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Pain impacts the lives of billions of people around the world – both directly and indirectly. It is complex and transcends beyond an unpleasant sensory experience to encompass emotional experiences. To date, there are no successful treatments for sufferers of chronic pain. Although opioids do not provide any benefit to chronic pain sufferers, they are still prescribed, often resulting in more complications such as hyperalgesia and dependence. In order to develop effective and safe medications to manage, and perhaps even treat pain, it is important to evaluate novel contributors to pain pathologies. As such, in this chapter we review the role of Toll-like receptor 4, a receptor of the innate immune system, that continues to gain substantial attention in the field of pain research. Positioned in the nexus of the neuro and immune systems, TLR4 may provide one of the missing pieces in understanding the complexities of pain. Here we consider how TLR4 enables a mechanistical understanding of pain as a multidimensional biopsychosocial state from molecules to cells to systems and back again.
Learn More >Opioid receptor agonists are effective analgesic agents. Central activation of the mu and/or kappa opioid receptors (KOR) is associated with CNS side effects, which limits their effectiveness. Recent studies indicated that peripherally restricted, selective KOR agonists were potent analgesics and devoid of CNS-related side effects. To confirm this hypothesis, we designed a novel, potent, and peripherally restricted KOR-selective agonist, ZYKR1. The analgesic efficacy, brain penetration and safety of ZYKR1 were assessed in pre-clinical models. ZYKR1 showed KOR agonistic activity in the cAMP assay, with an EC of 0.061 nM and more than 10-fold selectivity over the mu and delta opioid receptors (EC > 10 μM). ZYKR1 was not found to bind mu, delta opioid, and NOP receptors in radioligand binding assays. ZYKR1 produced concentration-dependent inhibition of electrically evoked contractions in isolated mouse vas deferens with an IC of 1.6 nM. ZYKR1 showed peripheral restriction and potent analgesic efficacy in various in-vivo animal models (acetic acid induced visceral pain mouse model, ED: 0.025 mg/kg, IV; ovariohysterectomy induced postoperative pain rat model, ED: 0.023 mg/kg, IV; and C48/80 induced pruritus mouse model, ED: 0.063 mg/kg, IV). In addition, ZYKR1 was devoid of motor coordination, physical dependence, dysphoria, and respiratory depression at 30, 400, 10 and 10-fold of efficacy dose, respectively. In conclusion, ZYKR1 has potent antinociceptive action in visceral pain and pruritus with limited CNS side effects in preclinical models owing to its peripheral restriction.
Learn More >To evaluate the efficacy of high-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex as a migraine prevention by conducting a systematic review and meta-analysis.
Learn More >Gout is a prevalent and painful inflammatory arthritis, and its global burden continues to rise. Intense pain induced by gout attacks is a major complication of gout.However, systematic studies of gout inflammation and pain are lacking. Using a monosodium urate (MSU) crystal-induced gout model, we performed genome-wide transcriptome analysis of the inflamed ankle joint, dorsal root ganglion (DRG), and spinal cord of gouty mice. Our results revealed important transcriptional changes, including highly elevated inflammation and broad activation of immune pathways in both the joint and the nervous system, in gouty mice. Integrated analysis showed that there was a remarkable overlap between our RNAseq and human genome-wide association study (GWAS) of gout; for example, the risk gene, stanniocalcin-1 (STC1) showed significant upregulation in all three tissues. Interestingly, when compared to the transcriptomes of human osteoarthritis (OA) and rheumatoid arthritis (RA) joint tissues, we identified significant upregulation of cAMP/cyclic nucleotide-mediated signaling shared between gouty mice and human OA with high knee pain, which may provide excellent drug targets to relieve gout pain. Furthermore, we investigated the common and distinct transcriptomic features of gouty, inflammatory pain, and neuropathic pain mouse models in their DRG and spinal cord tissues. Moreover, we discovered distinct sets of genes with significant differential alternative splicing or differential transcript usage (DTU) in each tissue, which were largely not detected by conventional differential gene expression analysis approaches. Based on these results, our study provided a more accurate and comprehensive depiction of transcriptomic alterations related to gout inflammation and pain.
Learn More >Neuropathic pain (NP) is difficult to treat due to the heterogeneity of causes, symptoms and underlying mechanisms. It constitutes a great medical need that is not covered, and has a high number of therapeutic failures in recent randomized clinical trials.
Learn More >Migraine is a major neurological disorder affecting one in nine adults worldwide with a significant impact on health care and socioeconomic systems. Migraine is more prevalent in women than in men, with 17% of all women meeting the diagnostic criteria for migraine. In women, the frequency of migraine attacks shows variations over the menstrual cycle and pregnancy, and the use of combined hormonal contraception (CHC) or hormone replacement therapy (HRT) can unveil or modify migraine disease. In the general population, 18-25% of female migraineurs display a menstrual association of their headache. Here we present an overview on the evidence supporting the role of reproductive hormones, in particular estrogens, in the pathophysiology of migraine. We also analyze the efficacy and safety of prescribing exogenous estrogens as a potential treatment for menstrual-related migraine. Finally, we point to controversial issues and future research areas in the field of reproductive hormones and migraine.
Learn More >Bibliometric analyses assess the impact and influence of articles in the academic community. There is no previous work which used bibliometric analysis on microvascular decompression (MVD). This study aims to identify and characterize the current 100 most cited articles on MVD.
Learn More >Silent myocardial infarction (MI) is critical for clinical practice with increasing risk for women and the cause remains a medical mystery. Upon the discovery of female-specific Ah-type baroreceptor neurons (BRNs), we hypothesize that glutamate mediates depressor response through afferent-specific expression of particular glutamate receptors (mGluRs) leading descending inhibition of cardiac nociception. In vivo, tail-flick reflex and electromyography were assessed to evaluate glutamate-mediated blood pressure regulation, peripheral and cardiac nociception. The results showed that glutamate decreased mean arterial pressure (MAP) and increased peripheral nociception. Interestingly, glutamate-mediated capsaicin-induced cardiac nociception was strongly reduced in female rats compared with males. Furthermore, Nodose (NG) microinjection of mGluR7 agonist significantly increased MAP in males and slightly decreased that in females. Even though mGluR8 direct activation intensified baroreceptor activation, the sensitivity was similar between sexes. In vitro, the expression profiles of mGluRs were investigated using Western blot and identified BRNs using single-cell qRT-PCR under ischemic conditions. Glutamate in serum, NG and nucleus tractus solitary (NTS) was raised significantly in the model rats of both sexes vs. sham-controls. Female-specific expression of mGluR7 in the baroreflex afferent pathway, especially higher expression in Ah-type BRNs, contributes significantly to cardiac analgesia, which may explain that the pathogenesis of silent MI occurs mainly in female patients. Therefore, higher expression of mGluR7 in female-specific subpopulation of Ah-type baroreceptor neurons plays a critical role in cardiac analgesia and peripheral nociception.
Learn More >A physician confronts an elusive physical phenomenon.
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