Fig. 2

Mechanism of action: antidepressant drugs and modulation of neuroinflammation. a Antidepressants act by binding and inhibiting norepinephrine transporters at the pre-synaptic level, inhibiting the reuptake and therefore causing an increase in norepinephrine levels at the synaptic level. The persistence of norepinephrine in the synaptic cleft determines analgesia due to the presence of α-2-adrenergic receptors, which are coupled to an inhibitory G protein (Gi/o). Its activation determines the inhibition of the Ca 2+ voltage-dependent pre-synaptic channels and therefore inhibition of the release of excitatory neurotransmitters. At the same time, at post-synaptic level, K + channels are opened causing hyperpolarization of the cells and therefore reduction of excitability. This mechanism is of importance against allodynia and hyperalgesia associated with neuropathic pain. Moreover, antidepressants act as sodium channel blockers, inhibiting the ectopic discharges caused by nerve damage. b Amitriptyline plays an important role in the endogenous adenosine system to modulate neuropathic pain. Adenosine receptor A 3 AR is overexpressed in inflammatory cells, such as astrocytes, immune cells, and nociceptive neurons. The activation of A 3 AR by adenosine agonists may mediate antinociception through potentiation of inhibition of GABA, blocking NP. Therefore, amitriptyline is used both because it significantly reduces the expression of the mRNA of pro-inflammatory cytokines and because it determines the activation of the A 3 AR receptor, acting as an adenosine agonist and reducing the inflammatory response. c Nortriptyline has an important antiallodynic effect as it determines the recruitment of norepinephrine in the dorsal root ganglia. It acts on β2-adrenoceptors expressed by non-neuronal satellite cells, which are probably mTNFα-expressing satellite cells. Furthermore, both nortriptyline and venlafaxine inhibit the local production of TNF-α. Blocking TNF-α can relieve symptoms of NP. A, antidepressant drug; AR, adrenergic receptor; A 3 AR, adenosine receptor; Ca 2+ , calcium ion; Gi/o, inhibitory G protein; Na + , sodium ion; K + , potassium ion; POST, post-synaptic level; PRE, pre-synaptic level