The molecular mechanisms of CB-mediated changes to the membrane voltage have also been studied in detail. Cannabinoids reduce calcium influx by blocking the activity of voltage-dependent N-, P/Q- and L-type calcium channels. In addition to acting on calcium channels, activation of Gi/o and Gs, the two most commonly coupled G-proteins to cannabinoid receptors, has been shown to modulate potassium channel activity.  Recent studies have found that CB activation specifically facilitates potassium ion flux through GIRKs, a family of potassium channels.  Immunohistochemistry experiments demonstrated that CB is co-localized with GIRK and Kv1.4 potassium channels, suggesting that these two may interact in physiological contexts.
In the central nervous system, CB receptors influence neuronal excitability, reducing the incoming synaptic input.
This mechanism, known as presynaptic inhibition, occurs when a postsynaptic neuron releases endocannabinoids in retrograde transmission, which then bind to cannabinoid receptors on the presynaptic terminal. CB receptors then reduce the amount of neurotransmitter released, so that subsequent excitation in the presynaptic neuron results in diminished effects on the postsynaptic neuron. It is likely that presynaptic inhibition uses many of the same ion channel mechanisms listed above, although recent evidence has shown that CB receptors can also regulate neurotransmitter release by a non-ion channel mechanism, i.e., through Gi/o-mediated inhibition of adenylyl cyclase and protein kinase A.
Direct effects of CB receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons.
A series of behavioral experiments demonstrated that NMDAR, an ionotropic glutamate receptor, and the metabotropic glutamate receptors (mGluRs) work in concert with CB to induce analgesia in mice, although the mechanism underlying this effect is unclear.