inhibits Chronic Inflammatory and Neuropathic Pain via Block of Cav3.2 T-type Calcium Channels and Activation of CB2 Receptors
Berger, N. D., Gadotti, V. M., Petrov, R. R., Chapman, K., Diaz, P., & Zamponi, G. W. (2014) · Molecular Pain · doi:10.1186/1744-8069-10-77 · Cited by 43 · see citing works
Cannabinoid CB2 receptors are upregulated via bivalent histone modifications and control primary afferent input to the spinal cord in neuropathic pain
Ghosh, K. K., Zhang, G.-F., Chen, H., Chen, S., & Pan, H. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101999 · Cited by 43 · see citing works
“Our findings are consistent with previous studies showing that selective CB2 agonists reduce neuropathic pain (9, 11, 12).”
Result
The spinal anti-inflammatory mechanism of motor cortex stimulation: cause of success and refractoriness in neuropathic pain?
Silva, G. D., Lopes, P. S. S., Fonoff, E. T., & Pagano, R. L. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0216-1 · Cited by 43 · see citing works
Functional Characterization and Analgesic Effects of Mixed Cannabinoid Receptor/T-Type Channel Ligands
You, H., Gadotti, V. M., Petrov, R. R., Zamponi, G. W., & Diaz, P. (2011) · Molecular Pain · doi:10.1186/1744-8069-7-89 · Cited by 42 · see citing works
“This fits with reports showing that CB2 receptors are expressed at peripheral nerve endings and play a role in the inflammatory pain or neuropathic pain states [15,37], and the observation that local administration of CB2 agonists contribute to analgesia during in inflammatory pain [37-39].”
The role of carbon monoxide, heme oxygenase 1, and the Nrf2 transcription factor in the modulation of chronic pain and their interactions with opioids and cannabinoids
Pol, O. (2020) · Medicinal Research Reviews · doi:10.1002/med.21726 · Cited by 42 · see citing works
Microglial Cannabinoid CB2 Receptors in Pain Modulation
Xu, K., Wu, Y., Tian, Z., Xu, Y., Wu, C., & Wang, Z. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032348 · Cited by 41 · see citing works
“For example, intrathecal administration of AM1241 attenuates allodynia or thermal hyperalgesia induced by CFA, SNL [6], CCI, or bone cancer models [93].”
BackgroundInfluential
Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy
Nasirinezhad, F., Jergová, S., Pearson, J. P., & Sagen, J. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.11.024 · Cited by 41 · see citing works
“, 2004), and it has been suggested that CB2 receptors are upregulated in sensory neurons and the CNS following peripheral nerve injury (Beltramo et al., 2006; Hsieh et al., 2011; Wotherspoon et al., 2005).”
Background
Contributions of Academic Laboratories to the Discovery and Development of Chemical Biology Tools
Huryn, D. M., Resnick, L., & Wipf, P. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400132d · Cited by 40 · see citing works
Mechanisms Involved in Extraterritorial Facial Pain following Cervical Spinal Nerve Injury in Rats
Kobayashi, A., Shinoda, M., Sessle, B. J., Honda, K., Imamura, Y., Hitomi, S., Tsuboi, Y., Okada‐Ogawa, A., & Iwata, K. (2011) · Molecular Pain · doi:10.1186/1744-8069-7-12 · Cited by 39 · see citing works
Activation of spinal cannabinoid CB2 receptors inhibits neuropathic pain in streptozotocin-induced diabetic mice
Ikeda, H., Ikegami, M., Kai, M., Ohsawa, M., & Kamei, J. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.07.040 · Cited by 38 · see citing works
CB2 receptor deletion on myeloid cells enhanced mechanical allodynia in a mouse model of neuropathic pain
Nent, E., Nozaki, C., Schmöle, A., Otte, D. M., & Zimmer, A. (2019) · Scientific Reports · doi:10.1038/s41598-019-43858-4 · Cited by 37 · see citing works
Activation of cannabinoid receptor 2 inhibits experimental cystitis
Wang, Z., Wang, P., & Bjorling, D. E. (2013) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00585.2012 · Cited by 38 · see citing works
Paeonol alleviates primary dysmenorrhea in mice via activating CB2R in the uterus
Peng, Y., Zheng, X., Fan, Z., Zhou, H., Zhu, X., Wang, G., & Liu, Z. (2019) · Phytomedicine · doi:10.1016/j.phymed.2019.153151 · Cited by 36 · see citing works
IUPHAR review: Navigating the role of preclinical models in pain research
Karimi, S. A., Zahra, F. T., & Martin, L. J. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107073 · Cited by 35 · see citing works
Low-Dose Cannabinoid Type 2 Receptor Agonist Attenuates Tolerance to Repeated Morphine Administration via Regulating μ-Opioid Receptor Expression in Walker 256 Tumor-Bearing Rats
Zhang, M., Wang, K., Ma, M., Tian, S., Wei, N., & Wang, G. (2015) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000001129 · Cited by 33 · see citing works
The Antinociceptive Effects of JWH-015 in Chronic Inflammatory Pain Are Produced by Nitric Oxide-cGMP-PKG-KATP Pathway Activation Mediated by Opioids
Negrete, R., Hervera, A., Leánez, S., Martín-Campos, J. M., & Pol, O. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026688 · Cited by 33 · see citing works
Benzydamine—An Affordable Over-the-Counter Drug with Psychoactive Properties—From Chemical Structure to Possible Pharmacological Properties
Ősz, B.-E., Jîtcă, G., Sălcudean, A., Rusz, C.-M., & Vari, C.-E. (2023) · Pharmaceuticals · doi:10.3390/ph16040566 · Cited by 31 · see citing works
Effect of M as‐related gene ( Mrg ) receptors on hyperalgesia in rats with CFA ‐induced inflammation via direct and indirect mechanisms
Jiang, J., Wang, D., Zhou, X.-L., Huo, Y., Chen, T., Hu, F.-J., Quirion, R., & Hong, Y. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12326 · Cited by 31 · see citing works
“For example, inflammation has been shown to enhance the expression of opioid receptors in peripheral nerve terminals (Stein and Zollner, 2009) and cannabinoid receptors in DRG and in hindpaws (Hsieh et al., 2011).”
Background
Sex Differences in Tolerance to Delta-9-Tetrahydrocannabinol in Mice With Cisplatin-Evoked Chronic Neuropathic Pain
Henderson, A. N., Crawford, L. C., Sepúlveda, D. E., Hale, D. E., Lesperance, J., & Morgan, D. J. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.684115 · Cited by 30 · see citing works
Potentiation of microglial endocannabinoid signaling alleviates neuroinflammation in Alzheimer's disease
Rapaka, D., Bitra, V. R., Challa, S. R., & Adiukwu, P. C. (2021) · Neuropeptides · doi:10.1016/j.npep.2021.102196 · Cited by 29 · see citing works
The Role of the Cannabinoid System in Opioid Analgesia and Tolerance
Özdemir, E. (2020) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557520666200313120835 · Cited by 28 · see citing works
The CB2 cannabinoid receptor as a therapeutic target in the central nervous system
Cabañero, D., Martín‐García, E., & Maldonado, R. J. (2021) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.1971196 · Cited by 29 · see citing works
Spontaneous Cannabinoid Receptor 2 (CB2) Expression in the Cochlea of Adult Albino Rat and Its Up-Regulation after Cisplatin Treatment
Martín‐Saldaña, S., Trinidad, A., Ramil, E., Sánchez, A., Coronado, M. J., Martínez-Martínez, E., García, J. M., García‐Berrocal, J. R., & Ramírez‐Camacho, R. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161954 · Cited by 27 · see citing works
“In the peripheral nervous system, CB2 agonists have analgesic effects by acting at dorsal root ganglia (as well as at spinal cord) [32].”
Background
Effects of Cannabinoid Type 2 Receptor Agonist AM1241 on Morphine-Induced Antinociception, Acute and Chronic Tolerance, and Dependence in Mice
Zhang, M., Dong, L., Zou, H., Li, J., Li, Q., Wang, G., & Li, H. (2018) · Journal of Pain · doi:10.1016/j.jpain.2018.04.009 · Cited by 26 · see citing works
Spinal Cord FAAH in Normal Micturition Control and Bladder Overactivity in Awake Rats
Füllhase, C., Russo, A., Castiglione, F., Benigni, F., Campeau, L., Montorsi, F., Gratzke, C., Bettiga, A., Stief, C. G., Andersson, K., et al. (2012) · The Journal of Urology · doi:10.1016/j.juro.2012.11.165 · Cited by 26 · see citing works
Intrathecal Actions of the Cannabis Constituents Δ(9)-Tetrahydrocannabinol and Cannabidiol in a Mouse Neuropathic Pain Model
Casey, S. L., Mitchell, V. A., Sokolaj, E. E., Winters, B. L., & Vaughan, C. W. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158649 · Cited by 26 · see citing works
Chronic pain in Alzheimer's disease: Endocannabinoid system
Blanton, H. L., Reddy, P. H., & Benamar, K. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114287 · Cited by 26 · see citing works
Cannabinoids to treat spinal cord injury
Arévalo‐Martín, Á., Molina‐Holgado, E., & García‐Ovejero, D. (2015) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2015.03.008 · Cited by 26 · see citing works
The role of carbon monoxide on the anti-nociceptive effects and expression of cannabinoid 2 receptors during painful diabetic neuropathy in mice
Castany, S., Carcolé, M., Leánez, S., & Pol, O. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4271-4 · Cited by 26 · see citing works
“* Olga Pol opol@santpau.es 2009; Hsieh et al. 2011; Hervera et al. 2012a), suggesting that the administration of selective CB2R agonists might be an interesting target to explore for the treatment of painful diabetic neuropathy.”
Antinociceptive effects induced through the stimulation of spinal cannabinoid type 2 receptors in chronically inflamed mice
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 · see citing works
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 · see citing works
“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.”
Background
Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation
Feng, 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 · see citing works
“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 · see citing works
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 · see citing works
“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-”
Background
Inhibition of the regulator of G protein signalling RGS4 in the spinal cord decreases neuropathic hyperalgesia and restores cannabinoid CB1 receptor signalling
Bosier, 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 · see citing works
Preparation and Characterization of Liposomal β-Caryophyllene (Rephyll) by Nanofiber Weaving Technology and Its Effects on Delayed Onset Muscle Soreness (DOMS) in Humans: A Randomized, Double-Blinded, Crossover-Designed, and Placebo-Controlled Study
Amalraj, A., Jacob, J., C., K. V. A., & Gopi, S. (2020) · ACS Omega · doi:10.1021/acsomega.0c03456 · Cited by 20 · see citing works
The Central Role of Glia in Pathological Pain and the Potential of Targeting the Cannabinoid 2 Receptor for Pain Relief
Wilkerson, J. L., & Milligan, E. D. (2011) · ISRN Anesthesiology · doi:10.5402/2011/593894 · Cited by 20 · see citing works
“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).”
BackgroundMethodInfluential
Considerations for Cannabinoids in Perioperative Care by Anesthesiologists
Laudański, K., & Wain, J. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030558 · Cited by 22 · see citing works
Effects of Se-phenyl thiazolidine-4-carboselenoate on mechanical and thermal hyperalgesia in brachial plexus avulsion in mice: Mediation by cannabinoid CB1 and CB2 receptors
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Influential
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Intraplantar β-Caryophyllene Alleviates Pain and Inflammation in STZ-Induced Diabetic Peripheral Neuropathy via CB2 Receptor Activation
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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
ORCID: Zhu, Chang Z
Dart, Michael J
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
DOI: 10.1111/j.1476-5381.2010.01046.x
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: British Journal of Pharmacology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
Health Sciences › Medicine › Physiology › 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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Central and peripheral sites of action for CB 2 receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats

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