Table 1

Cannabinoids multimodal analgesic mechanisms of action

Cannabinoids antinociception pathways
Peripheral

  • Peripheral CB2 receptors activation can lead to pain modulation by inhibiting production and release of inflammatory mediators (reactive oxygen species and cytokines).

  • Endocannabinoids can release peripheral endogenous opioids.

  • Peripheral CB1 receptors act to gate the transduction of pain from noxious stimuli.

Spinal

  • CB1 receptors are highly expressed on dorsal horn and DRG. CB1 activation leads to inhibition of pronociceptive neurotransmitters release from primary afferent terminals.

  • CB2 receptors expressed on spinal inhibitory interneurons and glial cells.

  • Anandamide exerts its actions at the onset of pain, whereas 2-AG plays a role in the resolution of pain.

Supraspinal

  • Cannabinoids modulate:

    • Ascending pain signals in the thalamus.

    • Descending signals in the brain stem.

    • Pain sensation in the frontal-limbic circuits (THC targets preferentially the affective qualities of pain).

  • Anandamide has a ‘biphasic effect’. On demand release during acute pain, causes antinociceptive effects. High concentration of anandamide due to prolonged stimulation leads to pronociceptive responses via TRPV1 binding.

  • AEA, anandamide; 2-AG, 2-arachidonoylglycerol; CB1, cannabinoid receptor type 1; CBD, cannabidiol; DRG, dorsal root ganglion; THC, Δ⁹-tetrahydrocannabinol; TRPV1, transient receptor potential vanilloid type-1.