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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unilateral intraplantar injection of Freund's complete adjuvant (FCA) into 1 hind paw of rats was used as a model of peripheral inflammation and persistent pain in order to examine time course effects of a continuous barrage of nociceptive input on the second-messenger transducing systems in the spinal cord. cAMP, cGMP and inositol 1,4,5-trisphosphate (insP3) were extracted from the lumbosacral cord at days 1, 7, 14, 21 and 42 following FCA injection and quantified by either radioreceptor-assay (RRA) or radioimmunoassay (RIA). The lumbosacral contents of cAMP and cGMP when quantified in whole lumbosacral cord segment were not significantly changed by FCA treatment at all time points. InsP3 accumulation was significantly increased on days 14, 21 and 42 following FCA injection relative to sham-treated time-matched controls. However, cGMP and insP3 contents were significantly increased in the left longitudinal half of the lumbar enlargement ipsilateral to the injected paw on day 21 following FCA treatment, but not in the sham-treated time-matched controls. With [3H]insP3 as a ligand, Scatchard (Rosenthal) analyses of the concentration-dependent saturation curves showed that the densities (Bmax) of insP3 receptors (insP3R) were significantly increased throughout the time course of adjuvant-induced peripheral inflammation. The binding affinities (KD) for insP3R were significantly decreased on days 7, 14 and 21 following FCA injection corresponding to the times of most stable and peak inflammation. InsP3R from the cerebelli of the same rats as used in the lumbosacral insP3R characterization was used as a positive control in this study and did not show any change in both Bmax and KD as a result of FCA treatment, thus demonstrating that the changes in lumbosacral insP3R characteristics might be specific to the nociceptive sensory pathway such as the spinal cord. Thus it appears that sustained afferent nociceptive input induced by FCA injection increased the accumulation of cGMP, insP3 and insP3R density in the spinal cord through increased neuronal activities of functional receptors coupled to major classes of chemical mediators of nociception including neuropeptides and excitatory aminoacids. Changes in insP3 accumulation in the lumbosacral cord following FCA injection were significantly correlated with changes in insP3R density. Changes in the ratios of lumbosacral insP3 contents and insP3R density were also significantly correlated with changes in body weight and hind paw size induced by FCA injection.(ABSTRACT TRUNCATED AT 400 WORDS)
Pain 1994 Jul
PMID:Regulation of the second-messenger systems in the rat spinal cord during prolonged peripheral inflammation. 797 Aug 40

Recent studies have suggested that a spinal cholinergic system is important in spinal nociceptive modulation. In the present study, the role of a nitric oxide (NO)-generating system in spinal cholinergic modulation of nociception was examined in awake rats. Intrathecal (i.t.) administration of the cholinergic muscarinic receptor antagonist atropine produced a dose-dependent (1.4-14.4 nmol) decrease in the mechanical threshold for tail withdrawal, which was reversed rapidly (2-3 min) by subsequent i.t. administration of the NO precursor, L-arginine (10 pmol to 10 nmol). Intrathecal administration of L-arginine alone (10 pmol to 10 nmol) produced a dose-dependent increase in the mechanical nociceptive withdrawal threshold of the tail. The reflexive withdrawal of the tail produced by noxious heat was not significantly affected by i.t. administration of either atropine or L-arginine. Inhibition of the NO-cGMP pathway by i.t. administration of either Nw-nitro-L-arginine methyl ester (L-NAME, 10 nmol) or methylene blue (10 nmol) significantly enhanced the magnitude and prolonged the time course of the decrease in the mechanical threshold for tail withdrawal produced by i.t. pretreatment with atropine (1.4 nmol). Neither L-NAME nor methylene blue affected mechanical withdrawal thresholds in rats pretreated with saline. These data suggest that the production of endogenous NO is required for tonic inhibition of spinal nociceptive mechanical transmission. Moreover, the present data support the speculation that there exists in the lumbar spinal cord a tonic, cholinergic modulation of NO synthase.
Pain 1993 Jul
PMID:Endogenous nitric oxide is required for tonic cholinergic inhibition of spinal mechanical transmission. 839 74

There is considerable evidence to implicate N-methyl-D-aspartate (NMDA) receptor activation in the mechanisms that underly thermal hyperalgesia in the spinal cord. As many of the effects of NMDA receptor activation appear to be ultimately mediated through production of nitric oxide (NO), recent reports have begun to define the role of NO in spinal nociceptive processing. From this evidence, it is likely that NO, produced in neurons in the spinal cord that contain NO synthase, like NMDA, plays a pivotal role in multisynaptic local circuit nociceptive processing in the spinal cord. Collectively, these reports suggest that the reflex withdrawal response to noxious heat is not mediated through activation of NMDA receptors and subsequent production of NO and cGMP, but that the acute NMDA-produced facilitation of thermal reflexes is NMDA-, NO- and cGMP-mediated and that a sustained production of NO and subsequent activation of soluble guanylate cyclase (GC-S) in the lumbar spinal cord appears to be required for maintenance of the thermal hyperalgesia produced in persistent pain models. As our knowledge and understanding of the new and intriguing class of neurotransmitters typified by NO emerges, it is likely that the next few years of pain and analgesia research will focus on the cellular events underlying mechanisms of chronic pain.
Pain 1993 Feb
PMID:Nitric oxide (NO) and nociceptive processing in the spinal cord. 751 60

Nitric oxide (NO) donors such as sodium nitroprusside (SNP, 0.01-1 micrograms) or 3-morpholino-sydnonimine (SIN-1, 0.1-10 micrograms) administered intracerebroventricularly (i.c.v) produced a dose-dependent potentiation of beta-endorphin-induced antinociception assessed by the tail-flick test in ICR mice. The same i.c.v. treatment with SNP or SIN-1 did not affect the antinociception induced by mu-, delta-, or kappa-opioid receptor agonists. The goal of the present study was to determine if the potentiation of the beta-endorphin-induced antinociception by NO donors is mediated by the activation of NO-cGMP system. Co-administration of hemoglobin (30-120 micrograms) or methylene blue (1.25-5 micrograms), but not N omega-nitro-L-arginine (1-5 micrograms) given i.c.v. dose-dependently attenuated the potentiating effects of SNP or SIN-1 on beta-endorphin-induced antinociception. However, the same i.c.v. treatments of mice with hemoglobin, methylene blue or N omega-nitro-L-arginine did not directly affect the i.c.v. administered beta-endorphin-induced antinociception. On the other hand, the treatment of mice with a combination of NO donor (SNP, 0.1 micrograms or SIN-1, 1 microgram) and zaprinast (a cGMP phosphodiesterase inhibitor, 1 microgram) further potentiated beta-endorphin-induced antinociception. These results indicate that the potentiating effect of SNP or SIN-1 on beta-endorphin-induced antinociception is mediated by the increased production of NO-cyclic GMP in the brain. However, the NO-cGMP system is not directly involved in the beta-endorphin-induced antinociception.
Pain 1995 Dec
PMID:Activation of a NO-cyclic GMP system by NO donors potentiates beta-endorphin-induced antinociception in the mouse. 871 39

1. RR may act as a preferential capsaicin antagonist in the pig nasal mucosa in vivo. However, the present data reveal a narrow concentration range for the selective actions of RR. Moreover, RR has systemic cardiovascular side effects despite local i.a. infusion in the IMA. 2. Acoustic rhinometry is a useful method for investigations of changes in nasal cavity volume in the pig in vivo. 3. The NK1-receptor antagonist RP-67,580 lacks NK1-receptor blocking properties in the pig in vivo. In contrast, CP-96,345 and SR 140.333 significantly blocked SP-mediated vascular effects in the pig nasal mucosa and superficial skin, indicating species dependent NK1-receptor selectivity. Capsaicin-induced vasodilatation in the IMA was not attenuated after administration of CP-96,345 and SR 140.333 whereas the superficial blood flow in the nasal mucosa and skin was slightly reduced. The CGRP-receptor antagonist hCGRP 8-37 markedly reduced the capsaicin-evoked vascular effects in the pig nasal mucosa and superficial skin. 4. Vanilloid receptors, as revealed by 3H-RTX binding, are present in the pig nasal mucosa although with different characteristics compared to vanilloid receptors in the pig dorsal horn. Capsaicin, RTX and LA evoked vasodilatation in the pig nasal mucosa in a similar fashion, indicating activation of sensory nerves. The LA (proton)-evoked vasodilatation was significantly attenuated after local i.a. infusion of hCGRP 8-37, closely resembling the results obtained from the capsaicin challenge before and after CGRP-receptor blockade. Capsazepine did not reduce the capsaicin-and LA-evoked vasodilation in the pig nasal mucosa. This agrees well with the observation that capsazepine did not inhibit RTX binding to vanilloid receptors in pig nasal mucosal membranes. 5. Capsaicin desensitisation of the human nasal mucosa attenuated the subjective pain response as well as the reduction of the cross-sectional area in the nasal cavity evoked by LA and hypertonic saline. This finding gives further support to the hypothesis that protons may act as endogenous ligands to the vanilloid receptor also in man. 6. Systemic administration of the NOS inhibitor L-NNA significantly reduced basal nasal V Con and increased C Vol in the pig. The effects evoked by L-NNA were similar in magnitude to those of phenylephrine and UK 14304, although of much longer duration. Administration of L-NNA did not reduce the vasodilator responses to SP and ACh, suggesting that these substances may mediate their vascular effects via one or several other mechanisms beside the NO/cGMP pathway. Moreover, capsaicin-, VIP-, and nitroprusside-evoked vasodilatation was not reduced after NOS inhibition. 7. Heavy physical exercise and alpha-adrenoceptor agonists reduce nasal cavity NO levels acutely in man. This may be due to a reduced supply of substrates for NO synthesis in the paranasal sinus epithelium, the primary NO production site in the upper airways. However, prolonged use of the alpha 2-adrenoceptor agonist oxymetazoline for 10 days, did not reduce basal nasal cavity NO levels. Nasal cavity NO levels and C Vol were not altered after topical administration of the NOS inhibitor L-NAME. Nor did we see any change in C Vol after local challenge with NO gas in the nasal cavity. The present results indicate that the human nasal mucosa is largely insensitive to NO gas in contrast to the bronchial mucosa and lung. 9. In conclusion, the present results suggest that vanilloid receptors are present on sensory nerves in the pig nasal mucosa and that LA (protons) may act as an endogenous ligand to this receptor. Sensory neuropeptides, especially CGRP, may be of importance for nasal congestion upon sensory nerve activation. Hence, selective, non-peptide CGRP-receptor antagonists may be of potential use in nasal disorders characterised by nasal congestion. NO is of importance for basal nasal vascular regulation. However, whether NOS inhibitors have potential as useful nasal de
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PMID:Sensory neuropeptides and nitric oxide in nasal vascular regulation. 880 Mar 74

The effects of caffeine and nitric oxide synthesis inhibition on the antinociceptive action of ketorolac were assessed using the pain-induced functional impairment model in the rat. Nociception was induced by the intra-articular injection of uric acid. Ketorolac, but not caffeine, produced an antinociceptive effect which was reduced by NG nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis. Caffeine coadministration potentiated the ketorolac effect. L-NAME induced a dose-dependent reduction of this potentiation. The results suggest the participation of the L-arginine-nitric oxide-cyclic GMP pathway in the caffeine potentiation of ketorolac-induced antinociception.
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PMID:Effect of caffeine coadministration and of nitric oxide synthesis inhibition on the antinociceptive action of ketorolac. 885 98

The aim of this investigation was to evaluate the role played by cyclic nucleotides in the transduction of inflammatory pain and hyperalgesia. Unmyelinated afferents (n = 79) were exposed to stable analogues of cyclic AMP and cyclic GMP, to inflammatory mediators and to Methylene Blue, an inhibitor of guanylyl cyclase. Analogues of cyclic AMP at a concentration of 1 mM (n = 9) but not 10 microM (n = 16) sensitized nociceptor responses to noxious heat and enhanced interstimulus activity. In addition. mechanical thresholds were moderately, but significantly lowered after superfusion of the cyclic AMP analogue (1 mM). Addition of 10 microM cyclic AMP analogue to a mixture of excitatory inflammatory mediators (serotonin, histamine, bradykinin and prostaglandin E2, 10 microM each) did not further increase nociceptor activity (n = 15), in contrast to a previous report that cAMP sensitized bradykinin responses. Cyclic GMP analogues (10 microM, 1 mM) did not alter heat sensitivity or mechanical thresholds of polymodal C-fibres, nor did they enhance the ongoing activity that resulted from repeated heat stimulation. After inhibition of guanylyl cyclase with Methylene Blue, cyclic GMP analogues (1-10 microM) did not alter nociceptor responses evoked by application of the mixture of inflammatory mediators. The findings indicate that polymodal nociceptor sensitization and excitation is independent of cyclic GMP. Cyclic AMP can obviously contribute to the increased heat sensitivity of inflamed tissue, whereas cyclic GMP might be of importance in the recruitment of "silent" nociceptors.
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PMID:Stable analogues of cyclic AMP but not cyclic GMP sensitize unmyelinated primary afferents in rat skin to heat stimulation but not to inflammatory mediators, in vitro. 886 9

The impairment of endothelial function in hypercholesterolaemic animals and humans is known to be reversed by intravenous infusions of L-arginine (L-ARG), the precursor of NO. 22 patients with peripheral arterial obstructive disease (PAOD) received L-ARG (60 mmol) as intravenous infusions, each lasting three hours, daily for seven consecutive days. This treatment resulted in elongation of the painfree and maximum walking distances, as well as shortening of the period of time required for pain relief after walking the maximum distance. A rise in the ankle/arm pressure ratio (AAPR) was associated with an increase of arterial blood flow in both calves. The transcutaneous oxygen tension (tcpO2) in the ischaemic foot was also increased. After the 1st and the 7th infusion of L-ARG the spontaneous (PAR) as well as the ADP- and collagen-induced platelet aggregation were suppressed, the euglobulin clot lysis time (ECLT) shortened, plasma levels of platelet activator inhibitor (PAI) decreased, and cGMP levels increased. These data indicate beneficial effects of L-ARG as a therapeutic agent in patients with PAOD. We presume that in these patients high doses of exogenous L-ARG can be partially converted to NO.
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PMID:Treatment with L-arginine is likely to stimulate generation of nitric oxide in patients with peripheral arterial obstructive disease. 886 84

The utility of a new nitric oxide (NO) donor, NOC-18, and the contribution of the neurotransmitter NO to nociception in response to tissue injury in rats, were examined following the subcutaneous injection of formalin into the hindpaw. This model induces biphasic responses in pain-related behavior, such that C-fiber activation during the first phase triggers a state of central sensitization characterized by the second phase. Formalin-induced nociceptive behavior was facilitated by intracerebroventricular administration of NOC-18 in the second phase, but not the first phase. This enhancement was completely abolished by the soluble guanylate cyclase inhibitor, methylene blue. These findings indicate that NO causes nociception via the NO-cGMP pathway in the central nervous system and NOC-18 proved to be a convenient and useful tool for the investigation of nociception-related NO.
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PMID:A new nitric oxide donor, NOC-18, exhibits a nociceptive effect in the rat formalin model. 888 Jun 84

Adrenal medullary chromaffin cells implanted into the spinal subarachnoid space can reduce abnormal pain-related responses in chronic pain models. Persistent pain is thought to involve the activation of N-methyl-D-aspartate (NMDA) receptors and subsequent production of nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP). Changes in dorsal horn levels of cGMP in the rat were determined in conjunction with alterations in pain behaviors following peripheral nerve injury and adrenal medullary transplantation. Results indicated increased spinal cGMP levels in parallel with thermal and mechanical hyperalgesia and tactile allodynia consequent to chronic constriction injury of the sciatic nerve in rats. Adrenal medullary, but not control transplants, attenuated the hyperalgesia and allodynia and decreased spinal cGMP content. These results suggest that adrenal medullary transplants may reduce abnormal pain by intervention in the spinal NMDA-NO cascade.
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PMID:Alterations in rat spinal cord cGMP by peripheral nerve injury and adrenal medullary transplantation. 888 Jul 51


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