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Complete Freund's adjuvant (CFA)-induced arthritis in rats is a common animal model for studying chronic inflammatory pain. However, modelling of the disease is associated with unnecessary pain and impaired animal wellbeing, particularly in the immediate post-induction phase. Few attempts have been made to counteract these adverse effects with analgesics. The present study investigated the effect of buprenorphine on animal welfare, pain-related behaviour and model-specific parameters during the disease progression in a rat model of CFA-induced monoarthritis. The aim was to reduce or eliminate unnecessary pain in this model, in order to improve animal welfare and to avoid suffering, without compromising the quality of the model. Twenty-four male Sprague Dawley rats were injected with 20 μl of CFA into the left tibio-tarsal joint to induce monoarthritis. Rats were treated with either buprenorphine or carprofen for 15 days during the disease development, and were compared to a saline-treated CFA-injected group or a negative control group. Measurements of welfare, pain-related behaviour and clinical model-specific parameters were collected. The study was terminated after 3 weeks, ending with a histopathologic analysis. Regardless of treatment, CFA-injected rats displayed mechanical hyperalgesia and developed severe histopathological changes associated with arthritis. However, no severe effects on general welfare were found at any time. Buprenorphine treatment reduced facial pain expression scores, improved mobility, stance and lameness scores and it did not supress the CFA-induced ankle swelling, contrary to carprofen. Although buprenorphine failed to demonstrate a robust analgesic effect on the mechanical hyperalgesia in this study, it did not interfere with the development of the intended pathology.
Learn More >Increasing evidence suggests that epigenetic mechanisms have great potential in the field of pain. The changes and roles of epigenetics of the spinal cord and dorsal root ganglia in the chronic pain process may provide broad insights for future pain management. Pro-inflammatory cytokines and chemokines released by microglia and astrocytes, as well as blood-derived macrophages, play critical roles in inducing and maintaining chronic pain, while histone modifications may play an important role in inflammatory metabolism. This review provides an overview of neuroinflammation and chronic pain, and we systematically discuss the regulation of neuroinflammation and histone modifications in the context of chronic pain. Specifically, we analyzed the role of epigenetics in alleviating or exacerbating chronic pain by modulating microglia, astrocytes, and the proinflammatory mediators they release. This review aimed to contribute to the discovery of new therapeutic targets for chronic pain.
Learn More >Osteoarthritis (OA) causes joint pain, stiffness, and dysfunction in middle-aged and older adults; however, its pathogenesis remains unclear. Circular RNAs (circRNAs) are differentially expressed in patients with OA and participate in a multigene, multitarget regulatory network. CircRNAs are involved in the development of OA through inflammatory responses, including proliferation, apoptosis, autophagy, differentiation, oxidative stress, and mechanical stress. Most circRNAs are used as intracellular miRNA sponges in chondrocytes, endplate chondrocytes, mesenchymal stem cells, synoviocytes, and macrophages to promote the progression of OA. However, a small portion of circRNAs participates in the pathogenesis of OA by intracellular mechanisms, such as protein binding, methylation, or intercellular exosome pathways. In this sense, circRNAs might serve as potential novel biomarkers and therapeutic targets for OA.
Learn More >Chronic inflammation in the urinary bladder is a potential risk factor for bladder dysfunction, including interstitial cystitis/bladder pain syndrome (IC/BPS). Although several studies have reported that activation of transient receptor potential vanilloid 4 (TRPV4) contributes to bladder pain and overactive bladder with a cardinal symptom of acute or chronic cystitis, others have reported its involvement in the protective response mediated by lipopolysaccharides (LPS) to secrete anti-inflammatory/pro-resolution cytokines. Therefore, we investigated the potential benefit of an intravesical TRPV4 agonist for painful bladder hypersensitivity in a rat model of LPS-induced cystitis and determined whether its effects modulate the LPS signal for inflammatory reaction, cytokine release, and macrophage phenotype change. Previously, we showed that repeated intravesical instillations of LPS induce long-lasting bladder inflammation, pain, and overactivity in rats. In the present study, concurrent instillation of the selective TRPV4 agonist GSK1016790A (GSK) with LPS into the rat bladder improved LPS-induced bladder inflammation and reduced the number of mast cells. Furthermore, co-instillation of GSK prevented an increase in bladder pain-related behavior and voiding frequency caused by LPS. Cytokine profiling showed that LPS-stimulated inflammatory events, such as the production and secretion of pro-inflammatory cytokines (CXCL1, CXCL5, CXCL9, CXCL10, CCL3, CCL5, CCL20, and CX3CL1), are suppressed by GSK. Furthermore, TRPV4 activation switched LPS-stimulated pro-inflammatory M1-type macrophages to anti-inflammatory M2-type macrophages. These results suggest that TRPV4 activation in the bladder negatively regulates the pro-inflammatory response induced by LPS and prevents bladder hypersensitivity. These TRPV4 functions may be promising therapeutic targets for refractory IC/BPS.
Learn More >The balance of ion concentrations inside and outside the cell is an essential homeostatic mechanism in neurons and serves as the basis for a variety of physiological activities. In the central nervous system, NKCC1 and KCC2, members of the SLC12 cation-chloride co-transporter (CCC) family, participate in physiological and pathophysiological processes by regulating intracellular and extracellular chloride ion concentrations, which can further regulate the GABAergic system. Over recent years, studies have shown that NKCC1 and KCC2 are essential for the maintenance of Cl homeostasis in neural cells. NKCC1 transports Cl into cells while KCC2 transports Cl out of cells, thereby regulating chloride balance and neuronal excitability. An imbalance of NKCC1 and KCC2 after spinal cord injury will disrupt CI homeostasis, resulting in the transformation of GABA neurons from an inhibitory state into an excitatory state, which subsequently alters the spinal cord neural network and leads to conditions such as spasticity and neuropathic pain, among others. Meanwhile, studies have shown that KCC2 is also an essential target for motor function reconstruction after spinal cord injury. This review mainly introduces the physiological structure and function of NKCC1 and KCC2 and discusses their pathophysiological roles after spinal cord injury.
Learn More >Cancer-induced bone pain (CIBP) is a moderate to severe pain and seriously affects patients' quality of life. Spinal cord plays critical roles in pain generation and maintenance. Identifying differentially expressed proteins (DEPs) in spinal cord is essential to elucidate the mechanisms of cancer pain.
Learn More >The POINT project aims to provide evidence to optimise chronic pain management, prevent adverse consequences of opioids, and improve chronic pain patients' pain relief, functional capacity, and quality of life. We describe the outline of the project and its work packages. More specifically, we describe a cohort of persons with chronic pain and a cohort of long-term opioid users identified from a national registry linkage.
Learn More >Central and peripheral nervous systems are all involved in type 2 diabetic polyneuropathy mechanisms, but such subclinical changes and associations remain unknown. This study aims to explore subclinical changes of the central and peripheral and unveil their association.
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