Rescue of Noradrenergic System as a Novel Pharmacological Strategy in the Treatment of Chronic Pain: Focus on Microglia Activation

Abstract

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.

Modulation of sensitization processes in the management of pain and the importance of descending pathways: a role for tapentadol?

“…The multifaceted interaction between glia and neurons depends on several factors, including glial cell types, location of the regulatory process (peripheral nerve, spinal cord or brain) and type of the pain. In particular, NA has a protective effect on pro-inflammatory glia activation [13].…”

“…According to this evidence , it has been proposed that the rescue of the noradrenergic system has a major clinical relevance in preventing the transition from acute to chronic pain [13].…”

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

“…We have recently suggested that microglia may represent a feasible target for early intervention in different neuroinflammatory conditions [32][33][34]. Importantly, melatonin was shown to inhibit microglial pro-inflammatory polarization in hypoxic conditions in animal models [35][36][37].…”

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

“…Tramadol ((1 RS ,2 RS )-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol) and tapentadol (3-[(1 R ,2 R )-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol) are fully synthetic analgesic opioids that synergistically combine mu-opioid receptor (MOR) agonism with monoamine reuptake inhibition, justifying their classification as “atypical opioids” [ 1 , 2 , 11 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Such dual mechanism of action optimizes analgesia and minimizes opioid-typical side effects, such as drowsiness, nausea, vomiting, constipation, motor incoordination and respiratory depression [ 1 , 2 , 11 , 19 , 27 ], explaining their indications for the treatment of post-surgical, musculoskeletal, inflammatory, cancer and neuropathic pain, as well as mixed pain states [ 1 , 19 , 27 , 28 , 29 , 30 , 31 , 32 ]. Also, owing to the synergistic combination of their mechanisms of action, these opioids allow the dose administered to be reduced without compromising analgesic efficacy, thus reducing the potential for abuse and addiction [ 11 , 33 ].…”