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Cited by 103Pain Mechanisms and TreatmentsCannabis and Cannabinoid ResearchOsteoarthritis Treatment and Mechanisms

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Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint

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Burston, James J., Sagar, Devi Rani, Shao, Pin, Bai, Mingfeng, King, Emma, Brailsford, Louis, Turner, Jenna M., Hathway, Gareth J., Bennett, Andrew J., Walsh, David A., Kendall, David A., Lichtman, Aron, Chapman, Victoria·2013·PLoS ONE
DOI 10.1371/journal.pone.0080440PMC PMC3840025
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Abstract

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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Figure 1 (A) Repeated systemic administration of the CB2 receptor agonist JWH-133 (1 mg/kg; day 1–28) attenuated MIA-induced changes in weight bearing (p<0.001 area under the curve analysis of MIA + Vehicle vs. MIA + JWH133) and mechanical withdrawal thresholds (p<0.001 area under the curve analysis of MIA + Vehicle vs. MIA + JWH133) of the ipsilateral hindpaw, n = 8 rats per group). (B) Effects of repeated systemic administration of the CB2 receptor agonist JWH-133 (1 mg/kg; day 1–28) on MIA-induced changes in serum levels of IL-1β, TNF-α and IL-10. Analysis of IL-1β and TNF-α used a one sample t-test using detection limit of kit as hypothetical value as there was no variation in saline + vehicle group and MIA + JWH133 group, for IL-10 data a one-way ANOVA and a Bonferroni post-hoc test was used, **p<0.01, ***p<0.001 (n = 4–6 rat serum samples per group). (C–D) Effects of spinal JWH-133 on noxious (15 g and 26 g) mechanically evoked responses of WDR neurones in MIA-treated rats (n = 6 neurones in 6 rats) and saline-treated rats (n = 6 neurones). Spinal administration of vehicle did not alter evoked responses of neurons in MIA-treated rats (n = 7 neurones in 7 rats). Effects of JWH-133 (156 ng/50 µL) were abolished in the presence of SR144528 (n = 6 neurones in 6 rats; 0.001 µg/50 µl) as indicated by open circle data point on bottom two panels. Data are expressed as mean maximal inhibition (% of pre-drug response) ± SEM. Statistical analyses were performed using a Kruskal Wallis test or Mann Whitney test as appropriate (*p<0.05, **p<0.01 for MIA-JWH133 versus MIA-Vehicle and + p<0.05 for MIA-JWH133 versus MIA-JWH+SR144528). (D) Representative trace of innocuous (10 g) and noxious (15–60 g) mechanically evoked responses of a single dorsal horn neurone before and 30 minutes following spinal administration of JWH-133 (156 ng/50 µL) in MIA-treated rats.
Figure 1 (A) Repeated systemic administration of the CB2 receptor agonist JWH-133 (1 mg/kg; day 1–28) attenuated MIA-induced changes in weight bearing (p<0.001 area under the curve analysis of MIA + Vehicle vs. MIA + JWH133) and mechanical withdrawal thresholds (p<0.001 area under the curve analysis of MIA + Vehicle vs. MIA + JWH133) of the ipsilateral hindpaw, n = 8 rats per group). (B) Effects of repeated systemic administration of the CB2 receptor agonist JWH-133 (1 mg/kg; day 1–28) on MIA-induced changes in serum levels of IL-1β, TNF-α and IL-10. Analysis of IL-1β and TNF-α used a one sample t-test using detection limit of kit as hypothetical value as there was no variation in saline + vehicle group and MIA + JWH133 group, for IL-10 data a one-way ANOVA and a Bonferroni post-hoc test was used, **p<0.01, ***p<0.001 (n = 4–6 rat serum samples per group). (C–D) Effects of spinal JWH-133 on noxious (15 g and 26 g) mechanically evoked responses of WDR neurones in MIA-treated rats (n = 6 neurones in 6 rats) and saline-treated rats (n = 6 neurones). Spinal administration of vehicle did not alter evoked responses of neurons in MIA-treated rats (n = 7 neurones in 7 rats). Effects of JWH-133 (156 ng/50 µL) were abolished in the presence of SR144528 (n = 6 neurones in 6 rats; 0.001 µg/50 µl) as indicated by open circle data point on bottom two panels. Data are expressed as mean maximal inhibition (% of pre-drug response) ± SEM. Statistical analyses were performed using a Kruskal Wallis test or Mann Whitney test as appropriate (*p<0.05, **p<0.01 for MIA-JWH133 versus MIA-Vehicle and + p<0.05 for MIA-JWH133 versus MIA-JWH+SR144528). (D) Representative trace of innocuous (10 g) and noxious (15–60 g) mechanically evoked responses of a single dorsal horn neurone before and 30 minutes following spinal administration of JWH-133 (156 ng/50 µL) in MIA-treated rats.CC BY · PubMed Central
Figure 2 (A) CB2 mRNA expression in the ipsilateral and contralateral lumbar spinal cord of MIA- and saline-treated rats. Data are normalised to levels of β-actin (mean ± SEM, n = 4–5 per group), region/treatment comparison was performed with a one way ANOVA and Neuman-Keuls post-hoc test, ***p<0.001. (B) Representative images of CB2 receptor immunofluorescence localised with markers for neurones (Neu-N) and microglia (Iba-1) in the dorsal horn of spinal cord (scale bar = 10 µm). (C) Quantification of the number of Iba-1 positive and Neu-N positive cells in the dorsal horn of the spinal cord which co-express CB2 receptor immunofluorescence. Data are expressed as mean ± SEM, statistical analysis were performed using a one way ANOVA followed by Bonferroni post-hoc (n = 5–6 sections per rat, 5–6 rats per group),*p<0.05, **p<0.01. (D) Quantification of CB2 probe (AU) in ipsilateral and contralateral dorsal horn quadrants in sections from MIA-treated (n = 5) and saline-treated (n = 4) rats (mean + SEM, 5–6 spinal cord sections per rat),*p<0.05, **p<0.01.
Figure 2 (A) CB2 mRNA expression in the ipsilateral and contralateral lumbar spinal cord of MIA- and saline-treated rats. Data are normalised to levels of β-actin (mean ± SEM, n = 4–5 per group), region/treatment comparison was performed with a one way ANOVA and Neuman-Keuls post-hoc test, ***p<0.001. (B) Representative images of CB2 receptor immunofluorescence localised with markers for neurones (Neu-N) and microglia (Iba-1) in the dorsal horn of spinal cord (scale bar = 10 µm). (C) Quantification of the number of Iba-1 positive and Neu-N positive cells in the dorsal horn of the spinal cord which co-express CB2 receptor immunofluorescence. Data are expressed as mean ± SEM, statistical analysis were performed using a one way ANOVA followed by Bonferroni post-hoc (n = 5–6 sections per rat, 5–6 rats per group),*p<0.05, **p<0.01. (D) Quantification of CB2 probe (AU) in ipsilateral and contralateral dorsal horn quadrants in sections from MIA-treated (n = 5) and saline-treated (n = 4) rats (mean + SEM, 5–6 spinal cord sections per rat),*p<0.05, **p<0.01.CC BY · PubMed Central
Figure 3 (A) Representative images of GFAP immunofluorescence, a marker of reactive gliosis, in the ipsilateral and contralateral dorsal horn of the spinal cord. Images are from rats that received intra-articular injection of saline or MIA, and treatment with vehicle or the CB2 receptor agonist JWH133 (1 mg/kg, days 1–28) (scale bar = 5 µm). (B) Quantification of ipsilateral GFAP immunofluorescence expressed as a % of the immunofluorescence for the contralateral spinal cord for the three treatment groups (n = 6–7 sections per rat, n = 4 rats per treatment). Systemic administration of JWH-133 significantly attenuated increases in GFAP immunofluorescence, compared to the effects of vehicle, statistical analysis was conducted via a one-Way ANOVA with a Bonferroni post-hoc test,*p<0.05. (C) Example gel zymography of MMP-9 and MMP-2 activity in the spinal cord from the various treatment conditions, as well as positive controls for purified MMP 2 and MMP 9. (D) Quantification of MMP-9 and pro and active MMP-2 activity in the ipsilateral spinal cord in MIA-treated rats and saline-treated rats. Systemic administration of JWH-133 significantly attenuated increases in MMP-9, MMP-2 and active MMP-2 activity in the spinal cord in MIA-treated rats, compared to the effects of vehicle. Data are expressed as mean densitometry ± SEM (n = 4 rats per group), statistical analysis one-way ANOVA and Bonferroni post-hoc test,**p<0.01, ***p<0.001 vs. saline/Vehicle; #p<0.05, ###p<0.001 vs. MIA/Vehicle.
Figure 3 (A) Representative images of GFAP immunofluorescence, a marker of reactive gliosis, in the ipsilateral and contralateral dorsal horn of the spinal cord. Images are from rats that received intra-articular injection of saline or MIA, and treatment with vehicle or the CB2 receptor agonist JWH133 (1 mg/kg, days 1–28) (scale bar = 5 µm). (B) Quantification of ipsilateral GFAP immunofluorescence expressed as a % of the immunofluorescence for the contralateral spinal cord for the three treatment groups (n = 6–7 sections per rat, n = 4 rats per treatment). Systemic administration of JWH-133 significantly attenuated increases in GFAP immunofluorescence, compared to the effects of vehicle, statistical analysis was conducted via a one-Way ANOVA with a Bonferroni post-hoc test,*p<0.05. (C) Example gel zymography of MMP-9 and MMP-2 activity in the spinal cord from the various treatment conditions, as well as positive controls for purified MMP 2 and MMP 9. (D) Quantification of MMP-9 and pro and active MMP-2 activity in the ipsilateral spinal cord in MIA-treated rats and saline-treated rats. Systemic administration of JWH-133 significantly attenuated increases in MMP-9, MMP-2 and active MMP-2 activity in the spinal cord in MIA-treated rats, compared to the effects of vehicle. Data are expressed as mean densitometry ± SEM (n = 4 rats per group), statistical analysis one-way ANOVA and Bonferroni post-hoc test,**p<0.01, ***p<0.001 vs. saline/Vehicle; #p<0.05, ###p<0.001 vs. MIA/Vehicle.CC BY · PubMed Central
Figure 4 (A) CB2 receptor mRNA expression in the lumbar spinal cord was negatively correlated with macroscopic knee chondropathy scores. (B) GFAP mRNA expression in the lumbar spinal cord was positively correlated with macroscopic knee chondropathy scores. Data are expressed as mean (normalised to beta actin) ± SEM, statistical analysis (n = 11 separate spinal cord cases). Data were analysed with either a Pearson correlation or Spearman correlation depending on whether data passed normality testing.
Figure 4 (A) CB2 receptor mRNA expression in the lumbar spinal cord was negatively correlated with macroscopic knee chondropathy scores. (B) GFAP mRNA expression in the lumbar spinal cord was positively correlated with macroscopic knee chondropathy scores. Data are expressed as mean (normalised to beta actin) ± SEM, statistical analysis (n = 11 separate spinal cord cases). Data were analysed with either a Pearson correlation or Spearman correlation depending on whether data passed normality testing.CC BY · PubMed Central

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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)
DOI
10.1371/journal.pone.0080440
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
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 (medical) › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Pharmacology (medical) › 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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