Accepted

This systematic review and meta-analysis investigated the effect of phonophoresis when various gel types were used. Medline (using PubMed), EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were used to search for relevant studies from the date of their inception to June 28, 2021. We included studies that were randomized controlled trials (RCTs), included patients with a diagnosis of knee osteoarthritis, included treatment with either phonophoresis or therapeutic ultrasound with placebo gel, and reported clinical and functional outcomes. Continuous variables are expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Statistical analysis was performed using RevMan 5.3 software. We initially retrieved 2176 studies and finally analyzed nine RCTs including 423 patients. The intervention group significantly outperformed the control group in pain scores with NSAID gel (SMD = - 0.53, 95% CI [- 1.02, - 0.05], I = 73%) and in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) function score with corticosteroid gel (SMD = - 0.96, 95% CI [- 1.47, - 0.44], I = 20%). Phonophoresis alleviated pain and improved functional performance. Because of some limitations of this study, additional high-quality, large-scale RCTs are required to confirm the benefits.

The gut microbiota has been implicated in chronic pain disorders, including irritable bowel syndrome (IBS), yet specific pathophysiological mechanisms remain unclear. We showed that decreasing intake of fermentable carbohydrates improved abdominal pain in patients with IBS, and this was accompanied by changes in the gut microbiota and decreased urinary histamine concentrations. Here, we used germ-free mice colonized with fecal microbiota from patients with IBS to investigate the role of gut bacteria and the neuroactive mediator histamine in visceral hypersensitivity. Germ-free mice colonized with the fecal microbiota of patients with IBS who had high but not low urinary histamine developed visceral hyperalgesia and mast cell activation. When these mice were fed a diet with reduced fermentable carbohydrates, the animals showed a decrease in visceral hypersensitivity and mast cell accumulation in the colon. We observed that the fecal microbiota from patients with IBS with high but not low urinary histamine produced large amounts of histamine in vitro. We identified , carrying a histidine decarboxylase gene variant, as a major producer of this histamine. This bacterial strain was highly abundant in the fecal microbiota of three independent cohorts of patients with IBS compared with healthy individuals. Pharmacological blockade of the histamine 4 receptor in vivo inhibited visceral hypersensitivity and decreased mast cell accumulation in the colon of germ-free mice colonized with the high histamine-producing IBS fecal microbiota. These results suggest that therapeutic strategies directed against bacterial histamine could help treat visceral hyperalgesia in a subset of patients with IBS with chronic abdominal pain.

Repetitive transcranial magnetic stimulation (rTMS) could effectively relieve the pain and depression in neuropathic pain (NP) patients. However, the specific treatment parameters and exact mechanism are still unclear. Our purpose is to observe the effects of rTMS on pain and despair-like behavior in chronic constriction injury (CCI) rats and explore its possible mechanism. Thirty-two 8-week-old male Sprague-Dawley rats were randomly divided into 4 groups: sham operation group (S, n=8), CCI group (n=8), 1 Hz-rTMS group (n=8), and 10 Hz-rTMS group (n=8). The rTMS was applied to the left dorsal anterior agranular insular (AId) 1 week after the operation, once a day, 5 days/week for 4 consecutive weeks. Mechanical hyperalgesia, despair-like behaviors and sciatic nerve function were used to evaluate the effects of rTMS. Besides, glucose metabolism, the metabotropic glutamate receptors 5 (mGluR5), N-Methyl-D-Aspartic acid receptor type 2B (NMDAR2B), tumor necrosis factor-α (TNF-α), interleukin-6 (Ll-6), and interleukin-1β (Ll-1β) in AId were tested to explore the possible mechanism. Compared with 1 Hz-rTMS, the rats of 10 Hz-rTMS had higher the mechanical hyperalgesia, higher sugar preference and shorter swimming immobility time. Besides, the expressions of mGluR5, NMDAR2B, TNF-α, Ll-1β, and Ll-6 both in 1 Hz-rTMS and 10 Hz-rTMS groups were reduced compared to the CCI group; the 10 Hz-rTMS group had a more decrease than that of 1 Hz-rTMS. Furthermore, the [18]F-FDG uptake was lower than that in the 1 Hz-rTMS group. Compared with 1 Hz-rTMS, 10 Hz-rTMS could more effectively relieve mechanical hyperalgesia and reverse despair-like behavior in rats. The mechanism could be related to regulating mGluR5/NMDAR2B-related inflammatory signaling pathways in the AId.

Peripheral nerve injury-induced spinal microglial proliferation plays a pivotal role in neuropathic pain. So far, key intracellular druggable molecules involved in this process are not identified. The nuclear factor of activated T-cells (NFAT1) is a master regulator of immune cell proliferation. Whether and how NFAT1 modulates spinal microglial proliferation during neuropathic pain remain unknown. Here it is reported that NFAT1 is persistently upregulated in microglia after spinal nerve ligation (SNL), which is regulated by TET2-mediated DNA demethylation. Global or microglia-specific deletion of Nfat1 attenuates SNL-induced pain and decreases excitatory synaptic transmission of lamina II neurons. Furthermore, deletion of Nfat1 decreases microglial proliferation and the expression of multiple microglia-related genes, such as cytokines, transmembrane signaling receptors, and transcription factors. Particularly, SNL increases the binding of NFAT1 with the promoter of Itgam, Tnf, Il-1b, and c-Myc in the spinal cord. Microglia-specific overexpression of c-MYC induces pain hypersensitivity and microglial proliferation. Finally, inhibiting NFAT1 and c-MYC by intrathecal injection of inhibitor or siRNA alleviates SNL-induced neuropathic pain. Collectively, NFAT1 is a hub transcription factor that regulates microglial proliferation via c-MYC and guides the expression of the activated microglia genome. Thus, NFAT1 may be an effective target for treating neuropathic pain.

Pain has sensory and affective components. Unlike traditional, reflex-based pain assays, operant pain assays can produce more clinically relevant results by addressing the cognitive and motivational aspects of pain in rodents. This paper presents a protocol for assessing mechanical hypersensitivity following chronic constriction injury of the infraorbital nerves (CCI-ION) in rats using an orofacial operant pain system. Before CCI-ION surgery, rats were trained in an orofacial pain assessment device (OPAD) to drink sweetened condensed milk while making facial contact with the metal spiked bars and lick-tube. In this assay, rats can choose between receiving milk as a positive reinforcer or escaping an aversive mechanical stimulus that is produced by a vertical row of small pyramid-shaped spikes on each side of the reward access hole. Following 2 weeks of training in the OPAD and before the CCI-ION surgery, baseline mechanical sensitivity data were recorded for 5 days for each rat during a 10 min testing session. During a session, the operant system automatically records the number of reward bottle activations (licks) and facial contacts, contact duration, and latency to the first lick, among other measures. Following baseline measurements, rats underwent either CCI-ION or sham surgery. In this protocol, mechanical hypersensitivity was quantified by measuring the number of licks, latency to the first lick, the number of contacts, and the ratio of licks to facial contacts (L/F). The data showed that CCI-ION resulted in a significant decrease in the number of licks and the L/F ratio and an increase in the latency to the first lick, indicating mechanical hypersensitivity. These data support the use of operant-based pain assays to assess mechanical pain sensitivity in preclinical pain research.

Previous studies revealed inconsistent results regarding association between migraine and cognitive impairment. In addition, previous studies found inconsistent results regarding the association between migraine and risk of dementia. Thus, the study aimed to make a meta-analysis exploring comparison result in different types of cognitive function between migraine patients and non-migraine subjects. In addition, meta-analysis was made to explore the association between migraine and risk of dementia.

The aim of the study was to investigate whether MwoA and MwA are different manifestations of a single disease, distinct clinical entities, or located at two poles of a spectrum.