Neuropathic pain, antidepressant drugs, and inflammation: a narrative review

Abstract

Background: Neuropathic pain (NP) is a chronic and disabling condition, caused by a lesion or disease of the somatosensory nervous system, characterized by a systemic inflammatory state. Signs and associated symptoms are rarely recognized, and response to usual analgesic drugs is poor. Antidepressant drugs are first-line agents for the treatment of NP. This narrative review aims to summarize the role of antidepressant drugs in treating NP and their mechanism of action, focusing on the effects on inflammatory cytokines.

Main text: Peripheral nerve injury leads to a local inflammatory response and to the disruption of the blood-medullary barrier, allowing the influx of peripheral immune cells into the central nervous system. Antidepressants have antinociceptive effects because they recruit long-term neuronal plasticity. Amitriptyline modulates the inflammatory response due to the reduction of the mRNA of pro-inflammatory cytokines acting as an adenosine agonist and leading to the activation of the A₃AR receptor. Through toll-like receptors, local inflammation determines the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) that drives and stimulates the hyperflammation in NP. Nortriptyline has an important antiallodynic effect in NP as it determines the recruitment of norepinephrine in the dorsal root ganglia. By modulating the β2-adrenoreceptors expressed by non-neuronal satellite cells, it inhibits the local production of TNF-α and determines a reduction of NP symptoms. Following the administration of antidepressants, there is a reduction in the production of TNF-α in the brain which in turn transforms the function of the α2-adrenergic receptor from an inhibitor to an activator of the release of norepinephrine. This is important to prevent the development of chronic pain.

Conclusion: Inflammatory cytokines are the main players in a bidirectional communication between the central and peripheral nervous system and the immune system in NP. Antidepressants have an important role in NP. Further research should explore the interaction between neuroinflammation in NP, the effects of antidepressants and the clinical relevance of this interaction.

Keywords: Antidepressant drugs; Antidepressants; Cytokines; Neuroinflammation; Neuropathic pain; Pain.

Fig. 1

Diagnostic pathway for neuropathic pain. At first, a detailed medical history is useful to recognize signs and symptoms of NP. Timing of onset, location, and distribution of the pain and its possible association with trauma are analyzed. In addition, the quality of pain should be recorded using pain descriptors, i.e., shooting, burning, or aching. Pain intensity can be quantified using a numeric rating scale (NRS) or alternatively with the visual analogue scale. Afterwards, a physical examination is necessary to evaluate temperature sensation with warm and cold metal rollers, touch sensation with camel hairbrush, and pain sensation with pins. Subsequently, questionnaires are offered to patients to provide a good overview of the subjective perception and the psychosocial component of pain. The most used are the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), the Douleur Neuropathique en 4 Questions (DN4), their self-administered versions (S-LANSS and I-DN4 respectively), the PainDETECT, the Neuropathic Pain Symptom Inventory (NPSI), and the Neuropathic Pain Scale (NPS). Lastly, to establish the presence of lesions or diseases of the somatosensory system, diagnostic investigations are employed. These include quantitative sensory testing (QST), neurophysiological testing with laser/pain-related evoked potentials, skin biopsy, corneal confocal microscopy, and axon reflex tests. QST uses standardized mechanical and thermal stimuli to examine nociceptive and non-nociceptive afferent pathways in peripheral nerves and the central nervous system. Nerve conduction studies and the use of somatosensory evoked potentials are useful to demonstrate, localize, and quantify damage along peripheral or central sensory pathways. Among the neurophysiological techniques, the most used are the evoked potentials of nociceptive stimuli: they can be radiant or contact thermal stimuli, which selectively activate nociceptors, giving rise, respectively, to potentials evoked by laser and contact heat. In case of inconclusive electrophysiological tests or when small fiber pathology is suspected, skin biopsy may be used to confirm a somatosensory lesion. Skin biopsy is a minimally invasive procedure in which a few millimeters of skin containing intraepidermal C fibers are obtained, which are then stained immunohistochemically

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