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Oxaliplatin (OXA) is a third-generation platinum compound with clinical activity in multiple solid tumors. Due to the repetition of chemotherapy cycle, OXA-induced chronic neuropathy presenting as paresthesia and pain. This study explored the neuropathy of chemotherapy pain and investigated the analgesic effect of 2-bromopalmitate (2-BP) on the pain behavior of OXA-induced rats. The chemotherapy pain rat model was established by the five consecutive administration of OXA (intraperitoneal, 4 mg/kg). After the establishment of OXA-induced rats, the pain behavior test, inflammatory signal analysis and mitochondrial function measurement were conducted. OXA-induced rats exhibited mechanical allodynia and spinal inflammatory infiltration. Our fluorescence and western blot analysis revealed spinal astrocytes were activated in OXA rats with up-regulation of astrocytic markers. In addition, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome mediated inflammatory signal cascade was also activated. Inflammation was triggered by dysfunctional mitochondria which represented by increase in cyclooxygenase-2 (COX-2) level and manganese superoxide dismutase (Mn-SOD) activity. Intrathecally injection of 2-BP significantly attenuated dynamin-related protein 1 (Drp1) mediated mitochondrial fission, recovered mitochondrial function, suppressed NLRP3 inflammasome cascade, and consequently decreased mechanical pain sensitivity. For cell research, 2-BP treatment significantly reversed tumor necrosis factor-α (TNF-α) induced mitochondria membrane potential deficiency and high reactive oxygen species (ROS) level. These findings indicate 2-BP decreases spinal inflammation and relieves OXA-induced neuropathic pain via reducing Drp1-mediated mitochondrial dysfunction.
Learn More >Toll like receptor 9 (TLR9) is a critical sensor for danger-associated molecular patterns (DAMPs) and a crucial marker of non-sterile/sterile inflammation among all TLRs. However, the significance of TLR9 in inflammatory pain remains unclear. Here, we subcutaneously injected Complete Freund's adjuvant (CFA) into the plantar surface of the hind paw, to established a mouse model of inflammatory pain, and we examined expression and distribution of TLR9 in this model. There was a significant increase of TLR9 mRNA and reduction of mechanical paw withdrawal threshold in mice intraplantar injected with CFA. By contrast, mechanical paw withdrawal threshold significantly increased in mice treated with TLR9 antagonist ODN2088. Furthermore, TLR9 is found predominantly distributed in the neurons by immunofluorescence experiment. Accordingly, neuronal TLR9 downregulation in the spinal cord prevented CFA-induced persistent hyperalgesia. Overall, these findings indicate that neuronal TLR9 in the spinal cord is closely related to CFA-induced inflammatory pain. It provides a potential treatment option for CFA-induced inflammatory pain by applying TLR9 antagonist.
Learn More >Murine ulcerative dermatitis (UD) is a common, multifactorial skin disease of C57BL/6 and C57BL/6-background strains of mice. Many treatment options have been previously reported but have been variably successful and may interfere with specific research studies. Janus kinase (JAK) inhibitors, such as oclacitinib, have been used to treat allergic dermatitis in humans, dogs, and other species. Additionally, topical oclacitinib was shown to improve an induced model of dermatitis in mice. We hypothesized that topical application of oclacitinib in conjunction with hind limb nail trimming would improve UD lesion scores more than our institutional standard treatment regime using meloxicam, topical antibiotic ointment, and nail trimming or nail trimming alone. To test this, mice with naturally occurring UD were recruited to the study and assigned to one of three treatment groups (n = 14/group): nail trim only; nail trim plus meloxicam and topical triple antibiotic ointment; or nail trim plus topical oclacitinib. UD was assessed on days 1, 7, and 14 for all treatment groups, and scored based on a previously published scoring system that quantitatively scored UD lesions based on pruritus, character of the lesion, size of lesion, and location of lesion. Here we found that mean UD scores decreased from day 1 to day 7 and from day 1 to day 14 for all treatment groups. However, there was no significant difference in mean UD score between the treatment groups at any timepoint. These data show that topical oclacitinib and nail trimming together improved UD lesion scores comparably to our institutional standard treatment and nail trimming alone. However, further studies may be warranted to investigate other potential applications of oclacitinib to treat UD.
Learn More >Vestibular Migraine (VM) is the most common cause of non-positional episodic vestibular symptoms. Patients with VM commonly report increased motion sensitivity, suggesting that vestibular responses to head movement may identify changes specific to VM patients. Here we explore whether the vestibulo-ocular reflex (VOR) gain alters in response to a clinical "headshake" maneuver in patients with VM. Thirty patients with VM in the inter-ictal phase, 16 patients with Benign Positional Paroxysmal Vertigo (BPPV) and 15 healthy controls were recruited. Patients responded to the question "Do you feel sick reading in the passenger seat of a car?" and completed a validated motion sickness questionnaire as a measure of motion sensitivity. Lateral canal vHIT testing was performed before and after headshaking; the change in VOR gain was calculated as the primary outcome. Baseline VOR gain was within normal limits across all participants. There was no significant change in VOR gain after headshaking in any group ( = 0.264). Patients were 4.3 times more likely to be in the VM group than in the BPPV group if they reported nausea when reading in the passenger seat of a car. We postulate that a headshake stimulus may be insufficient to disrupt cortical interactions and induce a change in VOR gain. Alternatively, changes in VOR gain may only be apparent in the acute phase of VM. Reading in the passenger seat of a car was considered uncomfortable in all VM patients suggesting that this specific question may be useful for the diagnosis of VM.
Learn More >Guidelines recommend patient education materials (PEMs) for low back pain (LBP), but no systematic review has assessed PEMs on their own. We investigated the effectiveness of PEMs on process, clinical, and health system outcomes for LBP and sciatica.
Learn More >Neuropathic pain, whose symptoms are characterized by spontaneous and irritation-induced painful sensations, is a condition that poses a global burden. Numerous neurotransmitters and other chemicals play a role in the emergence and maintenance of neuropathic pain, which is strongly correlated with common clinical challenges, such as chronic pain and depression. However, the mechanism underlying its occurrence and development has not yet been fully elucidated, thus rendering the use of traditional painkillers, such as non-steroidal anti-inflammatory medications and opioids, relatively ineffective in its treatment. Astrocytes, which are abundant and occupy the largest volume in the central nervous system, contribute to physiological and pathological situations. In recent years, an increasing number of researchers have claimed that astrocytes contribute indispensably to the occurrence and progression of neuropathic pain. The activation of reactive astrocytes involves a variety of signal transduction mechanisms and molecules. Signal molecules in cells, including intracellular kinases, channels, receptors, and transcription factors, tend to play a role in regulating post-injury pain once they exhibit pathological changes. In addition, astrocytes regulate neuropathic pain by releasing a series of mediators of different molecular weights, actively participating in the regulation of neurons and synapses, which are associated with the onset and general maintenance of neuropathic pain. This review summarizes the progress made in elucidating the mechanism underlying the involvement of astrocytes in neuropathic pain regulation.
Learn More >Individuals with fibromyalgia and obesity experience significant impairment in physical functioning. Pain catastrophizing, kinesiophobia, and pain acceptance have all been identified as important factors associated with the level of disability. The objective of this study was to evaluate the role of pain catastrophizing, kinesiophobia, and pain acceptance as mediators of the association between perceived pain severity and physical functioning in individuals with fibromyalgia and obesity.
Learn More >This study aimed to test for the possible antinociceptive effect of the naturally occurring terpene citral in rodent models of acute and chronic orofacial pain and to test for the possible involvement of transient receptor potential (TRP) channels in this effect. Acute nociceptive behavior was induced in one series of experiments by administering formalin, cinnamaldehyde, menthol or capsaicin to the upper lip. Nociceptive behavior was assessed by orofacial rubbing, and the effects of pre-treatment with citral (0.1, 0.3 or 1.0 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint or mustard oil injected into the masseter muscle, preceded by citral or vehicle (control) treatment. The chronic pain model involved infraorbital nerve transection (IONX) that induced mechanical hypersensitivity which was assessed by von Frey hair stimulation of the upper lip. Motor activity was also evaluated. Docking experiments were performed using TRPV1 and TRPM8 channels. Citral but not vehicle produced significant (p<0.01, ANOVA) antinociception on all the acute nociceptive behaviors, and these effects were attenuated by TRPV1 antagonist capsazepine, TRPM3 antagonist mefenamic acid and by TRPM8 desensitization, but not by ruthenium red and TRPA1 antagonist HC-030031. The IONX animals developed facial mechanical hypersensitivity that was significantly reduced by citral but not by vehicle. The docking experiments revealed that citral may interact with TRPV1 and TRPM8 channels. These results indicate the potential use of citral as an inhibitor of orofacial nociception in both acute and chronic pain states through TRPV1, TRPM3 and TRPM8 channels. See also Figure 1(Fig. 1).
Learn More >The mechanisms underlying chronic postsurgical pain after joint replacement (JR) are complex, and it has been suggested that chronic postsurgical pain can develop as a result of inadequate acute pain management. Few studies have addressed acute pain after JR using specific animal models. This study aimed to develop a novel JR model focused on postsurgical pain assessment and the time course of pain recovery.
Learn More >Vitamin D is an essential, fat soluble micronutrient long-known for its effects on calcium homeostasis and bone health. With advances in technology, it is being discovered that Vitamin D exerts its effects beyond the musculoskeletal system. Vitamin D has since been noted in nervous system health and functioning, and is becoming a target of interest in brain health, aging, and chronic pain outcomes.
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