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Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
Learn More >Pain and its alleviation are currently a highly studied issue in human health. Research on pain and response to analgesia has evolved to include the effects of genetics, heritability, and sex as important components in both humans and animals. The laboratory mouse is the major animal studied in the field of pain and analgesia. Studying the inbred mouse to understand how genetic heritable traits and/or sex influence pain and analgesia has added valuable information to the complex nature of pain as a human disease. In the context of biomedical research, identifying pain and ensuring its control through analgesia in research animals remains one of the hallmark responsibilities of the research community. Advancements in both human and mouse genomic research shed light not only on the need to understand how both strain and sex affect the mouse pain response but also on how these research achievements can be used to improve the humane use of all research animal species. A better understanding of how strain and sex affect the response to pain may allow researchers to improve study design and thereby the reproducibility of animal research studies. The need to use both sexes, along with an improved understanding of how genetic heritability affects nociception and analgesic sensitivity, remains a key priority for pain researchers working with mice. This review summarizes the current literature on how strain and sex alter the response to pain and analgesia in the modern research mouse, and highlights the importance of both strain and sex selection in pain research.
Learn More >Surgery is often accompanied by scar formation, which results in a pathological state called fibrosis. Fibrosis is characterized by the excess depositionof extracellular matrix molecules in the connective tissue, leading to tissue contracture and chronic pain. To understand the molecular mechanisms underlying these processes and their causative relationships, we performed comprehensive analyses of gene expression changes in the hind paw tissue of a mouse model established by generating a scar in the sole. Subcutaneous tissue was extensively stripped from the sole of the operation group mice, while a needle was inserted in the sole of the sham group mice. Pain threshold, as evaluated by mechanical stimulation with von Frey fiber, decreased rapidly in the operated (ipsilateral) paw and a day later inthe non-operated (contralateral) paw. The reductions were maintained for more than 3 weeks, suggesting that chronic pain spread to the other tissues via the central nervous system. RNA from the paw and the dorsal root ganglion (L3-5) tissues were subjected to microarray analyses 1 and 2 weeks following the operation. The expressions of a number of genes, especially those coding for extracellular matrix molecules and peripheral perceptivenerve receptors, were altered in the operation group mice paw tissues. The expression of few genes was altered in the dorsal root ganglion tissues; distinct upregulation of some nociceptive genes such as cholecystokinin B receptor was observed. Results of real-time polymerase chain reaction, and immune and histochemical staining of some of the gene products confirmed the results of the microarray analysis. Analyses using a novel mouse model revealed the extensive involvement of extracellular matrix-related genes and peripheral perceptive nerve receptor genes resulting in scar formation with chronic pain. Future bioinformatics analyses will explore the association between these relationships.
Learn More >Chronic pain affects 1-3 million Canadian children and adolescents and their families. The primary objective of the Partnering For Pain project was to collaboratively identify the top 10 research priorities in pediatric chronic pain.
Learn More >Acute pain has an evolutionary role for the detection of and response to physical harm. In some cases, however, acute pain can impair function and lead to other morbidities. Chronic pain, meanwhile, can present as a psychopathological condition that significantly interferes with daily living. Most basic and translational pain research has focused on the molecular and cellular mechanisms in the spinal and peripheral nervous systems. In contrast, the brain plays a key role in the affective manifestation and cognitive control of pain. In particular, several cortical regions, such as the somatosensory cortex, prefrontal cortex, insular, and anterior cingulate cortex, are well-known to be activated by acute pain signals, and neurons in these regions have been demonstrated to undergo changes in response to chronic pain. Furthermore, these cortical regions can project to a number of forebrain and limbic structures to exert powerful top-down control of not only sensory pain transmission but also affective pain expression, and such cortical regulatory mechanisms are particularly relevant in chronic pain states. Newer techniques have emerged that allow detailed studies of central pain circuits in animal models, as well as how such circuits are modified by the presence of chronic pain and other predisposing psychosomatic factors. These mechanistic approaches can complement imaging in human studies. At the therapeutic level, a number of pharmacological and non-pharmacological interventions have recently been shown to engage these top-down control systems to provide analgesia. In this review, we will discuss how pain signals reach important cortical regions, and how these regions in turn project to sub-cortical areas of the brain to exert profound modulation of the pain experience. In addition, we will discuss the clinical relevance of such top-down pain regulation mechanisms.
Learn More >To review the new drug class of calcitonin gene-related peptide antagonists (monoclonal antibodies) and their clinical relevance in migraine prophylaxis. A literature search was performed in PubMed (January 2009 to November 2019) using the terms (CGRP), , and for clinical trials and studies. Reports from human studies in English were evaluated for clinical evidence supporting pharmacology, efficacy, and adverse events. Initial pharmacokinetic and preclinical studies were excluded. In chronic and episodic migraine, prophylaxis with injections of monoclonal antibodies antagonizing CGRP reduced monthly migraine days with minimal clinically significant adverse events. In addition, there is evidence supporting efficacy in refractory migraine despite optimal prophylaxis. This is the first target-specific migraine prophylaxis treatment to show efficacy with minimal adverse effects. A higher drug cost is a barrier but is balanced by improved quality of life. Current therapies have limited efficacy and tolerability because of poor side effect profiles. CGRP antagonists represent a shift to more precise migraine treatments. Monoclonal antibodies inhibiting CGRP are effective in migraine prophylaxis with minimal adverse effects. Targeting CGRP is a novel clinical strategy in managing migraine.
Learn More >Complex regional pain syndrome (CRPS) results in chronic and excruciating pain in patients. Conventional therapies lack effectiveness, rendering it one of the most difficult to treat neurological conditions.. Electroacupuncture (EA) is an effective alternative therapy for pain relief. Here, we investigated whether EA exerts analgesic effect on a rat model of CRPS type-I (CRPS-I) and related mechanisms. The rat chronic postischemic pain (CPIP) model was established to mimic CRPS-I. 100Hz EA exerted robust and persistent antiallodynic effect on CPIP model compared with 2 Hz EA or sham EA. EA markedly suppressed the overexpression of CXCL12/CXCR4 in spinal cord dorsal horn (SCDH) of CPIP model, leading to substantial decrease in neuronal and glial cell activities in SCDH. Pharmacological blocking CXCR4 mimicked EA-induced antiallodynic effect and related cellular events in SCDH, whereas exogenous CXCL12 abolished EA's effect. CXCR4 signaling resulted in ERK activation in SCDH, contributing to mechanical allodynia of CPIP model rats, whereas EA markedly reduced ERK activation. Therefore, we demonstrated that EA interferes with CXCL12/CXCR4 signaling in SCDH and downstream ERK pathway to exert robust antiallodynic effect on an animal model of CRPS-I. Our work suggests that EA may be a potential therapeutic option for CRPS-I in clinic. PERSPECTIVE: Our work identified that EA exerts robust antiallodynic effect on an animal model of CRPS-I, via mechanisms involving inhibition of CXCL12/CXCR4 signaling. EA further attenuates downstream neuronal and glial cell activation and ERK pathway in SCDH. This work suggests that EA may be a potential therapeutic option for CRPS-I management in clinic.
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