The treatment of neuropathic pain remains a clinical challenge. Analgesic drugs and antidepressants are frequently ineffective, and opioids may induce side effects, including hyperalgesia. Recent results on brainstem pain modulatory circuits may explain those clinical challenges. The dual action of noradrenergic (NA) modulation was demonstrated in animal models of neuropathic pain. Besides the well-established antinociception due to spinal effects, the NA system may induce pronociception by directly acting on brainstem pain modulatory circuits, namely, at the locus coeruleus (LC) and medullary dorsal reticular nucleus (DRt). The serotoninergic system also has a dual action depending on the targeted spinal receptor, with an exacerbated activity of the excitatory 5-hydroxytryptamine 3 (5-HT3) receptors in neuropathic pain models. Opioids are involved in the modulation of descending modulatory circuits. During neuropathic pain, the opioidergic modulation of brainstem pain control areas is altered, with the release of enhanced local opioids along with reduced expression and desensitization of μ-opioid receptors (MOR). In the DRt, the installation of neuropathic pain increases the levels of enkephalins (ENKs) and induces desensitization of MOR, which may enhance descending facilitation (DF) from the DRt and impact the efficacy of exogenous opioids. On the whole, the data discussed in this review indicate the high plasticity of brainstem pain control circuits involving monoaminergic and opioidergic control. The data from studies of these neurochemical systems in neuropathic models indicate the importance of designing drugs that target multiple neurochemical systems, namely, maximizing the antinociceptive effects of antidepressants that inhibit the reuptake of serotonin and noradrenaline and preventing desensitization and tolerance of MOR at the brainstem.

Chemotherapy-induced peripheral neuropathy (CIPN) is a problem during cancer treatment and for cancer survivors but the central mechanisms underlying CIPN remain understudied. This study aims to determine if CIPN is associated with alterations of noradrenergic modulation of nociceptive transmission at the spinal cord. CIPN was induced in male Wistar rats by paclitaxel injections. One month after CIPN induction, the behavioral effects of the administration of reboxetine (noradrenaline reuptake inhibitor), clonidine (agonist of α₂-adrenoreceptors; α_2–AR) and atipamezole (antagonist of α_2–AR) were evaluated using the von Frey and cold plate tests. Furthermore, we measured the expression of the noradrenaline biosynthetic enzyme dopamine-β-hydroxylase (DBH) and of α_2–AR in the spinal dorsal horn. Reboxetine and clonidine reversed the behavioral signs of CIPN whereas the opposite occurred with atipamezole. In the 3 pharmacological approaches, a higher effect was detected in mechanical allodynia, the pain modality which is under descending noradrenergic control. DBH expression was increased at the spinal dorsal horn of paclitaxel-injected animals. The enhanced noradrenergic inhibition during CIPN may represent an adaptation of the descending noradrenergic pain control system to the increased arrival of peripheral nociceptive input. A potentiation of the α_2–AR mediated antinociception at the spinal cord may represent a therapeutic opportunity to face CIPN.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common consequence of cancer treatment and pain is a frequent complaint of the patients. Paclitaxel, a cytostatic drug, generates a well-described peripheral nerve injury and neuroinflammation, which may be experimentally mimicked in animal models. We conducted a systematic review analyzing the experimental design, reporting and mechanisms underlying paclitaxel-induced neuropathy in the included studies to establish the perspectives of translation of the current literature in models of CIPN.Methods: We elected studies published in Pubmed and Scopus between 1 January 2018 and 3 December 2022.Results: According to a defined mesh of keywords searched, and after applying exclusion and inclusion criteria, 70 original studies were included and analyzed in detail. Most studies used male Sprague-Dawley rats to induce paclitaxel-induced neuropathy, used low doses of paclitaxel, and the analyzed studies mainly focused at 14-28 days of CIPN. Mechanical nociceptive tests were preferred in the behavioral evaluation. The mechanisms under study were mainly neuroinflammation of peripheral nerves. The overall methodological quality was considered moderate, and the risk of bias was unclear.Discussion: Despite the ample preclinical research in paclitaxel-induced neuropathy, this systematic review alerts to some flaws in the experimental design along with limitations in reporting, e.g., lack of representation of both sexes in experimental work and the lack of reporting of the ARRIVE guidelines. This may limit the reproducibility of preclinical studies in CIPN. In addition, the clinical features of CIPN should be considered when designing animal experiments, such as sex and age of the CIPN patients. In this way the experimental studies aiming to establish the mechanisms of CIPN may allow the development of new drugs to treat CIPN and translation in the research of CIPN could be improved.

The noradrenergic system is paramount for controlling pain and emotions. We aimed at understanding the descending noradrenergic modulatory mechanisms in joint inflammatory pain and its correlation with the diffuse noxious inhibitory controls (DNICs) and with the onset of anxiodepressive behaviours. In the complete Freund’s adjuvant rat model of Monoarthritis, nociceptive behaviors, DNICs, and anxiodepressive-like behaviors were evaluated. Spinal alpha2-adrenergic receptors (a2-AR), dopamine beta-hydroxylase (DBH), and noradrenaline were quantified concomitantly with a2-AR pharmacologic studies. The phosphorylated extracellular signal–regulated kinases 1 and 2 (pERK1/2) were quantified in the Locus coeruleus (LC), amygdala, and anterior cingulate cortex (ACC). DNIC was attenuated at 42 days of monoarthritis while present on days 7 and 28. On day 42, in contrast to day 28, noradrenaline was reduced and DBH labelling was increased. Moreover, spinal a2-AR were potentiated and no changes in a2-AR levels were observed. Additionally, at 42 days, the activation of ERKs1/2 was increased in the LC, ACC, and basolateral amygdala. This was accompanied by anxiety- and depressive-like behaviors, while at 28 days, only anxiety-like behaviors were observed. The data suggest DNIC is attenuated in prolonged chronic joint inflammatory pain, and this is accompanied by impairment of the descending noradrenergic modulation and anxiodepressive-like behaviors.