Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint
Open accessAbstract
Osteoarthritis (OA) of the joint is a prevalent disease accompanied by chronic, debilitating pain. Recent clinical evidence has demonstrated that central sensitization contributes to OA pain. An improved understanding of how OA joint pathology impacts upon the central processing of pain is crucial for the identification of novel analgesic targets/new therapeutic strategies. Inhibitory cannabinoid 2 (CB2) receptors attenuate peripheral immune cell function and modulate central neuro-immune responses in models of neurodegeneration. Systemic administration of the CB2 receptor agonist JWH133 attenuated OA-induced pain behaviour, and the changes in circulating pro- and anti-inflammatory cytokines exhibited in this model. Electrophysiological studies revealed that spinal administration of JWH133 inhibited noxious-evoked responses of spinal neurones in the model of OA pain, but not in control rats, indicating a novel spinal role of this target. We further demonstrate dynamic changes in spinal CB2 receptor mRNA and protein expression in an OA pain model. The expression of CB2 receptor protein by both neurones and microglia in the spinal cord was significantly increased in the model of OA. Hallmarks of central sensitization, significant spinal astrogliosis and increases in activity of metalloproteases MMP-2 and MMP-9 in the spinal cord were evident in the model of OA pain. Systemic administration of JWH133 attenuated these markers of central sensitization, providing a neurobiological basis for analgesic effects of the CB2 receptor in this model of OA pain. Analysis of human spinal cord revealed a negative correlation between spinal cord CB2 receptor mRNA and macroscopic knee chondropathy. These data provide new clinically relevant evidence that joint damage and spinal CB2 receptor expression are correlated combined with converging pre-clinical evidence that activation of CB2 receptors inhibits central sensitization and its contribution to the manifestation of chronic OA pain. These findings suggest that targeting CB2 receptors may have therapeutic potential for treating OA pain.
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Administration of MIA into the knee joint leads to upregulation of CB2 and CB1 receptor mRNA in the ipsilateral spinal cord of rats.
“Administration of MIA into the knee joint leads to upregulation of CB 2 and CB 1 receptor mRNA in the ipsilateral spinal cord of rats, suggesting that these receptors undergo compensatory changes in this osteoarthritis model, and may represent potential targets for novel osteoarthritis treatments (Burston et al, 2013;Malek et al, 2015).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2013
MIA induces chondrocyte death, cartilage degradation, and chronic nociception.
“MIA induces chondrocyte death, cartilage degradation, and chronic nociception (Burston et al, 2013).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2013
CB2 and CB1 receptors undergo compensatory changes in the MIA osteoarthritis model and may represent potential targets for novel osteoarthritis treatments.
“suggesting that these receptors undergo compensatory changes in this osteoarthritis model, and may represent potential targets for novel osteoarthritis treatments (Burston et al, 2013;Malek et al, 2015).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2013
The CB2 receptor agonist JWH133 attenuates MIA-induced allodynia and restores weight bearing on the arthritic joint.
“Furthermore, the CB 2 receptor agonist JWH133 attenuates MIA-induced allodynia and restores weight bearing on the arthritic joint (Burston et al, 2013).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2013
Intrathecal injection of JWH133 attenuates the firing of wide dynamic range neurons after MIA injection.
“Intrathecal injection of JWH133 also attenuates the firing of wide dynamic range neurons after MIA injection, indicating CB 2 receptor activation in the spinal cord may attenuate MIA-induced allodynia (Burston et al, 2013).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2013
CB2 receptor activation in the spinal cord may attenuate MIA-induced allodynia.
“indicating CB 2 receptor activation in the spinal cord may attenuate MIA-induced allodynia (Burston et al, 2013).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Burston et al, 2013
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- Authors
- Burston, J. J., Sagar, D. R., Shao, P., Bai, M., King, E., Brailsford, L., Turner, J. M., Hathway, G. J., Bennett, A. J., Walsh, D. A., Kendall, D. A., Lichtman, A., & Chapman, V.
- Affiliations
- University of Nottingham (GB)
- University of Pittsburgh (US)
- Virginia Commonwealth University (US)
- Corresponding author
- Chapman, Victoria
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-11-25
- Volume
- 8
- Issue
- 11
- Pages
- e80440
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3840025
- OpenAlex
- W2119352256
- Cited by
- 103
- References
- 47
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 4 · 2021: 10 · 2020: 9 · 2019: 4 · 2018: 11 · 2017: 15 · 2016: 8 · 2015: 13 · 2014: 7
- FWCI
- 6.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
- VCU Scholars Compass (Virginia Commonwealth University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Virginia Commonwealth University
- Universidade Federal de Minas Gerais
- Versus Arthritis (18769)
- National Institutes of Health
- Medical Research Council (MR/K00414X/1)
- National Institute on Drug Abuse (P01DA009789, P50DA005274)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Keywords
- CB2 receptor, osteoarthritis pain, central sensitization, JWH-133, spinal cord, microglia, astrocytes, MMP-2, MMP-9, neuroinflammation, analgesic targets, chronic pain
- MeSH terms
- Animals, Cannabinoids, Electrophysiology, Enzyme-Linked Immunosorbent Assay, Humans, Pain, Spinal Cord, Rats, Sprague-Dawley, Osteoarthritis, Knee, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Receptor, Cannabinoid, CB2, Rats
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