FIGURE 2.

Chemical structures of some plant (A), synthetic cannabinoids (B) and endocannabinoids (C) that bind to cannabinoid receptors (D). It is interesting to note that cannabinoids could activate intracellular pathways by direct activation of its receptors (\protect❶ and ❷) or modulate other family receptors (\protect❸ and ❹), which contribute to the biological effect of these molecules (particularly for the endocannabinoids). In general terms, classic cannabinoid receptors (CB₁ and CB₂) are GPCRs, which are canonically coupled to G_i/o proteins. Consequently, under CB_1/2 receptors: (i) a decrease of adenylyl cyclase (AC) activity; (ii) an inactivation of Ca²⁺ channels; and (iii) activation of inwardly rectifying K⁺ channels are achieved. These are signal transduction systems associated with inhibition of neurotransmitter release. The inhibition of AC occurs via activation of Gα_i-mediated signaling whereas Gα_o-activation results in inhibition of voltage-dependent Ca²⁺ channels (VDCCs) through the release of associated βγ subunits (apparently CB₂ receptors are ineffective, compared with CB₁, for shifting ionic currents via βγ subunits). In addition to PKA inhibition, CB_1/2 receptor signaling also leads to the downstream activation of MAPK which can regulate nuclear transcription factors and consequently expression of several genes. Note that GPR18 seems to be coupled to G_i/o proteins, whereas GPR55 has been associated with an increase of intracellular Ca²⁺ via G_α12/13. In the case of TRPV1 channels (a non-selective cation channel for Ca²⁺, Mg²⁺, and Na⁺ ions), it is well-known that agonist can be used rationally for the treatment of pain considering that this channel under constant activation desensitizes the nociceptive neuron. Finally, although not fully investigated, cannabinoid compounds could also activate PPAR_α/δ, which are involved in pain modulation and transmission.