Computational Approach Reveals Pronociceptive Potential of Cannabidiol in Osteoarthritis: Role of Transient Receptor Potential Channels

Spread the love

. 2021 Sep 24;14(10):964.

doi: 10.3390/ph14100964.

Affiliations

Free PMC article

Item in Clipboard

Jakub Mlost et al. Pharmaceuticals (Basel). .

Free PMC article

Abstract

Systems pharmacology employs computational and mathematical methods to study the network of interactions a drug may have within complex biological pathways. These tools are well suited for research on multitarget drugs, such as natural compounds, in diseases with complex etiologies, such as osteoarthritis (OA). The present study focuses on cannabidiol (CBD), a non-psychoactive constituent of cannabis, targeting over 60 distinct molecular targets as a potential treatment for OA, a degenerative joint disease leading to chronic pain with a neuropathic component. We successfully identified molecular targets of CBD that were relevant in the context of OA treatment with both beneficial and detrimental effects. Our findings were confirmed by in vivo and molecular studies. A key role of PPARγ in mediating the therapeutic potential of CBD was revealed, whereas upregulation of multiple transient receptor potential channels demasked CBD-induced heat hyperalgesia. Our findings pave the way for novel CBD-based therapy with improved therapeutic potential but also encourage the use of bioinformatic tools to predict the mechanism of action of CBD in different conditions. We have also created an accessible web tool for analogous analysis of CBD pharmacology in the context of any disease of interest and made it publicly available.

Keywords: cannabidiol; chronic pain; neuropathic pain; osteoarthritis; systems pharmacology.

Conflict of interest statement

Katarzyna Starowicz is on the Scientific Advisory Boards for Phytecs, Inc., and consults on how endogenous cannabinoids function in the central nervous system. Phytecs had no financial contribution to the current work. The other authors have no conflicts of interest to declare.

Figures

Figure 1

Figure 1

Venn diagram of potential therapeutic targets of CBD in the neuropathic component of OA (A). Lists of disease-associated targets were obtained from the Open Targets Platform, and a list of CBD targets was created based on a literature search. Ten CBD targets associated with neuropathic pain and osteoarthritis were visualized in STRING and clustered into either ionotropic receptors or proteins associated with the endocannabinoid system (B).

Figure 2

Figure 2

Graph presenting CBD target interactions with other proteins associated with osteoarthritis and neuropathic pain. Node color represents the number of interactions for a specific protein (vertex degree). Network was visualized with the “Influential” package in R.

Figure 3

Figure 3

Analgesic potential of 10 mg/kg CBD at Day 20 and 21 post MIA induction. Baseline assessment was performed at Day 20 post MIA, whereas post-treatment assessment was performed 2 h after i.p. administration of CBD (10 mg/kg) (AC). Two-way ANOVA identified treatment as significant source of variation in all tests (p < 0.0001). Individual data points are shown in box and whisker plots presenting the means ± min to max. ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group. Each experimental group included N = 5–6 rats. The difference was considered significant when p < 0.05. * Denotes significant differences compared with the vehicle-treated control group of healthy animals.

Figure 4

Figure 4

Analgesic potential of 50 mg/kg CBD at Day 27 and 28 post MIA induction. Assessment was performed after a 6-day wash-out period on the same rats presented in Figure 4. Pain was assessed at baseline at Day 27 post MIA (Baseline) and 2 h after i.p. administration of CBD (50 mg/kg) at Day 28 post MIA (Post-treatment) (AC). Two-way ANOVA revealed significant treatment effect in all tests (p < 0.0001). Individual data points are shown in box and whisker plots presenting the means ± min to max. Each experimental group included N = 5–6 rats. ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group. The difference was considered significant when p < 0.05. * Denotes significant differences compared with the vehicle-treated control group of healthy animals; # denotes difference compared with the vehicle-treated MIA group.

Figure 5

Figure 5

Analgesic potential of 50 mg/kg CBD at Day 20 and 21 post MIA induction modulated by coadministration of TRPV1 and TRPA1 antagonists. CBD was administered i.p. two hours before assessment. The TRPV1 antagonist SB-366791 (SB; 1 mg/kg) and TRPA1 antagonist AP-18 (AP; 0.2 mg/kg) were administered i.p. 30 min before the assessment. Pain was assessed at baseline at day 20 post MIA and 2 h after i.p. administration of CBD with or without antagonists at day 21 post MIA (AC). Two-way ANOVA revealed significant treatment effect in all tests (p < 0.0001). Individual data points are shown in box and whisker plots presenting means ± min to max. The control and MIA groups included N = 8 rats, whereas the CBD group without antagonists (CBD, SB, AP) included N = 5 rats. ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group; ▼ denotes samples in MIA + CBD + SB-366791 group; ♦ denotes samples in MIA + CBD + AP-18 group. The difference was considered significant when p < 0.05. * Denotes significant differences compared with the vehicle-treated control group of healthy animals; # denotes difference compared with the vehicle-treated MIA group; $ denotes difference compared with the CBD group.

Figure 6

Figure 6

Analgesic potential of 50 mg/kg CBD at Day 27 and 28 post MIA induction modulated by coadministration of TRPV4 and PPARγ antagonists. Assessment was performed after a 6-day wash-out period on the same rats presented in Figure 5, which were coadministered CBD (50 mg/kg) with SB-366791 (SB; 1 mg/kg) and the TRPA1 antagonist AP-18 (AP; 0.2 mg/kg). CBD alone or in combination with the PPARγ antagonist GW9662 (GW, 2 mg/kg) was administered i.p. Two hours before assessment, the TRPV4 antagonist HC-067047 (HC, 10 mg/kg) was administered i.p. 30 min before the assessment. Pain was assessed at baseline at day 27 post MIA and 2 h after i.p. administration of CBD with or without antagonists at day 28 post MIA (AC). Two-way ANOVA revealed significant treatment effect in all tests (p < 0.0001). Individual data points are shown in box and whisker plots presenting means ± min to max. The control and MIA groups included N = 8 rats, whereas the CBD group without antagonists (CBD, AP/HC, SB/GW) included N = 5 rats. ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group; ▼ denotes samples in MIA + CBD + SB-366791 or HC-067047 group; ♦ denotes samples in MIA + CBD + AP-18 or GW9662 group. The difference was considered significant when p < 0.05. * Denotes significant differences compared with the vehicle-treated control group of healthy animals; # denotes difference compared with the vehicle-treated MIA group; $ denotes difference compared with the CBD group.

Figure 6

Figure 6

Analgesic potential of 50 mg/kg CBD at Day 27 and 28 post MIA induction modulated by coadministration of TRPV4 and PPARγ antagonists. Assessment was performed after a 6-day wash-out period on the same rats presented in Figure 5, which were coadministered CBD (50 mg/kg) with SB-366791 (SB; 1 mg/kg) and the TRPA1 antagonist AP-18 (AP; 0.2 mg/kg). CBD alone or in combination with the PPARγ antagonist GW9662 (GW, 2 mg/kg) was administered i.p. Two hours before assessment, the TRPV4 antagonist HC-067047 (HC, 10 mg/kg) was administered i.p. 30 min before the assessment. Pain was assessed at baseline at day 27 post MIA and 2 h after i.p. administration of CBD with or without antagonists at day 28 post MIA (AC). Two-way ANOVA revealed significant treatment effect in all tests (p < 0.0001). Individual data points are shown in box and whisker plots presenting means ± min to max. The control and MIA groups included N = 8 rats, whereas the CBD group without antagonists (CBD, AP/HC, SB/GW) included N = 5 rats. ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group; ▼ denotes samples in MIA + CBD + SB-366791 or HC-067047 group; ♦ denotes samples in MIA + CBD + AP-18 or GW9662 group. The difference was considered significant when p < 0.05. * Denotes significant differences compared with the vehicle-treated control group of healthy animals; # denotes difference compared with the vehicle-treated MIA group; $ denotes difference compared with the CBD group.

Figure 7

Figure 7

Molecular changes in CBD-associated target expression in the lumbar spinal cord. Gene expression of Pparg (A), Gpr55 (B), Cnr2 (C), Faah (D), Trpv1 (E), Trpv4 (F), Trpm8 (G), Trpa1 (H), Garba5 (I) and Htr3a (J) was evaluated in the lumbar spinal cord at Day 28 post MIA and 5 h after drug administration. CBD was administered at a dose of 50 mg/kg at both Days 21 and 28 post MIA injection either alone (CBD) or in combination with AP-18 (0.2 mg/kg) at Day 21 and HC-067047 (10 mg/kg) at Day 28 post MIA (HC). ANOVA revealed significant changes in all tested parameters with p < 0.05. Individual data points are shown in boxes presenting the mean ± SEM of fold change normalized to the reference gene beta-2 microglobulin (B2m). ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group; ▼ denotes samples in MIA + CBD + AP-18 followed by HC-067047 group. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test with a p < 0.05 confidence interval. Each experimental group includes N = 4–6 rats. * Denotes significant differences vs. control; # Denotes significant differences vs. MIA; $ Denotes significant differences vs. CBD.

Figure 7

Figure 7

Molecular changes in CBD-associated target expression in the lumbar spinal cord. Gene expression of Pparg (A), Gpr55 (B), Cnr2 (C), Faah (D), Trpv1 (E), Trpv4 (F), Trpm8 (G), Trpa1 (H), Garba5 (I) and Htr3a (J) was evaluated in the lumbar spinal cord at Day 28 post MIA and 5 h after drug administration. CBD was administered at a dose of 50 mg/kg at both Days 21 and 28 post MIA injection either alone (CBD) or in combination with AP-18 (0.2 mg/kg) at Day 21 and HC-067047 (10 mg/kg) at Day 28 post MIA (HC). ANOVA revealed significant changes in all tested parameters with p < 0.05. Individual data points are shown in boxes presenting the mean ± SEM of fold change normalized to the reference gene beta-2 microglobulin (B2m). ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group; ▼ denotes samples in MIA + CBD + AP-18 followed by HC-067047 group. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test with a p < 0.05 confidence interval. Each experimental group includes N = 4–6 rats. * Denotes significant differences vs. control; # Denotes significant differences vs. MIA; $ Denotes significant differences vs. CBD.

Figure 8

Figure 8

Molecular changes in CBD-associated target gene expression in the lumbar spinal cord. Gene expression of Mapk3 (A), Mapk14 (B), Prkcg (C), Prkaca (D), Ptgs2 (E) and Alox12 (F) was evaluated in the lumbar spinal cord at Day 28 post MIA and 5 h after drug administration. CBD was administered at a dose of 50 mg/kg at both Days 21 and 28 post MIA injection either alone (CBD) or in combination with AP-18 (0.2 mg/kg) at Day 21 and HC-067047 (10 mg/kg) at Day 28 post MIA (HC). ANOVA revealed significant changes in all tested parameters with p < 0.05. Individual data points are shown in boxes presenting the mean ± SEM of fold change normalized to the reference gene beta-2 microglobulin (B2m). ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group; ▼ denotes samples in MIA + CBD + AP-18 followed by HC-067047 group. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test with a p < 0.05 confidence interval. Each experimental group includes N = 4–6 rats. * Denotes significant differences vs. control; # Denotes significant differences vs. MIA; $ Denotes significant differences vs. CBD.

Figure 9

Figure 9

Molecular changes in CBD-associated target expression in rat cartilage and subchondral bone. Expression of Pparg (A), Gpr55 (B), Cnr2 (C), Faah (D), Trpv1 (E), Trpv4 (F), Trpm8 (G), Trpa1 (H), Garba5 (I) and Htr3a (J) was evaluated in cartilage and subchondral bone tissue at Day 28 post MIA and 5 h after drug administration. CBD was administered at a dose of 50 mg/kg at both Days 21 and 28 post MIA injection either alone (CBD) or in combination with AP-18 (0.2 mg/kg) at Day 21 and HC-067047 (10 mg/kg) at Day 28 post MIA (HC). ANOVA revealed significant changes in expression of Trpv1, Trpv4, and Trpm8 with p < 0.01. Individual data points are shown in boxes presenting the mean ± SEM of fold change normalized to the reference gene beta-2 microglobulin (B2m). ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group; ▼ denotes samples in MIA + CBD + AP-18 followed by HC-067047 group. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test with a p < 0.05 confidence interval. Each experimental group includes N = 4–6 rats. * Denotes significant differences vs. control; # Denotes significant differences vs. MIA; $ Denotes significant differences vs. CBD.

Figure 9

Figure 9

Molecular changes in CBD-associated target expression in rat cartilage and subchondral bone. Expression of Pparg (A), Gpr55 (B), Cnr2 (C), Faah (D), Trpv1 (E), Trpv4 (F), Trpm8 (G), Trpa1 (H), Garba5 (I) and Htr3a (J) was evaluated in cartilage and subchondral bone tissue at Day 28 post MIA and 5 h after drug administration. CBD was administered at a dose of 50 mg/kg at both Days 21 and 28 post MIA injection either alone (CBD) or in combination with AP-18 (0.2 mg/kg) at Day 21 and HC-067047 (10 mg/kg) at Day 28 post MIA (HC). ANOVA revealed significant changes in expression of Trpv1, Trpv4, and Trpm8 with p < 0.01. Individual data points are shown in boxes presenting the mean ± SEM of fold change normalized to the reference gene beta-2 microglobulin (B2m). ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group; ▼ denotes samples in MIA + CBD + AP-18 followed by HC-067047 group. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test with a p < 0.05 confidence interval. Each experimental group includes N = 4–6 rats. * Denotes significant differences vs. control; # Denotes significant differences vs. MIA; $ Denotes significant differences vs. CBD.

Figure 10

Figure 10

Molecular changes in inflammatory factor expression in rat cartilage and subchondral bone. Gene expression of Il6 (A), Ccl2 (B), Fabp3 (C), Comp (D), Ptgs2 (E) and Alox12 (F) was evaluated in cartilage and subchondral bone tissue at Day 28 post MIA and 5 h after drug administration. CBD was administered at a dose of 50 mg/kg at both Days 21 and 28 post MIA injection, either alone (CBD) or in combination with AP-18 (0.2 mg/kg) at Day 21 and HC-067047 (10 mg/kg) at Day 28 post MIA (HC). ANOVA revealed significant changes in expression of Il6, Ccl2, Fabp3, Comp with p < 0.005. Individual data points are shown in boxes presenting the mean ± SEM of fold change normalized to the reference gene beta-2 microglobulin (B2m). ● denotes samples in control group; ■ denotes samples in MIA group; ▲ denotes samples in MIA + CBD group; ▼ denotes samples in MIA + CBD + AP-18 followed by HC-067047 group. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test with a p < 0.05 confidence interval. Each experimental group includes N = 4–6 rats. * Denotes significant differences vs. control; # Denotes significant differences vs. MIA; $ Denotes significant differences vs. CBD.

Figure 11

Figure 11

Schematic representation of the CBD mechanism of action within OA pathophysiology.

References

    1. Bryk M., Starowicz K. Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB2 receptor in the arthritis progression and pain: An updated review. Pharmacol. Rep. 2021;73:681–699. doi: 10.1007/s43440-021-00270-y. – DOI PMC PubMed
    1. Mlost J., Kostrzewa M., Malek N., Starowicz K., Mlost J., Kostrzewa M., Malek N., Starowicz K. Molecular Understanding of the Activation of CB1 and Blockade of TRPV1 Receptors: Implications for Novel Treatment Strategies in Osteoarthritis. Int. J. Mol. Sci. 2018;19:342. doi: 10.3390/ijms19020342. – DOI
    1. Mlost J., Kostrzewa M., Borczyk M., Bryk M., Chwastek J., Korostyński M., Starowicz K. CB2 agonism controls pain and subchondral bone degeneration induced by mono-iodoacetate: Implications GPCR functional bias and tolerance development. Biomed. Pharmacother. 2021;136:111283. doi: 10.1016/j.biopha.2021.111283. – DOI PubMed
    1. Mlost J., Bryk M., Starowicz K. Cannabidiol for pain treatment: Focus on pharmacology and mechanism of action. Int. J. Mol. Sci. 2020;21:8870. doi: 10.3390/ijms21228870. – DOI PMC PubMed
    1. O’Sullivan S.E. Cannabinoid activation of peroxisome proliferator-activated receptors: An update and review of the physiological relevance. Wiley Interdiscip. Rev. Membr. Transp. Signal. 2013;2:17–25. doi: 10.1002/wmts.73. – DOI

Grant support

LinkOut – more resources

  • Full Text Sources

Schaka

Related Posts

Dose-Related Inhibition of Capsaicin Responses by Cannabinoids CBG, CBD, THC and their Combination in Cultured Sensory Neurons

Aurora Cannabis Launches Genetics Licensing Business

Aurora Cannabis Launches Genetics Licensing Business

Steep Hill Announces Expansion to Illinois

Thompson Duke Industrial Secures Another Patent for Cannabis Oil Vaporizer Device Filling Equipment

Signez la pétition !!!

 

846 signatures

Pétition ASBL Cannabis Belgique

Pourquoi une pétition ?

Nous sommes des personnes qui en avons assez de devoir aller dans la rue et avoir affaire à des réseaux criminels sans savoir où cela va nous conduire par après.

Nous sommes des personnes ayant des maladies, qui pour certaines sont rares, et utilisant pour médication le cannabis sous diverses formes (CBD,THC,THCv,CBDa,,,) sous l'accord de notre médecin.

Nous sommes des personnes responsables et honnêtes qui avons une vie épanouie et sans problèmes de vie ou sociaux.

Nous avons également une passion pour la plante de cannabis en elle-même et la cultiver est notre bonheur. De plus, nous pouvons nous soigner avec notre médication sans avoir peur des produits ou autres additifs contenus dans une plante que l'on peut trouver autre part.

Nous souhaitons pouvoir avoir notre médicament dans les normes de la santé publique, car un cannabis sain aide à réduire les frais de santé parfois conséquents pour la collectivité et le malade lui-même.

Nous sommes également des personnes responsables avec un rôle dans la société qui en avons assez d’être considérés comme des « hippies ou autres drogués », nous avons juste choisi notre médication et celle-ci a apporté les preuves de son efficacité dans le monde.

Nous connaissons déjà les produits dérivés comme le CBD et le THC que nous maîtrisons pour nous aider dans notre maladie « Je précise que nous ne sommes pas médecin et que nous nous basons sur 20 ans d’expérience médicale du cannabis des membres de notre ASBL et l'avis du médecin de famille ».

Nous désirons simplement ne plus nous cacher, et pouvoir aider les autres personnes le souhaitant.

Nous somme soucieux des ados et de la prévention à leur égard. Effectivement, nous sommes les acteurs parfaits pour répondre aux questions qu’ils se posent vu notre expérience cannabique et, de plus, nous pourrons leur expliquer les risques qu’ils encourent en achetant du cannabis dans la rue.

Le projet complet peut être demandé via mail " info@mcb.care " et sur le site internet : " http://mcb.care "

@ASBL McB

**votre signature**

Partagez avec vos amis

Articles récents

Catégories