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)

The nitric oxide synthase (NOS) inhibitor L-nitroarginine methyl ester has been found to exhibit antinociceptive activity in a rat model of pain [Kitto, K.F. et al., Neurosci. Lett., 148 (1992) 1-5; Lee, J.H. et al., NeuroReport, 3 (1992) 841-844; Moore, P.K. et al., Br. J. Pharmacol., 102 (1991) 198-202]. We investigated the hypothesis that hind paw injection of formalin increases the number of dorsal horn neuronal nitric oxide synthase (nNOS) containing neurons. Results showed a bilateral increase in the number of nNOS-positive neurons at the L4-5 dorsal horn area following formalin injection. The increase was always greater on the ipsilateral side compared to the contralateral side. This upregulation of nNOS following formalin stimulation of the hind paw suggested that nitric oxide (NO) may play a role in the central mechanism of hyperalgesia that follows peripheral inflammation.
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PMID:Induction of spinal cord neuronal nitric oxide synthase (NOS) after formalin injection in the rat hind paw. 880 30

A range of substituted isothiourea compounds including S-isopropylisothiourea (IPTU), S-methylisothiourea (SMT), S-ethylisothiourea (ETU), N-pentylisothiourea (PTU), S-(2 aminoethyl)isothiourea (AETU), and S-acetamidoisothiourea (AATU) inhibit mouse spinal cord/cerebellar neuronal nitric oxide synthase (nNOS) and bovine aortic endothelial cell eNOS in vitro. IP administration of isothioureas increased mean arterial blood pressure of the urethane-anaesthetised mouse (rank order of effect: IPTU > ETU > SMT > AETU). PTU and AATU were without vasopressor activity. IPTU (50 mg/kg, IP) inhibited late phase formalin-induced hindpaw licking behaviour in the mouse while SMT (50 mg/kg, IP) was without effect. Neither compound influenced the formalin-induced increase in hindpaw weight reflecting a lack of significant peripheral antioedema effect in this model. IPTU (50 mg/kg, IP) but not SMT (50 mg/kg, IP) inhibited mouse spinal cord and cerebellar NOS activity measured ex vivo in animals killed 45 min after injection. The present study confirms the potent NOS inhibitory effect of selected substituted isothioureas in vitro. Little or no isoform selectivity (i.e., nNOS vs. eNOS) was apparent. The potent vasopressor effect of isothioureas indicates that these compounds may be of limited use as tools to study the role of nitric oxide in pain perception.
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PMID:Inhibition of nitric oxide synthase by isothioureas: cardiovascular and antinociceptive effects. 895 52

Dipyrone injected intraperitoneally (i.p.) or subplantarly into the mouse paw caused dose-related antinociception against the early and the late phases of formalin-induced licking, with mean ID50 values of 154.5 and 263.7 micromol/kg, and 2.6 and 1.2 micromol/paw, respectively. Given either by intracerebroventricular (i.c.v.) or by intrathecal (i.t.) routes, dipyrone produced a similar inhibition of both phases of the formalin-induced licking, with mean ID50 values of 0.4 and 1.3 micromol/site, and 0.4 and 0.9 micromol/site against the early and the late phase of the formalin response, respectively. Dipyrone, given by i.p., subplantar, i.t. or i.c.v. routes, caused dose-related antinociception of capsaicin-induced licking. The mean ID50 values were: 207.6 micromol/kg, 2.2 micromol/paw, 0.4 micromol/site and 0.14 micromol/site, respectively. In addition, dipyrone given i.p. caused a significant increase of the latency both in the hot-plate and the tail-flick assays. Dipyrone, given i.p., i.t. or i.c.v., reversed significantly the hyperalgesia caused by i.t. injection of glutamate, with mean ID50 values of 9 micromol/kg, 29 nmol/site and 94 nmol/site, respectively. The antinociception caused by dipyrone was not influenced by naloxone, L-arginine, phaclofen, glibenclamide, p-chlorophenylalanine methyl ester, pertussis toxin or by adrenal gland hormones, when assessed against the formalin assay. Dipyrone analgesic action was not secondary to its anti-inflammatory effect, nor was it associated with non-specific effects such as muscle relaxation or sedation actions of animals. Dipyrone at a higher concentration caused significant inhibition of [3H]glutamate binding (37%) in cerebral cortical membranes from both mice and rats. However, dipyrone had no significant effect on brain constitutive neuronal nitric oxide synthase activity. It is concluded that dipyrone produces peripheral, spinal and supraspinal antinociception when assessed on formalin and capsaicin-induced pain as well as in glutamate-induced hyperalgesia in mice. Dipyrone antinociception seems unlikely to involve an interaction with the L-arginine-nitric oxide pathway, serotonin system, activation of Gi protein sensitive to pertussis toxin. interaction of ATP-sensitive K+ channels, GABA(B) receptors, or the release of endogenous glucocorticoids. However, a modulatory effect on glutamate-induced hyperalgesia and, to a lesser extent, an interaction with glutamate binding sites, seems to account for its analgesic action.
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PMID:Spinal and supraspinal antinociceptive action of dipyrone in formalin, capsaicin and glutamate tests. Study of the mechanism of action. 959 21

Interferon-gamma can facilitate the spinal nociceptive flexor reflex and may elicit neuropathic pain-related behavior in rats and mice. Immunoreactivity for the interferon-gamma receptor (IFN-gamma R) occurs in the superficial layers of the dorsal horn and the lateral spinal nucleus in the rat and mouse spinal cord, as well as in subsets of neurons in the dorsal root ganglia. The aim of the present study was to examine the cellular localization and origin of the IFN-gamma R in the spinal cord. As viewed by confocal microscopy, the immunopositivity for the IFN-gamma R was co-localized with that of the presynaptic marker synaptophysin and with neuronal nitric oxide synthase in the lateral spinal nucleus, whereas only a minor overlap with these molecules was observed in laminae I and II of the dorsal horn. There was no co-localization of the IFN-gamma R with markers for astrocytes and microglial cells. Ultrastructurally, the IFN-gamma R was found predominantly in axon terminals in the lateral spinal nucleus, but at postsynaptic sites in dendrites in laminae I and II. The IFN-gamma R expressed in neurons in dorsal root ganglia was transported in axons both centrally and peripherally. Hemisection of the spinal cord caused no reduction in immunolabelling of the IFN-gamma R in the dorsal horn or the lateral spinal nucleus. Since rhizotomy does not affect the immunolabelling in the lateral spinal nucleus, our observation indicates that the presynaptic receptors in this nucleus are derived from intrinsic neurons. The localization of the IFN-gamma R in the spinal cord differed from that of the AMPA glutamate receptor subunits 2 and 3 and the substance P receptor (NK1). Our results, showing localization of IFN-gamma R to pre- and postsynaptic sites in the dorsal horn and lateral spinal nucleus indicate that IFN-gamma can modulate nociception at the spinal cord level.
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PMID:Interferon-gamma receptors are expressed at synapses in the rat superficial dorsal horn and lateral spinal nucleus. 1064 Jan 90

Several lines of evidence have shown a role for the nitric oxide/cyclic guanosine monophosphate signaling pathway in the development of spinal hyperalgesia. However, the roles of effectors for cyclic guanosine monophosphate are not fully understood in the processing of pain in the spinal cord. The present study showed that cyclic guanosine monophosphate-dependent protein kinase Ialpha but not Ibeta was localized in the neuronal bodies and processes, and was distributed primarily in the superficial laminae of the spinal cord. Intrathecal administration of a selective inhibitor of cyclic guanosine monophosphate-dependent protein kinase Ialpha, Rp-8-[(4-chlorophenyl)thio]-cGMPS triethylamine, produced a significant antinociception demonstrated by the decrease in the number of flinches and shakes in the formalin test. This was accompanied by a marked reduction in formalin-induced c-fos expression in the spinal dorsal horn. Moreover, cyclic guanosine monophosphate-dependent protein kinase Ialpha protein expression was dramatically increased in the lumbar spinal cord 96 h after injection of formalin into a hindpaw, which occurred mainly in the superficial laminae on the ipsilateral side of a formalin-injected hindpaw. This up-regulation of cyclic guanosine monophosphate-dependent protein kinase Ialpha expression was completely blocked not only by a neuronal nitric oxide synthase inhibitor, 7-nitroindazole, and a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, but also by an N-methyl-D-aspartate receptor antagonist, dizocilpine maleate (MK-801). The present results indicate that noxious stimulation not only initially activates but also later up-regulates cyclic guanosine monophosphate-dependent protein kinase Ialpha expression in the superficial laminae via an N-methyl-D-aspartate-nitric oxide-cyclic guanosine monophosphate signaling pathway, suggesting that cyclic guanosine monophosphate-dependent protein kinase Ialpha may play an important role in the central mechanism of formalin-induced inflammatory hyperalgesia in the spinal cord.
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PMID:Expression and action of cyclic GMP-dependent protein kinase Ialpha in inflammatory hyperalgesia in rat spinal cord. 1065 33

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

Noxious challenge of the rat gastric mucosa by hydrochloric acid (HCl) is signaled to the nucleus tractus solitarii (NTS) and area postrema (AP). This study examined the participation of glutamate and tachykinins in the medullary transmission process. Activation of neurons was visualized by in situ hybridization autoradiography of c-fos messenger RNA (mRNA) 45 min after intragastric (IG) administration of 0.5 M HCl or saline. IG HCl caused many neurons in the NTS and some neurons in the AP to express c-fos mRNA. The NMDA glutamate receptor antagonist MK-801 (2 mg/kg), the NK(1) tachykinin receptor antagonist GR-205,171 (3 mg/kg) and the NK(2) receptor antagonist SR-144,190 (0.1 mg/kg) failed to significantly reduce the NTS response to IG HCl, whereas the triple combination of MK-801, GR-205,171 and SR-144,190 inhibited it by 45--50%. Only in rats that had been preexposed IG to HCl 48 h before the experiment was MK-801 alone able to depress the NTS response to IG HCl. In contrast, the c-fos mRNA response in the AP was significantly augmented by MK-801, an action that was prevented by coadministration of GR-205,171 plus SR-144,190. Inhibition of neuronal nitric oxide synthase with 7-nitroindazole (45 mg/kg) was without effect on the IG HCl-evoked c-fos mRNA expression in the NTS and AP. Our data show that glutamate acting via NMDA receptors and tachykinins acting via NK(1) and NK(2) receptors cooperate in the vagal afferent input from the acid-threatened stomach to the NTS and participate in the processing of afferent input to the AP in a different and complex manner. These opposing interactions in the AP and NTS and the increase in NMDA receptor function in the NTS after a gastric acid insult are likely to have a bearing on the neuropharmacology of dyspepsia.
Pain 2001 Jan
PMID:Cooperation of NMDA and tachykinin NK(1) and NK(2) receptors in the medullary transmission of vagal afferent input from the acid-threatened rat stomach. 1116 70

Using a reversible chronic constriction injury (CCI) model of neuropathic pain, we previously demonstrated that changes in thermal hyperalgesia correlate with the changes in peripheral microvascular blood flow in the affected paw, and that recovery can be assessed by normalization of both behavioral and vascular responses. Using the same model, this study examined age-related changes in recovery after nerve injury and the involvement of free radicals and nitric oxide (NO) in these changes. Four loose, nonconstrictive ligatures were applied to the sciatic nerve in the right, mid-thigh region of young and old (3 and 24 months) Sprague Dawley rats. All rats were monitored weekly (for 8-10 weeks) for their thermal threshold using a 46 degrees C water bath and some groups were used to examine endothelial and smooth muscle-dependent microvascular responses to substance P (SP) and sodium nitroprusside (SNP), respectively. These substances were perfused over the base of blisters raised on the footpad innervated by the injured nerve. Free radical activity in the sciatic nerve was assessed by measuring the activity of xanthine oxidase (XO) and lipid hydroperoxides (LPO). Young rats showed signs of recovery (reduction in thermal hyperalgesia and improvement of peripheral microvascular blood flow) from the fifth week. No signs of recovery were observed in old rats for 8 weeks, with some reduction in thermal hyperalgesia observed by weeks 9 and 10. XO activity was significantly higher in young injured nerves compared to sham (400%) and was even significantly greater in old injured nerves (680%). Similarly, old injured nerves showed 300% increase in LPO levels compared to sham. The role of reactive oxygen species (ROS) in delayed recovery in old rats was examined using the antioxidant tirilazad mesylate. Tirilazad (20 mg/kg) was injected intramuscularly (im) in the mid-thigh region starting on day 1 post CCI, (early treatment) or day 7 (late treatment). Levels of LPO in the injured sciatic nerves were significantly reduced using either early or late treatment, however tirilazad had opposing effects on recovery, prolonging or alleviating thermal hyperalgesia, respectively. The role of neuronal nitric oxide (nNO) was then examined using the specific neuronal nitric oxide synthase (nNOS) inhibitor, 3-bromo-7-nitroindazole (3Br-7NI) (10 mg/kg). 3Br-7NI resulted in a significant alleviation of thermal hyperalgesia with improvement in the vascular responses from weeks 5 and 6 onwards. A combination of 3Br-7NI and tirilazad treatment was also used but did not show an additive effect. The results suggest that ROS and nNO contribute to delayed recovery of injured nerves in old rats and to the maintenance of thermal hyperalgesia and the reduction in microvascular blood flow in the area innervated by the injured nerve. The results also raise the notion that possible interaction of free radicals with NO to form peroxynitrite might be responsible for such delayed recovery. Ironically, this study also reveals a positive role for free radicals in tissue repair and raises the notion that early intervention with antioxidants could exert a negative effect on repair of injured nerves.
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PMID:A role for free radicals and nitric oxide in delayed recovery in aged rats with chronic constriction nerve injury. 1149 76

Spinal cord tissue contains two enzyme systems capable of producing monoxide gases which in turn are linked to the stimulation of soluble guanylate cyclase, nitric oxide synthase (NOS) which produces NO and heme oxygenase (HO) which produces CO. Reports from several laboratories link these two enzyme systems to pain of inflammatory and neuropathic etiologies. Additional studies have demonstrated that the activation of the NOS system by morphine limits the spinal analgesic action of this drug. In this study we first employed the hot plate model of pain to demonstrate that the NOS inhibitor L-NAME and the HO inhibitor Sn-P potentiate the analgesic actions of intrathecally administered morphine while having no intrinsic analgesic action at the doses used. We then determined that L-NAME loses its ability to potentiate morphine in nNOS null-mutant mice, while Sn-P no longer potentiates morphine in mice lacking a functional HO-2 gene. The intrathecal injection of the cGMP analog 8-Br cGMP caused hyperalgesia in the hot plate assay. Focusing on the possible involvement of cGMP metabolism, we documented that morphine stimulates cGMP production in a spinal cord slice model in a concentration dependent and naloxone reversible manner. Both L-NAME and Sn-P were potent inhibitors of morphine-stimulated cGMP production. Buffer containing either CO or the NO donor compound SNAP stimulated cGMP production as well. In spinal cord slices from either nNOS or HO-2 null-mutant animals morphine did not stimulate cGMP production. Taken together our data suggest that spinal monoxide generation modifies the acute analgesic actions of morphine.
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PMID:Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. 1168 80

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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