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| Molecular marker | Depression | Pain |
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| Glutamate | (i) Reduced GluA1-containing AMPA receptors in amygdala, PFC, and hippocampus
(ii) Reduced GluA2-containing AMPA receptors in NAc
(iii) Ketamine’s antidepressant actions likely include increases in AMPA receptor signaling | (i) AMPA receptor upregulation in RVM mediates analgesia; AMPA receptor downregulation in RVM causes hyperalgesia
(ii) Reduced VGLUT1 and 3 levels in NAc
(iii) Reduced GluA2-containing AMPA receptors in NAc
(iv) Ketamine’s analgesic actions likely due to NMDA antagonism |
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| Norepinephrine | Decreased signaling in LC | Activation of RVM and PAG causes norepinephrine release and antinociception |
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| Dopamine | Decreased signaling in VTA and NAc | Decreased signaling in the NAc |
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| Serotonin | Altered signaling in PFC, ACC, VTA, and NAc | Can both inhibit and facilitate pain by projection to off and on cells in the RVM |
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| BDNF | Decreased serum levels | (i) Elevated serum levels in fibromyalgia
(ii) Decreased serum levels in migraine |
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| Endocannabinoids | CB1 knockout mice display depressive phenotype | (i) CB1 signaling in the RVM favors descending inhibition
(ii) CB1 signaling in the spinal dorsal horn decreases NMDA receptor activation |
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| CREB | (i) Increased activity in hippocampus has antidepressant effects
(ii) Signaling in NAc induces anhedonic behaviors | Signaling in the hippocampus, cortex, and NAc can alter pain sensitivity |
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| mTOR | Signaling in PFC underlies antidepressant effect of ketamine | Signaling in the hippocampus regulated pain-related synaptic plasticity |
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| Epigenetic | (i) Inhibition of HDACs and DNMTs in NAc has antidepressant effects
(ii) Activation of HMTs in NAc has antidepressant effects
(iii) Alterations of HDACs and DNMTs in cortex and hippocampus implicated in depressive behaviors | Changes in HDACs and DNMTs in hypothalamus, cortex, and brain stem can regulate sensory and affective pain behaviors |
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