Accepted

Interactive virtual reality (iVR) has been widely used for treatment purposes in patients with chronic musculoskeletal disorders. However, no consensus has been reached on the effects of iVR on pain, psychological distress, and functional disability. Therefore, this study aims to investigate the effects of iVR on pain, psychological distress, and functional disability in patients with chronic musculoskeletal disorders compared with no rehabilitation and conventional rehabilitation. Five electronic databases (PubMed, Cochrane CENTRAL, Scopus, EMBASE, and Web of Science) were searched from January 2016 to December 2021. All randomized controlled trials using iVR for treating pain, psychological distress, and functional disability in patients with chronic musculoskeletal disorders were included. A subgroup analysis was conducted to compare the effects of nonimmersive and immersive types of iVR on the outcomes of interest. Our study provides good quality evidence that iVR reduced overall pain by 9.28 points as compared with no rehabilitation and by 8.09 points as compared with conventional rehabilitation. In the subgroup analysis, nonimmersive iVR showed a reduction in psychological distress (standardized mean differences = -0.35) as compared with no rehabilitation. However, no statistically significant difference in the outcomes existed between nonimmersive and immersive iVR. Furthermore, there were no statistically significant differences in the outcomes of functional disability. iVR is recommended for reducing pain intensity more than no rehabilitation or conventional rehabilitation. Meanwhile, nonimmersive iVR has been proposed for psychological distress improvement, with effects similar to those of conventional rehabilitation. However, iVR may not be an effective intervention in the case of functional disability.

Calcitonin gene-related peptide-targeted drugs have proven safe and effective for migraine prevention in large randomized-controlled, double-blind trials with an average duration of six months. Open-label studies may provide additional information on the long-term safety and efficacy of these substances.

To systemically review clinical studies investigating the role of prolactin and its receptors in headache and migraine.

One aim of the Back Pain Consortium (BACPAC) Research Program is to develop an integrated model of chronic low back pain that is informed by combined data from translational research and clinical trials. We describe efforts to maximize data harmonization and accessibility to facilitate Consortium-wide analyses.

There are indications that use of menopausal hormone therapy (MHT) and oral contraceptives (OC) increases the risk of low back pain (LBP), with higher oestrogen levels involved in the underlying mechanisms. The purpose of the present study was to investigate associations between use of systemic MHT or OC and risk of chronic LBP in a large population-based data set.

Piceatannol (PCN), a SIRT1 activator, regulates multiple oxidative stress mechanism and has anti-inflammatory potential in various inflammatory conditions. However, its role in Diabetic insulted peripheral neuropathy (DN) remains unknown. Oxidative stress and mitochondrial dysfunction are major contributing factors to DN. Myriad studies have proven that sirtuin1 (SIRT1) stimulation convalesce nerve functions by activating mitochondrial functions like mitochondrial biogenesis and mitophagy. Diabetic neuropathy (DN) was provoked by injecting streptozotocin (STZ) at a dose of 55 mg/kg, i.p to male Sprague Dawley (SD) rats. Mechanical, thermal hyperalgesia was evaluated by using water immersion, Vonfrey Aesthesiometer, and Randall Sellito Calipers. Motor, sensory nerve conduction velocity was measured using Power Lab 4sp system whereas The Laser Doppler system was used to evaluate nerve blood flow. To induce hyperglycemia for the in vitro investigations, high glucose (HG) (30 mM) conditions were applied to Neuro2a cells. At doses of 5 and 10 µM, PCN was examined for its role in SIRT1 and Nrf2 activation. HG-induced N2A cells, reactive oxygen exposure, mitochondrial superoxides and mitochondrial membrane potentials were restored by PCN exposure, and their neurite outgrowth was enhanced. Peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) directed mitochondrial biogenesis was induced by increased SIRT1 activation by piceatannol. SIRT1 activation also enhanced Nrf2-mediated antioxidant signalling. Our study results inferred that PCN administration can counteract the decline in mitochondrial function and antioxidant activity in diabetic rats and HG-exposed N2A cells by increasing the SIRT1 and Nrf2 activities.

Intervertebral disc degeneration (IVDD) mainly manifests as an imbalance between the synthesis and degradation of cellular and extracellular matrix (ECM) components. The cytokine interleukin (IL)-1β-induced inflammatory response of intervertebral discs causes ECM degradation. The aim of this study was to investigate the effects of a 970-nm diode laser therapy (DLT) on inflammatory cytokine IL-1β and ECM degradation proteinases in nucleus pulposus (NP) tissues in a puncture-induced rabbit IVDD model. Thirty-six New Zealand white rabbits were randomly divided into six groups: the normal group, IVDD group, laser group, sham laser group, IVDD + anisomycin (p38MAPK signaling pathway agonist), and laser + anisomycin group. Effects of laser on IVDD progression were detected using radiographic and magnetic resonance imaging. Hematoxylin and eosin, Alcian blue, safranin O-fast green staining, western blotting, and immunohistochemistry staining were performed for the histological analysis and molecular mechanism underlying protection against puncture-induced matrix degradation in NP tissues by DLT. DLT reduced the degree of disc degeneration in the gross anatomy of the disc and increased the T2-weighted signal intensity of NP. Inflammatory cytokine IL-1β levels in the disc were significantly reduced after DLT suppressed the matrix-degrading proteinases MMP13 and ADAMTS-5 and upregulated the protein expression of collagen II and aggrecan. Moreover, it inhibited the p38MAPK signaling pathway in NP tissues in a puncture-induced rabbit IVDD model. DLT reduced puncture-induced overexpression of inflammatory cytokines, mainly IL-1β, thus inhibiting matrix degeneration of NP tissues and ameliorating IVDD. This may be related to inhibition of the p38 MAPK signaling pathway.

Spinal cord injury (SCI) in humans frequently causes intractable chronic pain. Females are susceptible to worsened pain compared to males, and females may show higher pain prevalence after SCI. Despite this difference in clinical prevalence of SCI pain, few preclinical studies have systematically studied in rodents sex differences in SCI-elicited pain-related behaviors. Here, we leverage data from a large cohort of mice to test whether contusion SCI consistently causes pain symptoms in mice, and to establish whether female (vs. male) mice display heightened hypersensitivity after SCI. Mechanical and heat sensory thresholds were assessed using the von Frey test and Hargreaves test, respectively. In an initial experiment, female mice receiving moderate 60 kDyn SCI or moderate-to-severe 75 kDyn SCI at T9 both exhibited mechanical and heat pain symptoms compared to sham controls. 75 kDyn SCI caused excess motor deficits that confounded defining pain sensitivity at acute times, so the moderate SCI force was used for subsequent experiments. Next, adult female and male C57BL6/J mice received sham surgery or T9 moderate contusion SCI. Comparing female to male mice after SCI, we reveal that mice of both sexes displayed mechanical and heat hypersensitivity compared to sham controls, from acute-to-chronic post-injury times. Females had amplified SCI-elicited hypersensitivity compared to males. Our data suggest that thoracic contusion SCI elicits consistent and persistent pain-associated symptoms, which are more intense in female vs. male mice. These results have important implications for uncovering sex-specific mechanisms and therapeutic targets to ameliorate neuropathic pain after SCI.

Neuropathic pain is associated with abnormal sensations and/or pain induced by non-painful stimuli, i.e., allodynia causing burning or cold sensation, pinching of pins and needles like feeling, numbness, aching or itching. However, no suitable therapy exists to treat these pain syndromes. Our laboratory explored novel potential therapeutic strategies using a suitable composition of neurotrophic factors and active peptide fragments-Cerebrolysin (Ever Neuro Pharma, Austria) in alleviating neuropathic pain induced spinal cord pathology in a rat model. Neuropathic pain was produced by constrictions of L-5 spinal sensory nerves for 2-10 weeks period. In one group of rats cerebrolysin (2.5 or 5 ml/kg, i.v.) was administered once daily after 2 weeks until sacrifice (4, 8 and 10 weeks). Ag, Cu and Al NPs (50 mg/kg, i.p.) were delivered once daily for 1 week. Pain assessment using mechanical (Von Frey) or thermal (Hot-Plate) nociceptive showed hyperalgesia from 2 weeks until 10 weeks progressively that was exacerbated following Ag, Cu and Al NPs intoxication in nerve lesioned groups. Leakage of Evans blue and radioiodine across the blood-spinal cord barrier (BSCB) is seen from 4 to 10 weeks in the rostral and caudal cord segments associated with edema formation and cell injury. Immunohistochemistry of albumin and GFAP exhibited a close parallelism with BSCB leakage that was aggravated by NPs following nerve lesion. Light microscopy using Nissl stain exhibited profound neuronal damages in the cord. Transmission electron microcopy (TEM) show myelin vesiculation and synaptic damages in the cord that were exacerbated following NPs intoxication. Using ELISA spinal tissue exhibited increased albumin, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and heat shock protein (HSP 72kD) upregulation together with cytokines TNF-α, IL-4, IL-6, IL-10 levels in nerve lesion that was exacerbated following NPs intoxication. Cerebrolysin treatment significantly reduced hyperalgesia and attenuated BSCB disruption, edema formation and cellular changes in nerve lesioned group. The levels of cytokines were also restored near normal levels with cerebrolysin treatment. Albumin, GFAP, MABP and HSP were also reduced in cerebrolysin treated group and thwarted neuronal damages, myelin vesiculation and cell injuries. These neuroprotective effects of cerebrolysin with higher doses were also effective in nerve lesioned rats with NPs intoxication. These observations suggest that cerebrolysin actively protects spinal cord pathology and hyperalgesia following nerve lesion and its exacerbation with metal NPs, not reported earlier.

Aging is a risk factor for several debilitating conditions including those related to chronic back pain and intervertebral disc degeneration, both of which have no cure. Mouse models are useful tools for studying disc degeneration and chronic back pain in a tightly controlled and clinically relevant aging environment. Moreover, mice offer the advantage of carrying out longitudinal studies to understand the etiology and progression of disc pathology induced by genetic or surgical strategies. Previously, age-related behavioral trends of discomfort and enhanced nociception in mice were reported; however, whether these measures are mediated by structural and pathological changes in the disc is unknown.