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Bone Morphogenetic Protein-2/4 (BMP2/4) have been recognized as promoters of astrocyte activity. Substantial evidence suggests BMP2/4 may be elevated and play a critical role in astrocyte activation upon spinal cord injury. Although neuropathic pain (NP) is similarly associated with astrocyte activation, the participation of BMP2/4 in this regard still remains unclear. A rat model of NP achieved by spinal nerve ligation (SNL) at L5 was used to evaluate the expression of glial fibrillary acidic protein (GFAP) and BMP2/4 in the spinal cord in days 1, 4, 7, 10 and 14. Next, normal rats received intrathecal exogenous BMP2/4 and the antagonist Noggin to assess the effect of BMP2/4 on astrocyte activation. In both experiments, von Frey filaments were used to evaluate changes in paw withdrawal threshold (PWT). In addition, Western blotting and immunofluorescence were performed to assess the expression of glial fibrillary acidic protein (GFAP), BMP2/4, p-Smad 1/5/8, p-STAT3 in the spinal cord. Firstly, SNL caused a significant increase in the expression of BMP4, while BMP2 levels remained unchanged. Secondly, exogenous BMP4 but not BMP2 induced a significant decrease in PWT, along with upregulation of GFAP. Moreover, exogenous BMP4 stimulated both p-Smad 1/5/8 and p-STAT3, while BMP2 only upregulated p-Smad 1/5/8. Finally, exogenous Noggin alleviated the decrease in PWT induced by BMP4, and reduced astrocyte activation, as well as p-STAT3 upregulation. Our results indicate only BMP4-and not BMP2-intervened in allodynia in rats by eliciting glial activation, probably through both p-Smad 1/5/8 andp-STAT3 signaling.
Learn More >Canine studies of spontaneous osteoarthritis (OA) pain add valuable data supporting drug treatment mechanisms that may translate to humans. A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in client-owned dogs with moderate OA pain to evaluate efficacy of LYA, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES1), an EP4 antagonist (LYB), and carprofen, versus placebo. Of 255 dogs screened, 163 were randomized (placebo/LYA/LYB/carprofen: = 43/39/42/39) and 158 completed treatment. Efficacy versus placebo was assessed using Bayesian mixed-effect model for repeated measure analyses of the Canine Brief Pain Inventory (CBPI) pain interference score (PIS; primary endpoint), pain severity score, and overall impression, as well as the Liverpool Osteoarthritis in Dogs (LOAD) mobility score. The posterior probability that the difference to placebo was <0 at week 2 was 80% for LYA and 54% for LYB for CBPI PIS (both <95% predefined threshold). For secondary endpoints, the posterior probability that the difference to placebo was <0 at week 2 ranged from 89 to 96% for LYA and from 56 to 89% for LYB. The posterior probabilities comparing carprofen to placebo groups were ≥90% for all efficacy endpoints. The proportion of dogs with one or more adverse event was not significantly different from placebo (32.6%) for LYA (35.9%) or carprofen (25.6%), but the rate for LYB (59.5%) was higher versus placebo ( = 0.017). LYA treatment demonstrated consistent improvement in all efficacy measures, suggesting that inhibition of mPGES1 may be an effective treatment for chronic pain associated with OA.
Learn More >Pain assessment and treatment is challenging among persons with dementia (PWDs). To better understand reports of pain interference, we examined ratings made by PWDs, as well as corresponding ratings about PWDs, as reported by the caregiver. We aimed to assess alignment between and predictors of caregiver and PWD report of pain interference.
Learn More >Cancer-induced pain occurs frequently in patients when tumors or their metastases grow in the proximity of nerves. Although this cancer-induced pain states poses an important therapeutical problem, the underlying pathomechanisms are not understood. Here, we implanted adenocarcinoma, fibrosarcoma and melanoma tumor cells in proximity of the sciatic nerve. All three tumor types caused mechanical hypersensitivity, thermal hyposensitivity and neuronal damage. Surprisingly the onset of the hypersensitivity was independent of physical contact of the nerve with the tumors and did not depend on infiltration of cancer cells in the sciatic nerve. However, macrophages and dendritic cells appeared on the outside of the sciatic nerves with the onset of the hypersensitivity. At the same time point downregulation of perineural tight junction proteins was observed, which was later followed by the appearance of microlesions. Fitting to the changes in the epi-/perineurium, a dramatic decrease of triglycerides and acylcarnitines in the sciatic nerves as well as an altered localization and appearance of epineural adipocytes was seen. In summary, the data show an inflammation at the sciatic nerves as well as an increased perineural and epineural permeability. Thus, interventions aiming to suppress inflammatory processes at the sciatic nerve or preserving peri- and epineural integrity may present new approaches for the treatment of tumor-induced pain.
Learn More >GPR88 is an orphan G protein coupled receptor (GPCR) considered as a promising therapeutic target for neuropsychiatric disorders; its pharmacology, however, remains scarcely understood. Based on our previous report of increased delta opioid receptor activity in null mice, we investigated the impact of GPR88 co-expression on the signaling of opioid receptors and revealed that GPR88 inhibits the activation of both their G protein- and b-arrestin-dependent signaling pathways. In knockout mice, morphine-induced locomotor sensitization, withdrawal and supra-spinal analgesia were facilitated, consistent with a tonic inhibitory action of GPR88 on µOR signaling. We then explored GPR88 interactions with more striatal versus non-neuronal GPCRs, and revealed that GPR88 can decrease the G protein-dependent signaling of most receptors in close proximity, but impedes b-arrestin recruitment by all receptors tested. Our study unravels an unsuspected buffering role of GPR88 expression on GPCR signaling, with intriguing consequences for opioid and striatal functions.
Learn More >There are insufficient studies providing Minimal Clinically Important Difference (MCID) for outcomes related to temporomandibular disorders (TMD).
Learn More >Self-reported side effects of pain medication are important determinants of treatment course that can affect patient adherence, medication discontinuation and physician decisions. Yet, few studies have investigated patient-level predictors of self-reported pain medication side effects. The present study sought to fill this gap by exploring the impact of physical or sexual abuse history on self-reported pain medication side effects and considered a mediation model in which those effects are transmitted through a centralized pain phenotype and pain catastrophizing.
Learn More >There is a growing interest in non-pharmacological pain treatment options such as cupping. This meta-analysis aimed to assess the effectiveness and safety of cupping in chronic pain. PubMed, Cochrane Library, and Scopus were searched through November 2018 for randomized controlled trials on effects of cupping on pain intensity and disability in patients with chronic pain. Risk of bias was assessed using the Cochrane risk-of-bias tool. Of the 18 included trials (n=1,172), most were limited by clinical heterogeneity and risk of bias. Meta-analyses found large short-term effects of cupping on pain intensity compared to no treatment (standardized mean difference [SMD]=-1.03; 95% confidence interval [CI]=-1.41,-0.65), but no significant effects compared to sham cupping (SDM=-0.27; 95%CI=-0.58,0.05) or other active treatment (SMD=-0.24; 95%CI=-0.57,0.09). For disability, there were medium-sized short-term effects of cupping compared to no treatment (SMD=-0.66; 95%CI=-0.99,-0.34), and compared to other active treatments (SMD=-0.52; 95%CI=-1.03,-0.0028), but not compared to sham cupping (SMD=-0.26; 95%CI=-0.57, 0.05). Adverse events were more frequent among patients treated with cupping compared to no treatment; differences compared to sham cupping or other active treatment were not statistically significant. Cupping might be a treatment option for chronic pain, but the evidence is still limited by the clinical heterogeneity and risk of bias. Perspective: This article presents the results of a meta-analysis aimed to assess the effectiveness and safety of cupping with chronic pain. The results suggest that cupping might be a treatment option; however, the evidence is still limited due to methodical limitations of the included trials. High quality trials seem warranted.
Learn More >Mechanical allodynia is a cardinal sign of several inflammatory pain disorders where Nerve Growth Factor, a prototypic neurotrophin, plays a crucial role by binding to TrkA receptors. Here, we took the advantage of our generated knock-in mouse model expressing a chimeric TrkA/TrkC receptor that seems to not specifically develop mechanical allodynia following inflammation, to identify the TrkA downstream pathways involved in this phenomenon. We confirmed and extended that disrupting TrkA specific pathways leads to a specific deficit in mechanical hypersensitivity development following somatic (systemic NGF administration and paw incision) and to a lesser extent, visceral injuries. Despite a deficit in thin, mainly peptidergic, fibres innervation in TrkAC mice, thermal hyperalgesia development was not different from WT mice. Inflammatory reaction (oedema, IL-6 content), pain behaviours following intraplantar capsaicin as well as TRPV1 calcium imaging response of DRG neurons were similar between TrkAC and WT mice. This deficiency in mechanical allodynia development in TrkAC mice is likely due to the alteration of the expression of different TrkA transduction pathways (i.e. Akt, p38 MAPK and c-Jun) especially p38 MAPK, in the DRG cell bodies, ultimately leading to an alteration of at least, ASIC3 channel overexpression, known to participate in nociceptor mechanosensory function.
Learn More >We aimed to evaluate associations of human leukocyte antigen variants with migraine or headache in hospital and population-based settings.
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