(A) Descending pain inhibition from the PAG can be initiated by electrical stimulation or direct microinjection of opioids. Recent evidence also indicates a role for COX inhibitors in the PAG as well. Opioids and cannabinoids inhibit pain by enhancing the baseline firing rate of off-cells and eliminating the off-cell pause in response to nociceptive stimuli. Inhibition of on-cell activity may abolish enhanced pain states. The on-cells and off-cells might correlate with pain facilitatory (+) and inhibitory (–) neurons in the RVM, respectively. At the level of the spinal cord, opioids can inhibit transmitter release from primary afferent terminals as well as activity of pain transmission neurons. Norepinephrine (NE) release from spinopetal noradrenergic fibers from medullary sites also inhibits pain transmission. Tricyclic antidepressants (TCAs) and other norepinephrine reuptake inhibitors enhance the antinociceptive effect of opioids by increasing the availability of spinal norepinephrine (box). Areas labeled “i–iii” in the small diagram correspond with labeled details of the larger diagram. α₂A, α₂-adrenergic receptor; DRG, dorsal root ganglion; SNRI, serotonin/norepinephrine reuptake inhibitor; SP, substance P. (B) Mice deficient in dopamine β-hydroxylase that do not produce norepinephrine show a diminished antinociceptive effect of morphine compared with control animals, suggesting that the presence of norepinephrine, presumably released in the spinal cord, is required for the full expression of morphine antinociception. The dashed line represents the 50% effect, and the corresponding dose is the ED₅₀ (that is the dose producing a 50% effect). % MPE, percentage maximal possible effect. ***P < 0.001 compared with the control group. Error bars represent SEM. Copyright National Academy of Sciences, USA (151).