Different types of pain can evolve toward a chronic condition characterized by hyperalgesia and allodynia, with an abnormal response to normal or even innocuous stimuli, respectively.
A key role in endogenous analgesia is recognized to descending noradrenergic pathways that originate from the locus coeruleus and project to the dorsal horn of the spinal cord. Impairment of this system is associated with pain chronicization.
More recently, activation of glial cells, in particular microglia, toward a pro-inflammatory state has also been implicated in the transition from acute to chronic pain. Both α2- and β2-adrenergic receptors are expressed in microglia, and their activation leads to acquisition of an anti-inflammatory phenotype.
This review analyses in more detail the interconnection between descending noradrenergic system and neuroinflammation, focusing on drugs that, by rescuing the noradrenergic control, exert also an anti-inflammatory effect, ultimately leading to analgesia.
More specifically, the potential efficacy in the treatment of neuropathic pain of different drugs will be analyzed.
On one side, drugs acting as inhibitors of the reuptake of serotonin and noradrenaline, such as duloxetine and venlafaxine, and on the other, tapentadol, inhibitor of the reuptake of noradrenaline, and agonist of the µ-opioid receptor.
Introduction
Chronic pain, a disease entity with a major impact on healthcare costs, is characterized by hyperalgesia, an increased response to noxious thermal and mechanical stimuli, and allodynia, in which nociceptive responses occur to normally innocuous stimuli such as light touch (known as mechanical allodynia).
Pain of different origins including:
(i) inflammatory pain following tissue injury,
(ii) cancer pain, and
(iii) neuropathic pain following nerve, spinal cord or brain (e.g., stroke) injuries can become chronic.
Chronic “pathologic” pain results from a maladaptive functional and structural transformation process, sustained by mechanisms of peripheral and central sensitizations involving an altered neuronal activity.
In the present review, we will briefly examine two key elements in the pathophysiology of chronic pain, recently proven to be correlated, i.e., the noradrenergic system and neuroinflammation.
The Impairment of Noradrenergic System in the Transition From Acute to Chronic Pain
Descending monoaminergic inhibitory pathways project from the brain stem to the spinal cord and finely regulate pain threshold.
Activation of descending serotonergic pathways has been shown to play a central role in the analgesic effects of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin–noradrenaline reuptake inhibitors (SNRIs e.g., duloxetine and venlafaxine) in acute models of pain.
Activation of different serotonin receptors can in fact produce either pro-nociceptive effects (5-HT2A, 5-HT3 receptors) or anti-nociceptive effects (5-HT1A, 5-HT7 receptors).
Impairment of endogenous adrenergic analgesia is thought to be responsible for the transition from acute to chronic pain (Table 1).
Table 1
Impairment of descending noradrenergic system in neuropathic pain: evidence from animal models.
| Animal model |
Preclinical phenotype |
Reference |
| Spinal nerve ligation |
Enhanced stimulus-evoked and spontaneous firing reduced by clonidine |
Patel et al., 2018 |
| L5-L6 spinal nerve ligation |
Increased extracellular glutamate in the LC and impaired pain-evoked endogenous analgesia after nerve injury |
Kimura et al., 2015 |
| L5-L6 spinal nerve ligation |
Mechanical hypersensitivity reduced by α2-agonists |
Hayashida et al., 2008 |
| Streptozotocin-induced diabetic rats |
Mechanical allodynia and thermal hyperalgesia reduced by duloxetine |
Kinoshita et al., 2013 |
| Rats with tibial nerve transection |
Mechanical and cold allodynia and heat hypersensitivity, all increased by α2-antagonists |
Hughes et al., 2013 |
| Incisional pain model combined with DβH-saporin |
Selective degeneration of NA neurons with delayed recovery of mechanical hypersensitivity and increased spinal glial activation reduced by α2-agonists |
Arora et al., 2016 |
LC, locus coeruleus; DβH-saporin, dopamine β-hydroxylase conjugated to saporin; NA, noradrenaline.
Neuroinflammation and Microglial Activation in the Pathophysiology of Chronic Pain: A Protective Role for Noradrenaline
Neuroinflammation is characterized by infiltration of immune cells, glial activation, and production of inflammatory mediators in the peripheral and central nervous system (CNS), and it plays a central role in the pathophysiology of chronic pain.
Glial activation, involving both astrocytes and microglia, represents a common pathophysiological event in chronic pain, Alzheimer’s disease (AD), and also depression, although neurodegenerative disorders are characterized by significant neuronal loss
Microglia are the resident immune cells of the CNS, with a primary role in maintaining CNS homeostasis, but are rapidly activated in response to any subtle change in the surrounding microenvironment
Although microglia appear to drive neuroinflammatory mechanisms in pain chronicization, an important role in central sensitization and chronic pain is also played by spinal astrocytes
Noradrenaline is known to exert strong anti-inflammatory activity in the CNS and its endogenous neuroprotective role in chronic pain is likely linked to this action
Overall, the preclinical data here reported suggest that the selective deficiency of noradrenergic system impacts both at neuronal and glial levels.
According to this scenario, the rescue of the noradrenergic system might represent a novel pharmacological approach to prevent the transition from acute to chronic pain ( Figure 1 ).
Rescue of Noradrenergic System as a Novel Pharmacological Approach to Reduce Microglia Activation and Neuroinflammation in Chronic Pain
Preliminary evidence obtained with the SNRIs duloxetine and ammoxetine opens the path for future studies with analgesic drugs, such as tapentadol, which combines MOR activation and potentiation of noradrenergic system.
Inhibition of microglial activation has been recently identified as a new mechanism which strongly contributes to the analgesic effects of duloxetine
Different molecular mechanisms seem to contribute to the effect of duloxetine on microglia.
The novel SNRI ammoxetine inhibits microglia activation.
it can be hypothesized that drugs that are able to rescue the noradrenergic system, such as SNRIs and tapentadol, can exert their analgesic efficacy by inhibiting microglia activation, thereby preventing the transition from acute to chronic pain.
Tapentadol is the only approved centrally acting analgesic that was developed from the beginning to enhance analgesic efficacy by combining two specific synergistic mechanisms of analgesic action.
Recent studies demonstrate the clinical efficacy of tapentadol in a broad spectrum of acute and chronic pain conditions including post-surgical, musculoskeletal, and neuropathic pains.
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