Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies

Abstract

This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.

Figure 1.

A historical timeline of key milestones in cannabis and cannabinoid research.

Figure 2.

Distribution of the cannabinoid receptors and enzymes associated with endocannabinoid synthesis and degradation in pain pathways. The endcannabinoid system is widely distributed throughout regions associated with pain processing and modulation in the brain, spinal cord and periphery; Most particularly the CB₁ receptor and the enzymes responsible for endocannabinoid synthesis (NAPE-PLD, DAGL) and degradation (FAAH, MGL). CB₂ receptors are less abundant in the brain and are primarily located on microglia, however studies have shown expression of CB₂ on neurons in the VTA, and several discrete nuclei of the brainstem. CB₁ is also expressed on microglia at a lower level than CB₂, and effects of CB₁ on microglia may be mediated by neuronal CB₁. Therefore, this was not depicted above. In the DRG and periphery both CB₁ and CB₂ receptors can be found on neurons (and glia in the dorsal horn), as well as the endocannabinoid enzymes. PFC – prefrontal cortex; VTA – Ventral Tegmental Area; PAG – periaqueductal grey; RVM – rostral ventromedial medulla; PBN – parabrachial nucleus; DMNX - dorsal motor nucleus of the vagus nerve; DRG – dorsal root ganglion; CB – cannabinoid receptor; NAPE-PLD – N-acylphosphatidylethanolamine-hydrolyzing phospholipase D; DAGL – diacylglycerol lipase; FAAH – fatty acid amide hydrolase; MGL – monoacylglycerol lipase.

Figure 3.

The caterpillar plot of 1544 nested comparisons extracted from 374 studies included in the meta-analysis. A Hedge’s G standardised mean difference effect size was calculated for each comparison. Overall effect size = 1.32

Figure 4.

Forest plot of drug classes assessed for antinociceptive efficacy in rat (A) and mouse (B) models of injury-related or pathological persistent pain. The size of the squares represents the weight (%) and its influence on the pooled result. N denotes the number of animals and K the number of comparisons of each sub-group.