(a) Neurons damaged by injury, toxins or pathogens release large amounts of Glu, (b) resulting in strong neuronal depolarization and Glu receptor activation and sustained rise in post-synaptic calcium and enhanced eCB production. CB₁ receptor expression is up-regulated in damaged neurons. eCB acting at pre-synaptic CB₁ receptors reduce neurotransmitter release and at post-synaptic CB₁ receptors increase Erk activity and allied gene expression (e.g. BDNF). (c) ATP, released from damaged cells, stimulates purinergic receptors expressed by astrocytes and enhances eCB production, which may participate in stimulating pre- and post-synaptic CB₁ receptors. (d) Neuronal damage is associated with microglial cell activation (M₁, proinflammatory phenotypes), resulting in free radicals and toxin release, as well as up-regulation of CB₂ receptor expression. (e) eCB produced by damaged neurons and stimulated astrocytes act on CB₂ receptors expressed by microglial cells, (f) leading to a switch in their phenotype (M₂, anti-inflammatory phenotype) and further up-regulation of CB₂ and P2X₇ receptor expression. (g) ATP released by damaged cell enhances the abundant and sustained production of eCB from microglia, which participates in stimulating pre- and post-synaptic CB₁ receptors, (h) as well as in recruiting peripheral monocytes/macrophages (in concert with the chemokine MCP-1 and the cytokine TNFα). The overall result is to limit the propagation of cell damage and favor cell repair (e.g. through the release of BDNF).

(a) CB₁ receptors are expressed by neurons and CB₂ receptors by peripheral immune cells. (b) Neuronal depolarization and neurotransmitter release (e.g. glutamate, Glu) leads to post-synaptic rise in calcium, which increases endocannabinoid (eCB) production. eCB act as retrograde signals onto presynaptic CB₁ receptors, reducing neurotransmitter release. (c) Δ⁹-tetrahydrocannabinol (THC) acts as a high-affinity partial agonist at CB₁ receptors, impinging on this eCB signaling.