Pathophysiological concepts of restless legs syndrome (RLS) are based mainly on neuroimaging and on neurophysiological data. Furthermore treatment effects contribute essentially to the present understanding of the disease, unless the genetic progress expected in the near future will clarify substantially open issues. The concept agreed on assumes a dysfunction of the dopaminergic system, possibly on the level of striatal and/or spinal dopamine receptors, and the A11 neuron group localized in the hypothalamus as an integrated part of the system. These neurons modulate spinal excitability, alterations of which in turn affect sensory processing predominantly of leg afferents in brain stem structures. Neurophysiologically excitability alterations can be measured by a variety of methods such as determination of pain thresholds, H-reflex testing, and quantitative sensory testing.

Ibuprofen first came to market about 50 years ago and rapidly moved to over-thecounter (OTC) sales. In April 2019, the National Agency for the Safety of Medicines and Health Products (ANSM) of France issued a warning for NSAID uses by patients with infectious diseases based on an analysis of 20 years of real-world safety data on ibuprofen and ketoprofen. Nevertheless, ibuprofen remains a mainstay in the analgesic armamentarium and with numerous randomized clinical trials, head-to-head studies, and decades of clinical experience. The authors offer a review of the safety of ibuprofen and how it may differ from other NSAIDs. Ibuprofen is associated with certain well-known gastrointestinal adverse effects that are related to dose and patient population. Among nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen has a comparatively low risk of cardiovascular adverse effects. It has been associated with renal and hepatic adverse effects, which appear to depend on dose, concomitant medications, and patient population. The association of ibuprofen with infections is more complex in that it confers risk in some situations but benefits in others, the latter in cystic fibrosis. Emerging interest in the literature is providing evidence of the role of ibuprofen as a possible endocrine disrupter as well as its potential antiproliferative effects for cancer cells. Taken altogether, ibuprofen has a favorable safety profile and is an effective analgesic for many acute and chronic pain conditions, although it-like other NSAIDs-is not without risk. After 50 years, evidence is still emerging about ibuprofen and its unique safety profile among NSAIDs.

Iron deficiency has been described as a risk factor in secondary restless legs syndrome (RLS), although it has not been investigated whether iron deficiency induces sensory symptoms in RLS patients. In this study, we established a mouse model of iron deficiency by administering a purified iron-deficient (ID) diet (<8 mg/kg iron) or nonpurified standard diet [normal diet (ND)] (<179 mg/kg iron) to male C57Bl/6 mice from postnatal d 28 for 1, 4, or 15 wk. The level of iron deficiency was assessed by the plasma iron concentration. After varying durations of iron deficiency, both acute and chronic sensory components of pain were measured using hot-plate and formalin tests, which preferentially assess Adelta- and C-fibers, respectively. Based on hot-plate reaction time, ID mice had a lower acute pain threshold than the ND mice after 4 and 15 wk but not after 1 wk. In addition, ID mice had an increased chronic pain response compared with the ND mice only in the late phase of the formalin-test after 1, 4, and 15 wk of iron deficiency. This increased pain response was accompanied by an elevated expression of c-Fos immunoreactive cells at the ipsilateral dorsal horn, suggesting that iron deficiency indirectly increases cell activity at the spinal cord level. These results demonstrate that iron deficiency increases acute and chronic pain responses in mice and may cause similar alterations to the acute pain threshold and sensitivity to C-fiber-mediated chronic pain in ID RLS patients.

The Restless Legs Syndrome (RLS) is a heterogeneous disease. Symptomatic or secondary forms encompass iron deficiency, uremia, pregnancy, polyneuropathy, and other causes. The so-called idiopathic RLS syndrome preferentially affects patients with a younger onset before the age of 30. Here we summarize pathophysiological results along the anatomical route, beginning at the cortex and followed by the basal ganglia, thalamus, A11 neurones, substantia nigra, brainstem nuclei, and spinal cord. Genetic risk variants for RLS have recently been identified in two genes, one of them the homeobox gene MEIS1, known to be involved in embryonic development and variants in a second locus containing the genes encoding mitogen-activated protein kinase MAP2K5, and the transcription factor LBXCOR1. A third one, the BTBD9 gene with unknown function encodes a BTB(POZ) domain. Accordingly, new concepts on pathophysiology have to bridge conventional knowledge with possible consequences deriving from these findings. Furthermore, this may create a framework to help understand why dopamine, opioid, and some anticonvulsant therapies are effective in RLS patients.

Restless legs syndrome (RLS) is a common neurological disorder whose exact pathophysiological mechanism remains unclear despite the successful use of dopaminergic treatment and recent discovery of predisposing genetic factors. As iron deficiency has been associated with RLS for some patients and there is evidence for decreased spinal dopamine D 3 -receptor (D3R) signaling in RLS, we aimed at establishing whether D3R activity and iron deficiency share common pathways within the pathophysiology of RLS sensory and motor symptoms.Using a combined mouse model of iron deficiency and dopamine D 3 -receptor deficiency (D3RϪ/Ϫ), circadian motor symptoms were evaluated by continuous recording of spontaneous wheel running activity. Testing the acute and persistent pain responses with the hot-plate test and formalin test, respectively, assessed sensory symptoms.A 15 week iron-deficient (ID) diet alone increased acute and persistent pain responses as compared to control diet. As compared to C57BL/6 (WT), homozygous D3RϪ/Ϫ mice already exhibited elevated responses to acute and persistent pain stimuli, where the latter was further elevated by concurrent iron deficiency. ID changed the circadian activity pattern toward an increased running wheel usage before the resting period, which resembled the RLS symptom of restlessness before sleep. Interestingly, D3RϪ/Ϫ shifted this effect of iron deficiency to a time point 3-4 h earlier.The results confirm the ability of iron deficiency and D3RϪ/Ϫ to evoke sensory and motor symptoms in mice resembling those observed in RLS patients. Furthermore this study suggests an increase of ID-related sensory symptoms and modification of ID-related motor symptoms by D3RϪ/Ϫ.

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