Figure 8.

Hypothetical mechanism to explain the modulation of neuropathic pain through CB₂ receptor activation. The release of IFN-γ by activated astrocytes and neurons plays an important role in the neuroinflammatory process leading to the development of neuropathic pain. IFN-γ promotes microglia activation by the induction of several inflammatory pathways, including an enhancement in iNOS and CCR2 activity. The activated microglia promote consolidation and progression of the neuropathic pain state. CB₂ receptors on microglial cells would control and limit the spreading of this neuroinflammatory process. Thus, the activity of CB₂ receptors in microglial cells would reduce the activation of these cells during neuropathic pain by regulating the expression of iNOS and CCR2. CB₂ receptors located in neurons could also participate in the neuropathic pain response by decreasing the production of IFN-γ. These inhibitory effects would restrict the activation of microglial cells and attenuate the development of neuropathic pain. In the absence of CB₂ receptors, IFN-γ would produce a more widespread activation of microglial cells, which would enhance the manifestations of neuropathic pain and would be responsible for the presence of a mirror image of pain in the contralateral side.