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. 2021 Nov 24:14:3603-3614.
doi: 10.2147/JPR.S336773. eCollection 2021.

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

Uma Anand  1 , Christian Oldfield  1 , Barbara Pacchetti  2 , Praveen Anand  1 , Mikael H Sodergren  1   2
Affiliations

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

Uma Anand et al. J Pain Res. .

Abstract

Background: The analgesic effects of Cannabis sativa are mediated by ∆9 tetrahydrocannabinol (THC), but the contributions of other bioactive complex components, including cannabigerol (CBG) and cannabidiol (CBD), are unclear. We describe the individual and combined effects of CBG, CBD and THC, on blocking capsaicin responses in dorsal root ganglion (DRG) neurons, in an in vitro model of nociceptor hypersensitivity.

Materials and methods: Adult rat DRG were dissected and enzyme digested to obtain a neuronal suspension in BSF2 medium containing 2% fetal calf serum, and the neurotrophic factors NGF and GDNF. After 48 h, cultured neurons were loaded with Fura-2 AM, to determine the effects of cannabinoids on capsaicin responses using calcium imaging. In control experiments, neurons were treated with vehicle, followed by 1 µM capsaicin. In cannabinoid treated cultures, CBG, CBD or THC were applied individually, or combined (1:1:1 ratio), followed by 1 µM capsaicin. Data from n = 6 experiments were analysed with Student's t-test and Pearson's correlation coefficient.

Results: CBG, CBD and THC, applied individually, elicited dose-related calcium influx in a subset of DRG neurons, and a corresponding dose-related reduction of subsequent responses to capsaicin. Maximum inhibition of capsaicin responses was observed at 30 µM CBG, 100 µM CBD, and 100 µM THC individually, and with combined CBD+CBG+THC (1:1:1) at 90 µM. THC+CBD+CBG combined in a 1:1:1 proportion has the potential to enhance the potency of these compounds applied individually. There was a high correlation between cannabinoid-mediated calcium influx and reduction of capsaicin responses: CBG = -0.88, THC = -0.97, CBD = -0.99 and combined CBG + THC + CBD = -1.00.

Conclusion: CBG, CBD and THC demonstrated potent dose-related inhibition of capsaicin responses in DRG neurons when applied individually in vitro, and enhanced when applied in combination, being most effective at 90 μM. Thus, efficacy and tolerability of THC could be improved in combination with CBG and CBD at optimal concentrations, which deserve further studies in vivo.

Keywords: CBD; CBG; DRG neurons; THC; TRPV1; cannabinoid; pain.

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Conflict of interest statement

This study was funded by EMMAC Life Sciences Ltd. Barbara Pacchetti and Mikael H Sodergren are employees of EMMAC Life Sciences Ltd. Barbara Pacchetti reports personal fees from EMMAC Life Sciences, outside the submitted work. Mikael H Sodergren reports consultancy for and personal fees from Emmac Life Sciences, outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed and report no other potential conflicts of interest for this work. No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1
Figure 1
Image showing a field of view of cultured rat DRG neurons, with individual cells highlighted for analysis; bar=100 µm (A). Sample traces showing absence of response to vehicle followed by rapid rise in calcium in response to capsaicin (B). Sample traces showing response to 30 µM CBD followed by 1 µM capsaicin (C). Similar traces of response to 30 µM CBG and capsaicin (D). Sample traces of responses to 100 µM THC and capsaicin (E). Sample traces of responses to the 30 µM mix of CBG+CBD+THC (1:1:1), followed by capsaicin (F). Scale bars indicate change in 340/380 ratio on the y axis, and time in seconds on x axis.
Figure 2
Figure 2
Graphs showing dose-related calcium responses to cannabinoids (black bars), CBG (A), THC (B), CBD (C), and combined CBD+CBG+THC (D). Each graph also shows the inhibitory effects of the added cannabinoids on capsaicin responses (grey bars) at the indicated concentrations, expressed as a percentage of calcium influx in response to 1 µMol capsaicin. The inhibition of capsaicin responses was inversely proportional to the cannabinoid concentrations. *P < 0.05, **P < 0.1, ***P < 0.001.
Figure 3
Figure 3
Graph showing comparison of dose-related reduction of capsaicin responses due to cannabinoids applied individually (patterned bars), or in combination (black bars).
Figure 4
Figure 4
Graph showing the percentage inhibition of 1 µM capsaicin responses in the presence of CBG, CBD and THC applied individually (patterned bars), and combined (black bars). *P < 0.05, ***P < 0.001.
See this image and copyright information in PMC

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