Terpenes and cannabinoids modulate pain signalling in nociceptive neurons via distinct pathways

Abstract Background Chronic pain affects more than a quarter of adults worldwide and is frequently inadequately controlled by currently licensed analgesics. Cannabis-based medicinal products are being investigated as an additional or alternative treatment option, but the mechanisms by which different cannabis-derived molecules influence pain signalling are incompletely understood. This review summarises current understanding of the pharmacology of phytocannabinoids and terpenes at peripheral sensory neurons, with emphasis on the lesser known or minor cannabinoids and terpenes that appear to act via mechanisms distinct from those of the classical cannabinoid receptors. Main body Cannabis sativa contains several hundred constituents, including the major cannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), more than one hundred minor phytocannabinoids, and a comparable number of terpenes, (including terpenoids) as well. The principal cannabinoid receptors type 1 (CB 1 ) and type 2 (CB 2 ) are present on dorsal root ganglion (DRG) neurons and are coupled to Gi/o proteins, with downstream effects on cyclic adenosine monophosphate (cAMP), TRP channel phosphorylation and neuronal excitability. Recent in vitro work suggests that some minor cannabinoids inhibit calcium influx in nociceptive neurons through activation of inwardly rectifying potassium channels, while certain terpenes appear to inhibit such responses through activation of the Na⁺/K⁺-ATPase. Independent groups have separately attributed terpene-induced antinociception in rodent models to adenosine A₂A receptor activation and to CB 2 receptor agonism, indicating that more than one mechanism is likely to be relevant. Clinical translation has been limited by the lack of consistent, clinically significant and high-quality data supporting the use of standardised cannabinoid treatments over placebo for chronic pain in clinical trials. Conclusion Multiple cannabis-derived molecules influence nociceptive signalling through receptors and pathways that extend beyond the classical CB 1 /CB 2 axis. THC acts principally as a partial agonist at CB 1 and CB 2 receptors, whereas CBD, minor cannabinoids and terpenes exhibit more complex and incompletely characterised pharmacology. The mechanistic diversity of these constituents provides a biological rationale for studying full-spectrum preparations, but the clinical magnitude of any synergy between cannabinoids and terpenes remains to be established in head-to-head randomised comparisons Data availability All data discussed in this review are available from previously published studies, which are cited throughout the manuscript. No primary research results or new datasets were generated.