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Osteoarthritis (OA) is a chronic progressive, painful disease of synovial joints, characterized by cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovitis. It is now widely appreciated that the innate immune system, and in particular Toll-like receptors (TLRs), contributes to pathological changes in OA joint tissues. Furthermore, it is now also increasingly recognized that TLR signaling plays a key role in initiating and maintaining pain. Here, we reviewed the literature of the past 5 years with a focus on how TLRs may contribute to joint damage and pain in OA. We discuss biological effects of specific damage-associated molecular patterns (DAMPs) which act as TLR ligands in vitro, including direct effects on pain-sensing neurons. We then discuss the phenotype of transgenic mice that target TLR pathways, and provide evidence for a complex balance between pro- and anti-inflammatory signaling pathways activated by OA DAMPs. Finally, we summarize clinical evidence implicating TLRs in OA pathogenesis, including polymorphisms and surrogate markers of disease activity. Our review of the literature led us to propose a model where multi-directional crosstalk between connective tissue cells (chondrocytes, fibroblasts), innate immune cells, and sensory neurons in the affected joint may promote OA pathology and pain.
Learn More >The TRIUMPH study assessed the efficacy and safety of high-purity synthetic trans-capsaicin (CNTX-4975) in subjects with chronic osteoarthritis-associated moderate to severe knee pain.
Learn More >Patient and Disease Characteristics Associates With Sensory Testing Results in Chronic Pancreatitis.
Abdominal pain is the most common symptom in chronic pancreatitis and has extensive impact on patients' lives. Quantitative sensory testing (QST) provides information on sensitivity to pain and mechanisms which can help quantify pain and guide treatment. The aims of this study were (1) to explore sensitivity to pain in patients with chronic pancreatitis using QST, and (2) to associate patient- and disease characteristics with QST results.
Learn More >α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone involved in cutaneous pigmentation in atopic dermatitis (AD) with severe itching. α-MSH elicits itch-related responses in mice. We therefore investigated whether α-MSH was involved in itching in AD. In the skin of AD patients and mice with atopy-like dermatitis, α-MSH and the prohormone convertase 2, which is the key processing enzyme for the production of α-MSH, were distributed mainly in keratinocytes. In the skin of mice with dermatitis, α-MSH receptors (MC1R and MC5R) were expressed at the mRNA level and were distributed in the dermis. In the dorsal root ganglion (DRG) of mice with dermatitis, mRNAs encoding MC1 and MC3∼5 were also expressed. MC1R antagonist agouti-signaling protein inhibited spontaneous scratching in mice with dermatitis. In healthy mice, intradermal α-MSH elicited itch-associated responses, which were inhibited by TP thromboxane (TX) receptor antagonist ONO-3708. In mouse keratinocytes, α-MSH increased the production of TXA, which was inhibited by adenylyl cyclase inhibitor SQ-22536 and Ca chelator EGTA. In mouse keratinocytes treated with siRNA for MC1R and/or MC5R, α-MSH-induced TXA production was decreased. α-MSH increased intracellular Ca ion concentration in DRG neurons and keratinocytes. These results suggest that α-MSH is involved in itching during AD and may elicit itching through the direct action of primary afferents and TXA production by keratinocytes.
Learn More >The clinical utility of conventional intravenous opioids is limited by the occurrence of opioid-related adverse events (ORAEs). Oliceridine is a novel G protein-biased μ-opioid receptor agonist designed to provide analgesia with an improved safety and tolerability profile. This phase III, double-blind, randomized trial [APOLLO-2 (NCT02820324)] evaluated the efficacy and safety of oliceridine for acute pain following abdominoplasty.
Learn More >Neuropathic pain is frequently driven by ectopic impulse discharge (ectopia) generated in injured peripheral afferent neurons. Observations in the spinal nerve ligation (SNL) model in rats suggest that cell bodies in the dorsal root ganglion (DRG) contribute three times more to the ectopic barrage than the site of nerve injury (neuroma). The DRG is therefore a prime interventional target for pain control. Since DRG ectopia is selectively suppressed with lidocaine at concentrations too low to block axonal impulse propagation, we asked whether targeted delivery of dilute lidocaine to the L5 DRG can relieve L5 SNL-induced tactile allodynia without blocking normal sensation or motor function. Results showed that intraforaminal injection of 10 µL bolus doses of 0.2% lidocaine suppressed allodynia transiently, while sustained infusion over 2 weeks using osmotic minipumps suppressed it for nearly 2 weeks. Bolus injections of morphine or fentanyl were ineffective. Lidocaine applied to the cut spinal nerve end or the L4 DRG did not affect allodynia suggesting that discharge originating in the neuroma and in neighboring "uninjured" afferents makes at best a minor contribution. Spike electrogenesis in the DRG is apparently the primary driver of tactile allodynia in the SNL model of neuropathic pain and it can be controlled selectively by superfusing the relevant DRG(s) with non-blocking concentrations of lidocaine. This approach has potential clinical application in conditions such as postherpetic neuralgia and phantom limb pain in which one or only a few identifiable ganglia are implicated as pain drivers.
Learn More >The aim of this study was to investigate chronotype in migraine patients and possible influences on the clinical expression of the disease.
Learn More >In this clinical and neurophysiological study using a novel cold stimulator we aim at investigating whether cold evoked potentials may prove to be a reliable diagnostic tool to assess trigeminal small-fibre function.Using a novel device consisting of micro-Peltier elements, we recorded cold evoked potentials after stimulating the supraorbital and perioral regions and the hand dorsum in 15 healthy participants and in two patients with exemplary facial neuropathic pain conditions. We measured peripheral conduction velocity at the upper arm and studied the brain generators using source analysis. In healthy participants and patients, we also compared cold evoked potentials with laser evoked potentials.In the healthy participants, cold stimulation evoked reproducible scalp potentials, similar to those elicited by laser pulses, though with a latency of about 30 ms longer. The mean peripheral conduction velocity, estimated at the upper arm, was 12.7 m/s. The main waves of the scalp potentials originated from the anterior cingulate gyrus and were preceded by activity in the bilateral opercular regions and bilateral dorso-lateral frontal regions. Unlike laser stimulation, cold stimulation evoked scalp potential of similar amplitude across perioral, supraorbital and hand dorsum stimulation. In patients with facial neuropathic pain, cold evoked potential recording showed the selective damage of cold pathways providing complementary information to laser evoked potential recording.Our clinical and neurophysiological study shows that this new device provides reliable information on trigeminal small-fibres mediating cold sensation, and might be useful for investigating patients with facial neuropathic pain associated with a distinct damage of cold-mediating fibres.
Learn More >To investigate the specific effect of insomnia on neuropsychological functioning in patients with very complex chronic pain.
Learn More >Transient receptor potential (TRP) channels are a family of functionally diverse and widely expressed cation channels involved in a variety of cell signaling and sensory pathways. Research in the last two decades has not only shed light on the physiological roles of the 28 mammalian TRP channels, but also revealed the involvement of specific TRP channels in a plethora of inherited and acquired human diseases. Considering the historical successes of other types of ion channels as therapeutic drug targets, small molecules that target specific TRP channels hold promise as treatments for a variety of human conditions. In recent research, important new findings have highlighted the central role of TRP channels in chronic pain, lower urinary tract disorders, and type 2 diabetes, conditions with an unmet medical need. Here, we discuss how these advances support the development of TRP-channel-based pharmacotherapies as valuable alternatives to the current mainstays of treatment.
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