Stockholm Medical Cannabis Conference

Synergistic Effects of Endocannabinoids in Neuropathic Pain Models: A Focus on TRPV1 Modulation

Synopsis: Unpacking the Study’s Core Components

Before delving into the nuances of this research, it’s pertinent to outline its central elements. The study, entitled “The Endocannabinoid Analgesic Entourage Effect: Investigations in Cultured DRG Neurons,” was published in the Journal of Pain Research in November 2022 [1]. Authored by Anand et al., this paper aims to scrutinize the analgesic effects of specific endocannabinoids — 2-AG, 2-PG, and 2-LG — on TRPV1 receptor activation in cultured rat dorsal root ganglion (DRG) neurons. The study extends our understanding of how these endocannabinoids modulate pain responses at a cellular level, contrasting their effects with those of phytocannabinoids in some instances.


The Global Challenge of Chronic Pain and Limitations of Current Analgesics

Phytocannabinoids, the bioactive constituents of the cannabis plant, have garnered significant attention for their multifaceted therapeutic properties, including their role in analgesia. Despite the global prevalence of chronic pain, affecting roughly one in fifteen individuals, current pharmacological interventions remain suboptimal, often falling short in efficacy and presenting a range of adverse effects.

Transitioning Focus: From Phytocannabinoids to Endocannabinoids

The present study, by Anand et al., shifts the spotlight from phytocannabinoids to endocannabinoids, the body’s endogenous lipid-signaling molecules. The investigative focus was on the analgesic potential of three specific endocannabinoids: 2-Arachidonoyl Glycerol (2-AG), 2-Palmitoyl Glycerol (2-PG), and 2-Linoleoyl Glycerol (2-LG) [1].

Methods: In Vitro Model

Employing an in vitro model using cultured rat dorsal root ganglion (DRG) neurons, the researchers meticulously quantified the individual and synergistic capacities of these endocannabinoids to modulate pain signaling initiated by capsaicin — the active ingredient in chili peppers known for activating TRPV1 ion channels.

Results: Dissecting the Latency and Efficacy

Strikingly, individual applications of each endocannabinoid produced a substantial delay in capsaicin-induced TRPV1 activation, with latency periods extending beyond four minutes. This latency was found to be analogous to the latency observed when all three endocannabinoids were co-applied (Figure 1).

Figure 1. Modulatory Impact of Individual and Combined Endocannabinoid Treatments on Capsaicin-Induced TRPV1 Activation in Cultured DRG Neurons.

The combinatory treatment showcased a broader inhibitory spectrum, influencing a larger subset of DRG neuronal populations. Specifically, this combined intervention suppressed capsaicin-triggered responses in an overwhelming 96% of the neurons examined (Figure 2).

Figure 2. Illustration of experimental paradigm: Rat DRG neurons were cultured in vitro, subjected to pre-treatment with individual or combined endocannabinoids, and subsequently exposed to 1 µM capsaicin for TRPV1 activation. Neurons with normal and delayed firing respectively were quantified using fluorescent calcium imaging and live microscopy.

Discussion & context:

A previous study by the same research group looked at whether phytocannabinoids like THC, CBD and CBG could cause delayed responses in a similar manner [2]. The authors could indeed observe phytocannabinoid-mediated effects on TRPV1-delayed responses when using THC, CBD and CBG, however only at concentrations many orders of magnitudes higher when using phytocannabinoids. At these concentrations, the phytocannabinoids caused significant TRPV1 activation by themselves, whereas at the low doses of endocannabinoids used in the newer study, no TRPV1 activation was observed, only delayed response.

Conclusion: Toward the Next-Generation of Pain Therapeutics

These findings not only elucidate the underlying molecular dynamics of pain signaling but also make a compelling case for the development of novel analgesics based on endocannabinoid modulation for chronic pain management [1].

Editor’s Comments:

A Paradigm Shift from Phytocannabinoids to Endocannabinoids

In the landscape of pain research, the current study stands as a seminal work, offering a nuanced understanding of the role of endocannabinoids in modulating the complex machinery of pain perception. Often overshadowed by their more illustrious counterparts — phytocannabinoids — the endocannabinoids 2-AG, 2-PG, and 2-LG have been meticulously examined here, not just by themselves but together as an ensemble in the body’s biochemical orchestra.

Methodological Rigor and Cellular Insights

The investigative rigor employed to unravel the intricacies of these lipid-based signaling molecules is commendable. Utilizing cultured rat dorsal root ganglion (DRG) neurons as a model system, the researchers have navigated through the complexities of cellular signaling with admirable precision. The study elegantly dissects the individual and synergistic actions of these endocannabinoids on capsaicin-induced TRPV1 activation — a canonical model for studying nociception.

The ‘Entourage Effect’: A Therapeutic Opportunity

What captivates the scientific intellect is not just the efficacy of individual endocannabinoids but the realization that their combined application has a broader, more inclusive inhibitory effect. This phenomenon, akin to an ‘entourage effect,’ sets the stage for multi-target therapeutic strategies that could revolutionize chronic pain management.

Significance of Latency and Signaling Cross-talk

The comparable latencies in TRPV1 inhibition, whether from singular or multiple endocannabinoids, are a fascinating observation. It underscores the intricate feedback loops and cross-talk among signaling pathways that govern cellular responses—a crucial insight for drug development.

Bridging the Gap: Endocannabinoids and Phytocannabinoids

Moreover, by looking into the details of previous research by the same authors, it becomes obvious that the potencies and efficacies of endocannabinoids and phytocannabinoids differ wildly at different concentrations. This comparative analysis adds a valuable layer of context, further accentuating the unique capabilities of endogenous compounds at lower doses.

Implications for Future Therapeutics and Concluding Remarks

As we navigate the labyrinthine challenges of treating chronic pain—a condition that beleaguers a staggering proportion of the global population—this research serves as both a beacon and a roadmap. It not only enriches our conceptual understanding of pain mechanisms but also offers tangible leads for the development of next-generation analgesics.

The current study is not just an addition to the scientific literature; it is a clarion call to rethink our approaches toward understanding and treating pain. Given its rigorous methodology, insightful findings, and profound implications, the paper is a substantive contribution to the ever-expanding field of cannabinoid pharmacology.

Stefan Broselid, Ph.D.
Editor-In-Chief, Aurea Care Medical Science Journal


  1. Anand U, Pacchetti B, Anand P, Sodergren MH. The Endocannabinoid Analgesic Entourage Effect: Investigations in Cultured DRG Neurons. J Pain Res. 2022;15:3493-3507. Published 2022 Nov 4. doi:10.2147/JPR.S378876
  2. Anand U, Oldfield C, Pacchetti B, Anand P, Sodergren MH. Dose-Related Inhibition of Capsaicin Responses by Cannabinoids CBG, CBD, THC and their Combination in Cultured Sensory NeuronsJ Pain Res. 2021;14:3603-3614. Published 2021 Nov 24. doi:10.2147/JPR.S336773