Table 3

THC and CBD mechanisms of action in pain modulation

THC and CBD mechanisms of action in pain modulation
THC

  • Partial agonist at CB1 and CB2 receptors (see table 2).

  • High binding affinity to CB1 receptor.

  • The frontal-limbic distribution of CB1 receptors explains the central mechanism of THC analgesia as it targets preferentially the affective qualities of pain.

  • Activation of supraspinal descending serotonergic and noradrenergic pain modulatory pathways.

  • Spinal 5-HT7, 5-HT2A and alpha-2 adrenoceptors activation.

  • CB2 receptor activation reduces cytokine-mediated neuroinflammation.

  • Non CB1/CB2 receptor-mediated antinociception by inhibiting nicotinic, 5-HT3 and NMDA receptors.

  • Activation of glycine receptors, contributing to analgesia in inflammatory and neuropathic pain.

CBD

  • Weak binding affinity for either CB1 or CB2 receptors. However, in the antagonist of CB1 and CB2, in the presence of THC.

  • Non-competitive negative allosteric modulator of the CB1.

  • Act synergistically with THC and contribute to its the analgesic effect while providing an ‘entourage effect’.

  • Regulates the perception of pain through non CB1/CB2 mechanisms.

  • Modulation of including non-cannabinoid GPCRs (5-HT1A), ion channels (TRPV1, TRPA1, TPRM8, NAGlyR) and PPARs.

  • Activation of glycine receptors, contributing to analgesia in inflammatory and neuropathic pain.

  • Augments anandamide (AEA) effects by inhibiting its uptake as well as its metabolizing enzyme, FAAH.

  • 2-AG, 2-arachidonoylglycerol; CB1, cannabinoid receptor type 1; CBD, cannabidiol; FAAH, fatty acid amide hydrolase; GPCR, G protein coupled receptor; GPR55, G protein coupled receptor 55; NAGlyR, N-arachidonoyl glycine receptor; NMDA, N-methyl-D-aspartate; PPAR, peroxisome proliferator-activated receptors; THC, Δ⁹-tetrahydrocannabinol; TRPV1, transient receptor potential vanilloid type-1.