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)

We report the development of a 'second-messenger' model in an attempt to re-evaluate the role of K+ as a desensitising agent. Despite unequivocal validation of the effectiveness of potassium-based dentifrices in the management of dentine hypersensitivity, the mechanism(s) of action of K+ remains unclear. Although experimental paradigms of the Nernst equation demonstrate a direct inhibitory effect of K+ ion upon nerve conduction, in vivo considerable constraints can be argued to preclude this mechanism of action. Indeed, measurements of solution velocity within individual dentinal tubules obtained by scanning electrochemical microscopy indicate that outward movement of tubular fluid may represent a far greater barrier to the inward diffusion of K+ ions than previously estimated from measurements of hydraulic conductance across bulk dentine. Despite such probable limited penetration of dentine tubules, K+ ions may desensitise deeply-located nerve terminals through activation of a second-messenger transduction pathway that is capable of controlling the gain of K+-evoked effects which remain physically restricted to the more superficial aspects of the tubule. In addition to a direct effect upon transmembrane potential K+ can also indirectly attenuate neural activity through effects upon levels of the endogenously-synthesised free radical, nitric oxide (NO). Stimulation of the release of NO by K+ has been observed using a variety of cell preparations, which include endothelium, smooth muscle, adrenal medulla, hypothalamus and cerebellum. Importantly, a growing number of studies now report that an increase in the production of NO is associated with analgesia through a modulation of nociceptive input and a downregulation of sensitised nociceptors, most likely achieved through an increase in intraneural content of cGMP. The clinical role of a K+-evoked liberation of NO as a principal mechanism in the management of dentine hypersensitivity is supported by recent findings which include: (1) the localisation of NADPH-diaphorase activity and inducible nitric oxide synthase (iNOS) immunoreactivity within odontoblasts, their processes in dentine, and the subodontoblast layer of the pulp; (2) iNOS causes a sustained release of large (nanomolar) amounts of NO; (3) NO is freely diffusible and capable of displaying remarkably potent effector actions at distant target cells; (4) the actions of NO may be enhanced by endogenous carrier molecules such as S-nitrosothiols; (5) the synthesis of NO can be evoked by concentrations of K+ ion far less (i.e. <1 mM) than those required for direct inhibitory effects upon neural activity.
Pain 1996 Nov
PMID:The enigma of potassium ion in the management of dentine hypersensitivity: is nitric oxide the elusive second messenger? 925 93

The purpose of this study was to examine whether mRNA of interleukin-A2, interleukin-6, phospholipase A2, and nitric oxide synthase was expressed in the nerve root and dorsal root ganglion of an animal model in which exposure to the nucleus pulposus induced mechanical hyperalgesia, a pain-related behavior. Autologous nucleus pulposus obtained from coccygeal discs was relocated on the L4 and L5 lumbar nerve roots after partial laminectomy. The reflex response to noxious mechanical stimuli to the hindpaw was measured preoperatively and to 4 weeks postoperatively. With a reverse transcription-polymerase chain reaction technique, expression of interleukin-1beta, interleukin-6, phospholipase A2, and inducible nitric oxide synthase genes in the nerve root and dorsal root ganglion was observed at 1, 2, and 4 weeks postoperatively. Mechanical hyperalgesia was observed from 3 days to 2 weeks postoperatively. The expression of interleukin-1beta, phospholipase A2, and inducible nitric oxide synthase mRNAs increased after only 1 week. This increase was related to mechanical hyperalgesia. Expression of interleukin-6 was detected in the neural tissue over time. It is possible that interleukin-1beta, phospholipase A2, and inducible nitric oxide in the nerve root or dorsal root ganglion, or in both, produce sciatic pain in the early stage of herniation of the lumbar disc.
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PMID:mRNA expression of interleukins, phospholipase A2, and nitric oxide synthase in the nerve root and dorsal root ganglion induced by autologous nucleus pulposus in the rat. 1063 62

The present study was undertaken to investigate the role of inducible nitric oxide synthase in a rat model of persistent pain. The effects of L-N6 (1-iminoethyl) lysine (L-NIL), a relatively potent and relatively selective inhibitor of inducible nitric oxide synthase, were investigated in carrageenan induced hyperalgesia L-NIL (0.1 microMole) injected intraplantar or intrathecal markedly enhanced carrageenan induced hyperalgesia. These effects were reversed during the third hour by co-administration of L-arginine (900 mg/kg i.p.) but not D-arginine. Methylene blue (MB), a soluble guanylate cyclase inhibitor, administered intrathecally (0.1 microg) had no effect on L-NIL potentiation of carrageenan hyperalgesia but abolished antinociception induced by L-arginine. Obtained results suggest that nitric oxide derived from inducible nitric oxide synthase play an inhibitory role in carrageenan produced hyperalgesia in rat.
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PMID:Inhibition of inducible nitric oxide synthase in persistent pain. 1066 81

Both nitric oxide (NO) and prostaglandins (PG) and their associated enzymes nitric oxide synthases (NOS) and cyclooxygenases (COX) (specifically COX-2) have been implicated in the development of hyperalgesia. This study examined the effects of naturally occurring chronic inflammation, chronic mastitis, on spinal nociceptive processing in sheep and focused on potential alterations in spinal PG and NO signaling pathways. Mechanical withdrawal thresholds were significantly lower in animals suffering from chronic inflammation (n=6) compared to control animals (n=6). Hyperalgesia was restricted to the side contralateral to the inflammation (decrease from ipsilateral side: hindlimb 33.2+/-5%, forelimb 19.4+/-5%). Neuronal NOS-immunoreactivity was significantly reduced bilaterally in lumbar and cervical spinal cord throughout laminae I-III (decrease 18.4+/-5% and 16.9+/-4%, respectively) and in lamina X (decrease 29.1+/-6% and 17.1+/-4%, respectively) in mastitic animals relative to control animals. No difference was detected in eNOS or iNOS-immunoreactivity or in NADPH-diaphorase staining, a marker of dynamically active NOS. RT-PCR failed to detect any change in levels of nNOS, eNOS, iNOS, COX-1 or COX-2 mRNAs. However, a marked increase in the PGE receptor, EP(3) (but not EP(2)) mRNA was detected in ipsilateral spinal cord tissue from animals with chronic inflammation. This increase in EP(3) receptor expression indicates that spinal PGs are important in the spinal response to chronic peripheral inflammation. Contralateral mechanical hyperalgesia may not be directly linked to changes in spinal EP(3) receptor mRNA expression, however, the bilateral changes in nNOS suggest that this pathway may contribute to the adaptive behavioural response observed.
Pain 2000 Jun
PMID:The role of nitric oxide and prostaglandin signaling pathways in spinal nociceptive processing in chronic inflammation. 1081 61

Nerve root dysfunction and sciatic pain in disc herniation are considered to be caused by mechanical compression and related to the presence of nucleus pulposus in the epidural space. Autologous nucleus pulposus has been shown to induce endoneural edema and to decrease nerve-conduction velocity in spinal nerve roots in experimental disc herniation models, and inflammatory mediators have been suggested to be involved in these mechanisms. Nitric oxide, a potent inflammatory mediator, is implicated in vasoregulation, neurotransmission, and neuropathic pain. Nitric oxide synthesis can be induced by different cytokines, e.g., tumor necrosis factor-alpha, which recently was shown to be of pathophysiological importance in experimental disc herniation. The enzyme nitric oxide synthase mediates the production of nitric oxide. Three series of experiments were performed in rat and pig disc herniation models to (a) investigate nitric oxide synthase activity in spinal nerve roots after exposure to autologous nucleus pulposus and (b) evaluate the effects of systemic treatment with aminoguanidine, a nitric oxide synthase inhibitor, on vascular permeability and nerve-conduction velocity. In a disc herniation model in the rat, calcium-independent nitric oxide synthase activity was measured in nerve roots exposed to nucleus pulposus; however, no nitric oxide synthase activity was detected in nerve roots from animals that underwent a sham operation, reflecting increased inducible nitric oxide synthase activity. In nucleus pulposus-exposed spinal nerve roots in the pig, the edema was less severe after systemic aminoguanidine administration than without aminoguanidine treatment. Aminoguanidine treatment also significantly reduced the negative effect of nucleus pulposus on nerve-conduction velocity in spinal nerve roots in the pig. These results demonstrate that nucleus pulposus increases inducible nitric oxide synthase activity in spinal nerve roots and that nitric oxide synthase inhibition reduces nucleus pulposus-induced edema and prevents reduction of nerve-conduction velocity. Furthermore, the results suggest that nitric oxide is involved in the pathophysiological effects of nucleus pulposus in disc herniation.
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PMID:Nitric oxide as a mediator of nucleus pulposus-induced effects on spinal nerve roots. 1111 5

Intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathophysiological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Responses to QUIS-induced injury include an inflammatory component, as well as the development of spontaneous and evoked pain behaviors. We hypothesized that QUIS-induced inflammation and subsequent gene expression contribute to the development and progression of pain-related behaviors and that blockade of inflammation-related gene expression leads to the amelioration of these behaviors. Using the QUIS model of spinal cord injury, we examined whether interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is able to reduce mRNA levels of inflammatory and cell death-related genes leading to a reduction of pain behaviors. The results demonstrate that animals receiving systemic injection of IL-10, 30 minutes following QUIS-induced SCI, showed a significant delay in the onset of excessive grooming behavior, a significant reduction in grooming severity, and a significant reduction in the longitudinal extent of a pattern of neuronal loss within the spinal cord characterized as "grooming-type damage." QUIS injections also resulted in an increase in mRNA levels of interleukin-1 beta (IL-1 beta), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), CD95 ligand (CD95-L, also called FAS-L/APO-1L), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Results of QUIS injury plus IL-10 treatment resulted in a significant downregulation of IL1-beta and iNOS mRNA and these results were supported by Western blot analysis of protein levels following IL-10 treatment. These data suggest that IL-10 reduces inflammation and that targeting injury-induced inflammation is an effective strategy for limiting the extent of neuronal damage following excitotoxic SCI and thus the onset and progression of injury-induced pain behaviors.
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PMID:Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. 1117 Jul 29

Migraine is a debilitating disorder affecting approximately 12% of Caucasian populations. The disease has a large genetic component, although at present the type and number of genes involved is unclear. Candidate gene studies may be useful strategies for identifying genes involved in complex diseases such as migraine, especially if the gene being examined contributes only a minor effect to the overall phenotype. Nitric oxide (NO) is emerging as a key molecule affecting the pain associated with migraine. Since NO synthase (NOS) enzymes catalyze the synthesis of NO, the genes that code for these enzymes are good candidates for migraine molecular genetic analysis. This study investigated the role of a functionally relevant bi-allelic tetranucleotide polymorphism located in the promoter region of the human inducible nitric oxide synthase (iNOS) gene in migraine etiology. A large group of migraine affected individuals (n = 261) were genotyped and compared with an age- and sex-matched group of unaffected controls (n = 252). Results of a chi-squared analysis indicated that allele distributions for both migraine cases and controls were not significantly different (chi2 = 1.93, P = 0.16). These findings offer no evidence for an allelic association of the tested iNOS polymorphism with the common forms of the disease and therefore do not support a role for this gene in migraine pathogenesis.
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PMID:No evidence for involvement of the human inducible nitric oxide synthase (iNOS) gene in susceptibility to typical migraine. 1142 80

Pro-inflammatory cytokines have been shown to be involved in the genesis, persistence, and severity of neuropathic pain following nerve injury. The transcription factor, nuclear factor-kappa B (NF-kappaB), plays a pivotal role in regulating pro-inflammatory cytokine gene expression. To elucidate the role of NF-kappaB in the pathogenesis of neuropathic pain, using a gene-based approach of NF-kappaB decoy, we tested whether the activated NF-kappaB affected pain behavior via the expression of inflammatory mediators. Single endoneurial injections of NF-kappaB decoy, at the site of nerve lesion, significantly alleviated thermal hyperalgesia for up to 2 weeks and suppressed the expression of mRNA of the inflammatory cytokines, iNOS, and adhesion molecules at the site of nerve injury. This finding suggests that a perineural inflammatory cascade, that involves NF-kappaB, is involved in the pathogenesis of neuropathic pain.
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PMID:NF-kappa B decoy suppresses cytokine expression and thermal hyperalgesia in a rat neuropathic pain model. 1144 11

Spaceflight alters many immune responses and among the regulatory components of an organisms response system that have been to be affected by spaceflight is the cytokine network. Spaceflight, as well as ground-based model systems of spaceflight, have been shown to affect the production and activation of various cytokines including interleukins (IL) and tumor necrosis factor (TNF). Levels of urinary IL-2 are elevated on the first day of spaceflight and again after returning from space. Most results from ground-based studies in rodents indicate either no alterations in cytokines or decreased levels. Results from this experiment indicate that HP 228, a potent cytokine restraining agent (CRA (TM)) was effective in attentuating many of the disuse deconditioning changes induced by the ground-based hindlimb suspension model that simulates weightlessness in rats. HP 228 is a novel heptapeptide with unnatural amino acids and can effectively restrain lipopolysaccharide (LPS)-induced increased levels of several key cytokines, including plasma TNF alpha, IL-1 beta and IL-6. HP 228 has also been shown to be effective in several rodent models of pain, inflammation and LPS-induced lethality, as well as in reducing inducible nitric oxide synthase.
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PMID:Effectiveness of a cytokine restraining agent (CRA (TM)) in attenuating disuse deconditioning induced by hindlimb unloading in rats. 1153 92

Nitric oxide (NO), a molecular messenger synthesized by nitric oxide synthase (NOS) from L-arginine and molecular oxygen, is involved in a number of physiological and pathological processes in mammalians. Three structurally distinct isoforms of NOS have been identified: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). Although NO mediates several physiological functions, overproduction of NO by nNOS has been reported in a number of clinical disorders including acute (stroke) and chronic (schizophrenia, Alzheimer s, Parkinson s and AIDS dementia) neurodegenerative diseases, convulsions and pain; overproduction of NO by iNOS has been implicated in various pathological processes including septic shock, tissue damage following inflammation and rheumatoid arthritis. On the contrary, NO produced by eNOS has only physiological roles such as maintaining physiological vascular tone. Accordingly, selective inhibition of nNOS or iNOS vs eNOS may provide a novel therapeutic approach to various diseases; in addition selective inhibitors may represent useful tools for investigating other biological functions of NO. For these reasons, after the identification of N-methyl-L-arginine (L-NMA) as the first inhibitor of NO biosynthesis, design of selective NOS inhibitors has received much attention. In this article the recent developments of new molecules endowed with inhibitory properties against the various isoforms of NOS are reviewed. Major focus is placed on structure-activity-selectivity relationships especially concerning compounds belonging to the non-amino acid-based inhibitors.
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PMID:Progress in the development of selective nitric oxide synthase (NOS) inhibitors. 1181 67


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