Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcineurin may be involved in affecting nociceptive processes in multiple circumstances. It is conceivable that interfering with calcineurin's normal role in contributing to glial resting membrane potential, via its effects on the ion channel (TRESK) [tandem-pore-domain weakly inward rectifying potassium channels (TWIK)-related spinal cord potassium channels] may facilitate nociception. Another aspect of calcineurin function may be its role in the pronociceptive signaling of nuclear factor of activated T-cells (NFAT). NFAT activation via mediators (e.g. Substance P, brain-derived neurotrophic factor, nerve growth factor, bradykinin) appears to be dependent on calcineurin function. This calcineurin-regulated NFAT signaling may subsequently lead to transcription of pronociceptive genes as well as upregulation of pronociceptive chemokine receptors in the dorsal root ganglion. In fact, multiple articles have described the clinical use of calcineurin-inhibitors leading to pain, a phenomenon referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Thus, it appears that calcineurin functions may encompass actions which promote or dampen nociceptive processes. A greater understanding of the physiology of calcineurin, especially as it relates to modulating nociception may lead to the development of novel analgesic targets in attempts to optimally alleviate patient discomfort.
Pain Physician
PMID:Calcineurin as a nociceptor modulator. 1966 90

Chemokines and chemokine receptors are widely expressed in the nervous system, where they play roles in the regulation of stem cell migration, axonal path finding, and neurotransmission. Chemokine signaling is also of key importance in the regulation of neuroinflammatory responses. The expression of the chemokine monocyte chemoattractant protein 1 (MCP1) and its receptor (CCR2) is upregulated by dorsal root ganglia neurons in rodent models of neuropathic pain. MCP1 increases the excitability of nociceptive neurons after a peripheral nerve injury, and disruption of MCP1 signaling blocks the development of neuropathic pain. In the spinal cord, microglial cells expressing CCR2 are thought to play an active role in the initiation and maintenance of pain hypersensitivity, and MCP1 may also alter the excitability of spinal neurons in some cases. Other predominant sites of CCR2 activation are found in the peripheral nervous system, thereby explaining, at least in some circumstances, the rapid anti-nociceptive effects of peripherally administered CCR2 antagonists. In this article we discuss the relative roles of CCR2 activation in the peripheral and central nervous systems in relation to the phenomenon of neuropathic pain.
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PMID:Chemokine signaling and the management of neuropathic pain. 1972 Jul 51

Invasion and metastasis are key components of cancer progression. Inflammatory mediators, including cytokines and chemokines, can facilitate tumor dissemination. A distinct and largely forgotten path is perineural invasion (PNI), defined as the presence of cancer cells in the perinerium space. PNI is frequently used by many human carcinomas, in particular by pancreas and prostate cancer, and is associated with tumor recurrence and pain in advanced patients. Neurotrophic factors have been identified as molecular determinants of PNI. A role for chemokines in this process has been proposed; the chemokine CX3CL1/Fractalkine attracts receptor positive pancreatic tumor cells to disseminate along peripheral nerves. Better understanding of the neurotropism of malignant cells and of the clinical significance of PNI would help the design of innovative strategies for the control of tumor dissemination and pain in cancer patients.
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PMID:Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. 2006 Jul 68

Millions of people worldwide suffer from neuropathic pain as a result of damage to or dysfunction of the nervous system under various disease conditions. Development of effective therapeutic strategies requires a better understanding of molecular and cellular mechanisms underlying the pathogenesis of neuropathic pain. It has been increasingly recognized that spinal cord glial cells such as microglia and astrocytes play a critical role in the induction and maintenance of neuropathic pain by releasing powerful neuromodulators such as proinflammatory cytokines and chemokines. Recent evidence reveals chemokines as new players in pain control. In this article, we review evidence for chemokine modulation of pain via neuronal-glial interactions by focusing on the central role of two chemokines, CX3CL1 (fractalkine) and CCL2 (MCP-1), because they differentially regulate neuronal-glial interactions. Release of CX3CL1 from neurons is ideal to mediate neuronal-to-microglial signaling, since the sole receptor of this chemokine, CX3CR1, is expressed in spinal microglia and activation of the receptor leads to phosphorylation of p38 MAP kinase in microglia. Although CCL2 was implicated in neuronal-to-microglial signaling, a recent study shows a novel role of CCL2 in astroglial-to-neuronal signaling after nerve injury. In particular, CCL2 rapidly induces central sensitization by increasing the activity of NMDA receptors in dorsal horn neurons. Insights into the role of chemokines in neuronal-glial interactions after nerve injury will identify new targets for therapeutic intervention of neuropathic pain.
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PMID:Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. 2011 31

Glial cell line-derived neurotrophic factor (GDNF) is involved in inflammation and pain, roles which remain to be delineated clinically. We aimed to evaluate the role of central nervous and peripheral GDNF in long-term pain patients and in controls by analysing intrathecal and blood concentrations of GDNF. Simultaneous measurements of pro-inflammatory cytokines IL-1beta, TNF-alpha and IL-6, anti-inflammatory cytokine IL-10 and chemokine IL-8 served to define inflammatory responses. Generally, blood levels of GDNF were higher than corresponding intrathecal levels. Pain was associated with levels of GDNF that were increased intrathecally, but decreased in blood. IL-8 was uniformly higher in pain patients.
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PMID:Glial cell line-derived neurotrophic factor is increased in cerebrospinal fluid but decreased in blood during long-term pain. 2012 77

Chronic pain associated with inflammation is a common clinical problem, and the underlying mechanisms have only begun to be unraveled. GRK2 regulates cellular signaling by promoting G-protein-coupled receptor (GPCR) desensitization and direct interaction with downstream kinases including p38. The aim of this study was to determine the contribution of GRK2 to regulation of inflammatory pain and to unravel the underlying mechanism. GRK2(+/-) mice with an approximately 50% reduction in GRK2 developed increased and markedly prolonged thermal hyperalgesia and mechanical allodynia after carrageenan-induced paw inflammation or after intraplantar injection of the GPCR-binding chemokine CCL3. The effect of reduced GRK2 in specific cells was investigated using Cre-Lox technology. Carrageenan- or CCL3-induced hyperalgesia was increased but not prolonged in mice with decreased GRK2 only in Na(v)1.8 nociceptors. In vitro, reduced neuronal GRK2 enhanced CCL3-induced TRPV1 sensitization. In vivo, CCL3-induced acute hyperalgesia in GRK2(+/-) mice was mediated via TRPV1. Reduced GRK2 in microglia/monocytes only was required and sufficient to transform acute carrageenan- or CCL3-induced hyperalgesia into chronic hyperalgesia. Chronic hyperalgesia in GRK2(+/-) mice was associated with ongoing microglial activation and increased phospho-p38 and tumor necrosis factor alpha (TNF-alpha) in the spinal cord. Inhibition of spinal cord microglial, p38, or TNF-alpha activity by intrathecal administration of specific inhibitors reversed ongoing hyperalgesia in GRK2(+/-) mice. Microglia/macrophage GRK2 expression was reduced in the lumbar ipsilateral spinal cord during neuropathic pain, underlining the pathophysiological relevance of microglial GRK2. Thus, we identified completely novel cell-specific roles of GRK2 in regulating acute and chronic inflammatory hyperalgesia.
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PMID:GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain. 2014 41

Opioid-induced glial activation and its proinflammatory consequences have been associated with both reduced acute opioid analgesia and the enhanced development of tolerance, hyperalgesia and allodynia following chronic opioid administration. Intriguingly, recent evidence demonstrates that these effects can result independently from the activation of classical, stereoselective opioid receptors. Here, a structurally disparate range of opioids cause activation of signaling by the innate immune receptor toll like receptor 4 (TLR4), resulting in proinflammatory glial activation. In the present series of studies, we demonstrate that the (+)-isomers of methadone and morphine, which bind with negligible affinity to classical opioid receptors, induced upregulation of proinflammatory cytokine and chemokine production in rat isolated dorsal spinal cord. Chronic intrathecal (+)-methadone produced hyperalgesia and allodynia, which were associated with significantly increased spinal glial activation (TLR4 mRNA and protein) and the expression of multiple chemokines and cytokines. Statistical analysis suggests that a cluster of cytokines and chemokines may contribute to these nociceptive behavioral changes. Acute intrathecal (+)-methadone and (+)-morphine were also found to induce microglial, interleukin-1 and TLR4/myeloid differentiation factor-2 (MD-2) dependent enhancement of pain responsivity. In silico docking analysis demonstrated (+)-naloxone sensitive docking of (+)-methadone and (+)-morphine to human MD-2. Collectively, these data provide the first evidence of the pro-nociceptive consequences of small molecule xenobiotic activation of spinal TLR4 signaling independent of classical opioid receptor involvement.
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PMID:Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences. 2017 37

Cathepsin S has been of increasing interest as a target of medicinal chemistry efforts given its role in modulating antigen-presentation by major histocompatibility class II (MHC II) molecules as well as its involvement in extracellular proteolytic activities. Inhibition of the cathepsin S enzyme reduces degradation of the invariant chain, a crucial chaperon which also blocks peptide-binding by MHC II molecules, thereby decreasing antigen presentation to CD4(+) T-cells. Extracellular cathepsin S may also be involved in angiogenesis and initiation and/or maintenance of neuropathic pain by cleavage of the membrane-bound chemokine fractalkine (CX3CL1). Cathepsin S inhibitors have thus been suggested to hold potential as therapeutics for a variety of diseases. The initial development of cathepsin S inhibitors targeted irreversible, covalent inhibitors, but more recently the focus has been on reversible inhibitors, representing both covalent modifiers of the enzyme and, of late, noncovalent inhibitors. This review details advances in cathepsin S inhibitor design as reported in the primary literature since 2006, focusing especially on structure-activity relationships of the various covalent and noncovalent inhibitor series.
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PMID:Recent advances in the design of cathepsin S inhibitors. 2033 80

Cold therapy is commonly used as a procedure to relieve pain symptoms, particularly in inflammatory diseases, injuries and overuse symptoms. A peculiar form of cold therapy (or stimulation) was proposed 30 years ago for the treatment of rheumatic diseases. The therapy, called whole-body cryotherapy (WBC), consists of exposure to very cold air that is maintained at -110 degrees C to -140 degrees C in special temperature-controlled cryochambers, generally for 2 minutes. WBC is used to relieve pain and inflammatory symptoms caused by numerous disorders, particularly those associated with rheumatic conditions, and is recommended for the treatment of arthritis, fibromyalgia and ankylosing spondylitis. In sports medicine, WBC has gained wider acceptance as a method to improve recovery from muscle injury. Unfortunately, there are few papers concerning the application of the treatment on athletes. The study of possible enhancement of recovery from injuries and possible modification of physiological parameters, taking into consideration the limits imposed by antidoping rules, is crucial for athletes and sports physicians for judging the real benefits and/or limits of WBC. According to the available literature, WBC is not harmful or detrimental in healthy subjects. The treatment does not enhance bone marrow production and could reduce the sport-induced haemolysis. WBC induces oxidative stress, but at a low level. Repeated treatments are apparently not able to induce cumulative effects; on the contrary, adaptive changes on antioxidant status are elicited--the adaptation is evident where WBC precedes or accompanies intense training. WBC is not characterized by modifications of immunological markers and leukocytes, and it seems to not be harmful to the immunological system. The WBC effect is probably linked to the modifications of immunological molecules having paracrine effects, and not to systemic immunological functions. In fact, there is an increase in anti-inflammatory cytokine interleukin (IL)-10, and a decrease in proinflammatory cytokine IL-2 and chemokine IL-8. Moreover, the decrease in intercellular adhesion molecule-1 supported the anti-inflammatory response. Lysosomal membranes are stabilized by WBC, reducing potential negative effects on proteins of lysosomal enzymes. The cold stimulation shows positive effects on the muscular enzymes creatine kinase and lactate dehydrogenase, and it should be considered a procedure that facilitates athletes' recovery. Cardiac markers troponin I and high-sensitivity C-reactive protein, parameters linked to damage and necrosis of cardiac muscular tissue, but also to tissue repair, were unchanged, demonstrating that there was no damage, even minimal, in the heart during the treatment. N-Terminal pro B-type natriuretic peptide (NT-proBNP), a parameter linked to heart failure and ventricular power decrease, showed an increase, due to cold stress. However, the NT-proBNP concentrations observed after WBC were lower than those measured after a heavy training session, suggesting that the treatment limits the increase of the parameter that is typical of physical exercise. WBC did not stimulate the pituitary-adrenal cortex axis: the hormonal modifications are linked mainly to the body's adaptation to the stress, shown by an increase of noradrenaline (norepinephrine). We conclude that WBC is not harmful and does not induce general or specific negative effects in athletes. The treatment does not induce modifications of biochemical and haematological parameters, which could be suspected in athletes who may be cheating. The published data are generally not controversial, but further studies are necessary to confirm the present observations.
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PMID:Whole-body cryotherapy in athletes. 2052 15

The chemokine fractalkine (FKN) is a critical mediator of spinal neuronal-microglial communication in chronic pain. Mature FKN is enzymatically cleaved from neuronal membranes and activation of its receptor, CX3CR1, which is expressed by microglia, induces phosphorylation of p38 MAPK. We used CX3CR1 knockout (KO) mice to examine pain behaviour in the absence of FKN signalling. Naive CX3CR1 KO mice had normal responses to acute noxious stimuli. However, KO mice showed deficits in inflammatory and neuropathic nociceptive responses. After intraplantar zymosan, KO mice did not display thermal hyperalgesia, whereas mechanical allodynia developed fully. In the partial sciatic nerve ligation model of neuropathic pain, both mechanical allodynia and thermal hyperalgesia were less severe in KO mice than in wild-types (WT). Dorsal horn Iba1 immunostaining and phosphorylation of p38 MAPK increased after injury in WT controls but not in KO animals. In WT mice, inflammation and nerve injury increased spinal cord CX3CR1 and FKN expression. FKN protein was also increased in KO mice following inflammation but not after neuropathy, suggesting the FKN/CX3CR1 system is differently affected in the two pain models. Loss of FKN/CX3CR1 neuroimmune communication attenuates hyperalgesia and allodynia in a modality-dependent fashion highlighting the complex nature of microglial response in pathological pain models.
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PMID:Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice. 2052 66


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