Accepted

Hip and knee osteoarthritis (HKOA) is a chronic disease characterized by joint pain that leads to reduced physical function and health-related quality of life (HRQoL). At present, no cure is available. Clinical trials indicate that people with HKOA benefit from physical activity in several health-related outcomes. However, few studies have evaluated the long-term positive effect of regular physical activity. This study analyzed participants with HKOA from a nationwide population-based cohort (EpiDoC Cohort) to assess the impact of physical activity on patients' physical function and HRQoL over a long-term follow-up. The regular weekly frequency of intentional physical activity was self-reported as non-frequent (0 times/week), frequent (1-2 times/week), or very frequent (≥ 3 times/week). This study followed 1086 participants over a mean period of 4.7 ± 3.4 years, during which 6.3% and 14.9% of participants reported frequent and very frequent physical activity, respectively. Using linear mixed models, we found that frequent (β =  - 0.101 [- 0.187, - 0.016]; β = 0.039 [- 0.002, 0.080]) and very frequent physical activity (β =  - 0.061 [- 0.118, - 0.004]; β = 0.057 [0.029, 0.084]) were associated with improved physical function and HRQoL over time, respectively, when compared with non-frequent exercise, adjusting for years to baseline, sex, age, years of education, body mass index, multimorbidity, hospitalizations, clinical severity, and unmanageable pain levels. These findings raise awareness of the importance of maintaining exercise/physical activity long term to optimize HRQoL and physical function. Further studies must address barriers and facilitators to improve the adoption of regular physical activity among citizens with HKOA.

Tenoxicam (TX) is a non-steroidal anti-inflammatory agent that can be used to control pain in various ophthalmic lesions like cataracts, refractive surgery, and corneal abrasion. TX has a very slightly aqueous solubility of 0.072 mg/mL resulting in difficulty to be formulated in ophthalmic solutions. This study aims to improve TX solubility by converting it into its potassium salt to achieve a target of 10 mg/mL (1%w/v) concentration of TX in the desired aqueous medium for the formulation of aqueous ophthalmic solutions. The synthesized TX salt was characterized by different evaluation parameters such as solubility studies, H NMR, IR, and elemental analyses. Different TX potassium solutions were formulated at concentrations of 0.5% and 1% w/v using different viscosity-imparting agents. The prepared solutions were characterized for their physicochemical properties including visual inspection, pH, rheological, in vitro release, and kinetic behavior. Also, the formulations were biologically evaluated in vivo using male albino rabbits. The obtained results showed the successful synthesis of TX salt, as indicated by IR and NMR, and elemental analysis. The solubility study showed that the solubility of TX was improved hugely to 18 mg/mL (250-fold). In addition, the results showed that the prepared formulations showed acceptable physicochemical properties. The highest release rate was obtained with formula F1, which contains no viscosity-imparting agents. While as, the lowest release rate was obtained in the case of formula F9, composed of Pluronic F127 (12% w/v). The in vivo results showed that TX optimized ophthalmic solutions F8 and F9 inhibited the redness and edema in an extended or sustained manner.

Cross-talk between peripheral neurons and immune cells is important in pain sensation. We identified Snx25 as a pain-modulating gene in a transgenic mouse line with reduced pain sensitivity. Conditional deletion of Snx25 in monocytes and macrophages, but not in peripheral sensory neurons, in mice (Snx25 mice) reduced pain responses in both normal and neuropathic conditions. Bone marrow transplantation using Snx25 and wild-type mice indicated that macrophages modulated pain sensitivity. Expression of sorting nexin (SNX)25 in dermal macrophages enhanced expression of the neurotrophic factor NGF through the inhibition of ubiquitin-mediated degradation of Nrf2, a transcription factor that activates transcription of Ngf. As such, dermal macrophages set the threshold for pain sensitivity through the production and secretion of NGF into the dermis, and they may cooperate with dorsal root ganglion macrophages in pain perception.

Currently, chemotherapy-induced neuropathic pain (CINP) has limited effective treatment. The roles of Oxytocin (OXT) and the oxytocin receptor (OXTR) in central analgesia have been well documented. However, the expression and function of OXTR in the peripheral nervous system remain unclear. Here, we evaluated the peripheral antinociceptive profiles of OXTR in CINP.

Microglia, resident macrophages of the central nervous system (CNS), are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases including neuropathic pain. However, molecular mechanisms that govern the spinal neuro-immune axis in the setting of neuropathic pain remain incompletely understood. Here we show that genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Mechanistically, microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through releasing lipocalin-2. Our results suggest that microglial TRPV4 channels reside at the center of the neuro-immune axis in the spinal cord that transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a promising new target for the treatment of chronic pain.

The management of persistent postoperative pain still remains a clinical challenge currently. Although ropivacaine (RVC) is widely used for postoperative analgesia as a local anesthetic, the short half-life makes it difficult to achieve the desired duration of analgesia. Herein, a novel RVC sustained-release microspheres encapsulated by zeolite imidazole framework-8 (RVC@ZIF-8) was synthesized for the first time, which prolonged the sustained-release of RVC and decreased the resulting drug toxicity. RVC can continuously release in vitro for at least 96 h with high drug loading of 30.6% and RVC@ZIF-8 had excellent biocompatibility and low cytotoxicity. In sciatic nerve block model, the sensory block time of RVC@ZIF-8 was significantly prolonged compared with RVC, achieving more than 72 h post injection and no inflammation or lesion were found. Based on high drug loading, ideal sustained-release and superior biological safety, RVC@ZIF-8 will be a novel delivery material for local anesthetic with potential application.

To evaluate both incidence and prevalence of drugs used for chronic diseases in survivors of adult-onset gynaecological cancer.

Low back pain (LBP) is a common biopsychosocial health problem. Meditation may provide a complementary treatment option for LBP patients.

P2X3 receptors and group II metabotropic glutamate receptors (mGluRs) have been found to be expressed in primary sensory neurons. P2X3 receptors participate in a variety of pain processes, while the activation of mGluRs has an analgesic effect. However, it's still unclear whether there is a link between them in pain. Herein, we reported that the group II mGluR activation inhibited the electrophysiological activity of P2X3 receptors in rat dorsal root ganglia (DRG) neurons. Group II mGluR agonist LY354740 concentration-dependently decreased P2X3 receptor-mediated and α,β-methylene-ATP (α,β-meATP)-evoked inward currents in DRG neurons. LY354740 significantly suppressed the maximum response of P2X3 receptor to α,β-meATP, but did not change their affinity. Inhibition of ATP currents by LY354740 was blocked by the group II mGluR antagonist LY341495, also prevented by the intracellular dialysis of either the G protein inhibitor pertussis toxin, the cAMP analog 8-Br-cAMP, or the protein kinase A (PKA) inhibitor H-89. Moreover, LY354740 decreased α,β-meATP-induced membrane potential depolarization and action potential bursts in DRG neurons. Finally, intraplantar injection of LY354740 also relieved α,β-meATP-induced spontaneous nociceptive behaviors and mechanical allodynia in rats by activating peripheral group Ⅱ mGluRs. These results indicated that peripheral group II mGluR activation inhibited the functional activity of P2X3 receptors via a G protein and cAMP/PKA signaling pathway in rat DRG neurons, which revealed a novel mechanism underlying analgesic effects of peripheral group II mGluRs.

Systemic sclerosis is a rheumatoid disease best known for its fibrotic skin manifestations called scleroderma. Alternatively activated (M2-type) macrophages are normally involved in the resolution of inflammation and wound healing but also in fibrosing diseases such as scleroderma. TRPA1 is a non-selective cation channel, activation of which causes pain and neurogenic inflammation. In the present study, we investigated the role of TRPA1 in bleomycin-induced skin fibrosis mimicking scleroderma.