Table 2

Cannabinoids mechanism of action in chronic pain

Cannabinoids mechanism of action in chronic pain
CB1 receptors

  • Central

  • Peripheral

  • Expressed abundantly centrally (CNS and spinal).

  • On presynaptic terminals of both glutamatergic and gamma aminobutyric acid (GABA) neurons.

  • GPCR receptors, coupled to Gi/Go α proteins.

  • CB1 receptor activation inhibits adenylate cyclase activity and reduce intracellular cAMP.

  • Activation of voltage-gated K+and inhibition of Ca2+ channels, inhibiting neurotransmitters release.

  • Peripheral CB1 receptors are mainly localized on sensory afferent terminals, modulating the transduction of pain from noxious stimuli, an important role in peripheral pain sensitization.

CB2 receptors

  • Central

  • Peripheral

  • The role of CB2 in the brain is still controversial.

  • Expressed in activated spinal microglia and astrocytes.

  • Like CB1, CB2 receptor is a GPCR and is coupled to Gi/Go α proteins. Thus, its stimulation inhibits adenylate cyclase activity.

  • CB2 receptors are abundantly expressed in the immune system cells.

  • CB2 receptor activation reduces the release of proinflammatory cytokines and lymphoangiogenic factors.

  • CB2 receptors represent key regulators of inflammatory and nociceptive responses.

  • CB2 receptors can control the activation and migration of immune cells.

TRPV1

  • TRPV1 channels are largely expressed in dorsal root ganglia, and sensory nerve fibers (Aδ and C-type).

  • TRPV1 has paradoxical effect on pain.

  • TRPV1 activation contributes to pain transmission, neurogenic inflammation.

  • TRPV1 “desensitization” occurs following TRPV1 stimulation due to increase of intracellular Ca2+ (see text).

  • This fast process of TRPV1 desensitization and inactivation leads to the paradoxical analgesic and anti-inflammatory effects of TRPV1 agonists.

  • There is intracellular crosstalk between TRPV1 and CB1 or CB2 as they are colocalized in peripheral and central neurons.

GPR55

  • GPR55 is activated by THC while antagonized by CBD.

  • There are heteromers between GPR55 and CB1 receptors.

  • GPR55 activation may play an opposite role to CB1 by enhancing neurotransmitter release.

  • GPR55 also involved in mechanical hyperalgesia resulted from neuropathic and inflammatory pain.

Other receptors

  • THC activates 5-HT7, 5-HT2A and alpha-2 adrenoceptors (descending inhibitory pathway).

  • THC, CBD, Anandamide directly activate glycine receptors, contributing to cannabinoid-induced analgesia in inflammatory and neuropathic pain.

  • 2-AG and CBD are positive allosteric modulators at the α2-containing GABAA receptor subtypes.

  • Cannabinoids (THC) inhibit nicotinic, 5-HT3, NMDA receptors contributing to analgesia.

  • THC, CBD, endocannabinoids activate PPARα and PPARγ receptors contributing to the analgesic, anti-inflammatory, and neuroprotective effects.

Opioid receptors

  • Crosstalk and heteromers between cannabinoids and opioids receptors (see text).

  • Synergistic interactions between cannabinoid and opioid analgesia.

  • CB2 activation triggers the release of beta-endorphin

Transport proteins and metabolizing enzymes

  • CBD augments Anandamide effects by inhibiting its uptake and metabolizing enzyme, FAAH.

  • This is an area of ongoing research.

  • AEA, anandamide; 2-AG, 2-arachidonoylglycerol; cAMP, cyclic adenosine monophosphate; CB1, cannabinoid receptor type 1; CBD, cannabidiol; FAAH, fatty acid amide hydrolase; GPCR, G protein coupled receptor; GPR55, G protein coupled receptor 55; NMDA, N-methyl-D-aspartate; THC, Δ⁹-tetrahydrocannabinol; TPVR1, transient receptor potential vanilloid type-1.