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

Analgesia has been reported to be facilitated by supraspinal nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). In the rostromedial medulla, an important pain-suppressing region, iontophoretically delivered 8-bromo-cGMP excited most single recorded cells (9/10), and methylene blue (a guanylyl cyclase inhibitor) inhibited all cells (7/7). Nitrite and ferrous ions together, shown voltammetrically ex vivo to yield nitric oxide (NO), excited some cells (14/28) and inhibited others (7/28). Methylene blue blocked excitation (3/3) but not inhibition (4/4) by the putative NO. Spontaneous or glutamate-evoked firing was gradually inhibited (23/32) or unaffected by N omega-nitro-L-arginine (a NO synthase inhibitor), but was mostly inhibited by L-arginine (the NO precursor) (23/26), although a rapid onset militated against elevated NO production. These substances, excepting L-arginine, produced changes consistent with an excitatory cGMP-NO cascade contributing to analgesia.
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PMID:Excitation of cells in the rostral medial medulla of the rat by the nitric oxide-cyclic guanosine monophosphate messenger system. 858 98

The involvement of nitric oxide in nociceptive processing was examined at the main loci of synaptic transmission within the rat somatosensory pathway from the caudal sural cutaneous nerve. Intrathecal (lumbar 1-3) administration of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (30 micrograms), inhibited nitric oxide synthase in this region of the spinal cord by greater than 80% but had no significant effect on nitric oxide synthase in parietal cerebral cortex, thalamus or medulla/pons. In a rat model of peripheral neuropathy (one to two week ligation of the caudal sural cutaneous nerve), intrathecal administration of the same dose of N omega-nitro-L-arginine methyl ester prevented the hyperalgesic response to thermal stimuli. Administration of 30 micrograms N omega-nitro-L-arginine methyl ester into the lateral ventricle had no effect on nitric oxide synthase in the lumbar 1-3 region of the spinal cord but gave substantial inhibition in higher areas of the somatosensory pathway (parietal cerebral cortex, thalamus and medulla/pons). Nitric oxide synthase in the parietal cerebral cortex (but not thalamus) was inhibited to a greater extent in the hemisphere ipsilateral to the site of administration. Administration of 30 micrograms N omega-nitro-L-arginine methyl ester into the lateral ventricle decreased thermal hyperalgesia, but only when N omega-nitro-L-arginine methyl ester was administered contralateral to the ligated caudal sural cutaneous nerve and therefore ipsilateral to the cortical nociceptive processing from this nerve. Intrathecal and intracerebroventricular administration of the selective inhibitor of nitric oxide-sensitive guanylyl cyclase, 1-H-[1,2,4]oxadiazalo[4,3-a]quinoxalin-1-one, also decreased the hyperalgesic response to thermal stimuli. These data demonstrate that, in a model of neuropathic pain, nitric oxide is involved in nociceptive processing at spinal and cerebrocortical synaptic loci of the somatosensory pathway and that its actions appear to be mediated through guanylyl cyclase.
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PMID:The nitric oxide-cyclic GMP pathway is required for nociceptive signalling at specific loci within the somatosensory pathway. 880 86

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 physiology of nociception involves a complex interaction of peripheral and central nervous system (CNS) structures, extending from the skin, the viscera and the musculoskeletal tissues to the cerebral cortex. The pathophysiology of chronic pain shows alterations of normal physiological pathways, giving rise to hyperalgesia or allodynia. After integration in the spinal cord, nociceptive information is transferred to thalamic structures before it reaches the somatosensory cortex. Each of these levels of the CNS contain modulatory mechanisms. The two most important systems in modulating nociception and antinociception, the N-methyl-D-aspartate (NMDA) and opioid receptor system, show a close distribution pattern in nearly all CNS regions, and activation of NMDA receptors has been found to contribute to the hyperalgesia associated with nerve injury or inflammation. Apart from substance P (SP), the major facilitatory effect in nociception is exerted by glutamate as the natural activator of NMDA receptors. Stimulation of ionotropic NMDA receptors causes intraneuronal elevation of Ca2+ which stimulates nitric oxide synthase (NOS) and the production of nitric oxide (NO). NO as a gaseous molecule diffuses out from the neuron and by action on guanylyl cyclase, NO stimulates in neighboring neurons the formation of cGMP. Depending on the expression of cGMP-controlled ion channels in target neurons, NO may act excitatory or inhibitory. NO has been implicated in the development of hyperexcitability, resulting in hyperalgesia or allodynia, by increasing nociceptive transmitters at their central terminals. Among the three subtypes of opioid receptors, mu- and delta-receptors either inhibit or potentiate NMDA receptor-mediated events, while kappa opioids antagonize NMDA receptor-mediated activity. Recently, CRH has been found to act at all levels of the neuraxis to produce analgesia. Modulation of nociception occurs at all levels of the neuraxis, thus, eliciting the multidimensional experience of pain involving sensory-discriminative, affective-motivational, cognitive and locomotor components.
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PMID:Nociception, pain, and antinociception: current concepts. 1182 34

The local peripheral (subcutaneous) injection of phosphodiesterase 3 inhibitor trequinsin dose-dependently enhanced formalin-evoked flinching during late second phase of this test. Treatment with the nitric oxide synthase inhibitor N-L-nitro-arginine methyl ester or guanylyl cyclase inhibitor 1-H-[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one significantly reversed trequinsin-induced pronociceptive effect. Results suggest that the peripheral phosphodiesterase 3 may play an important physiologic role on inflammatory pain by controlling cyclic AMP levels and therefore the nociceptor threshold.
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PMID:Peripheral participation of the phosphodiesterase 3 on formalin-evoked nociception. 1611 78

Zaprinast is a phosphodiesterase inhibitor that is active in various models of pain when administered locally. In addition, the antinociception of zaprinast is involved in the nitric oxide (NO)-cGMP pathway. However, the effect of zaprinast administered spinally has not been examined. Therefore, this study examined the effect of zaprinast on the formalin-induced nociception at the spinal level. Next, the role of the NO-cGMP-potassium channel pathway on the effect of zaprinast was further clarified. Catheters were inserted into the intrathecal space of male Sprague-Dawley (SD) rats. Pain was induced by applying 50 microl of a 5% formalin solution to the hindpaw. The change in the zaprinast-induced effect was examined after an intrathecal pretreatment with a NO synthase inhibitor (l-NMMA), a guanylyl cyclase inhibitor (ODQ) or a potassium channel blocker (glibenclamide). Zaprinast produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Intrathecal l-NMMA, ODQ and glibenclamide did not reverse the antinociception of zaprinast in either phase of the formalin test. These results suggest that zaprinast is effective against both acute pain and the facilitated pain state at the spinal level. However, the NO-sensitive cGMP-potassium channel pathway is not contributable to the antinociceptive mechanism of zaprinast in the spinal cord.
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PMID:Lack of the nitric oxide-cyclic GMP-potassium channel pathway for the antinociceptive effect of intrathecal zaprinast in a rat formalin test. 1611 33

In the literature, the pro- or antinociceptive effects of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) are discussed controversially. Our laboratory and others have reported that in the spinal cord a local lack of NO has an excitatory action on the ongoing (background) activity of dorsal horn neurones. Here, we tested the hypothesis that this effect of NO is mediated by cGMP and that part of the controversy is due to differences in the spinal and supraspinal actions of both compounds. In anaesthetised rats, impulse activity of lumbar dorsal horn neurones was recorded, and blockers of NO- and cGMP-synthesis, as well as the phosphodiesterase 5 (PDE5) inhibitor sildenafil (which increases the cGMP level), or 8-Bromo-cGMP (a membrane permeable cGMP analogue) were administered spinally or supraspinally. Topical superfusion of the spinal cord with a blocker of the guanylyl cyclase (ODQ) to reduce the cGMP level led to an increase in background activity of nociceptive lumbar dorsal horn neurones similar to that caused by l-NAME, a blocker of the NO synthase. Spinal superfusion with sildenafil or 8-Bromo-cGMP had no excitatory effect. In contrast, injections of sildenafil or 8-Bromo-cGMP into the third cerebral ventricle caused an increased background activity in lumbar dorsal horn neurones, while l-NAME and ODQ were ineffective. The results show that at the spinal level, a lack of cGMP and NO has an excitatory action on dorsal horn neurones, whereas supraspinally an elevated level of cGMP is excitatory.
Pain 2005 Oct
PMID:The possible role of the NO-cGMP pathway in nociception: different spinal and supraspinal action of enzyme blockers on rat dorsal horn neurones. 1615 78

The mechanism of intrathecal antinociceptive action of the phosphodiesterase 5 inhibitor sildenafil was assessed in diabetic rats using the formalin test. Intrathecal administration of sildenafil (12.5-50 microg) produced a dose-related antinociception during both phases of the formalin test in non-diabetic and diabetic rats. Intrathecal pretreatment with N-L-nitro-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor, 1-50 microg), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1-10 microg), KT5823 (protein kinase G (PKG) inhibitor, 5-500 ng), charybdotoxin (large-conductance Ca2+-activated K+ channel blocker, 0.01-1 ng), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-3 ng) and glibenclamide (ATP-sensitive K+ channel blocker, 12.5-50 microg), but not N-D-nitro-arginine methyl ester (D-NAME, 50 microg) or saline, significantly diminished sildenafil (50 microg)-induced antinociception in non-diabetic rats. Intrathecal administration of ODQ, KT5823, apamin and glibenclamide, but not L-NAME nor charybdotoxin, reversed intrathecal antinociception induced by sildenafil in diabetic rats. Results suggest that sildenafil produces its intrathecal antinociceptive effect via activation of NO-cyclic GMP-PKG-K+ channels pathway in non-diabetic rats. Data suggest that diabetes leads to a dysfunction in NO and large-conductance Ca2+-activated K+ channels. Sildenafil could have a role in the pharmacotherapy of diabetes-associated pain.
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PMID:Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats. 1630 95

The present study examined the antinociceptive effects induced by 2,3-bis(mesitylseleno)propenol, a bis-selenide alkene derivate, given orally, in chemical models of pain in rats and mice. Selenide administered orally (p.o.) into the rats caused antinociception against the first and second phases of the formalin test, with mean ID(50) values of 28.17 and 39.68 mg/kg, respectively. The antinociceptive effect caused by selenide (50 mg/kg, p.o.) on the formalin test was reversed by pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, a nitric oxide (NO) synthase inhibitor), methylene blue (a non-specific NO/guanylyl cyclase inhibitor) and glibenclamide (an ATP-sensitive K(+) channel inhibitor), but not by atropine (a muscarinic antagonist). Given orally selenide in mice produced an inhibition of glutamate-, histamine- and compound 48/80-induced nociception with mean ID(50) values of 27.58, 36.18 and 44.53 mg/kg, respectively. Moreover, oral treatment with selenide in mice decreased licking -- induced by serotonin (mean ID(50) value of >50 mg/kg). The data show that selenide exerts pronounced systemic antinociception in chemical (formalin, glutamate, histamine, compound 48/80 and serotonin-induced pain) models of nociception. Taken together, these results suggest that the antinociceptive effect of selenide on the formalin test involves the participation of nitric oxide/cyclic GMP/K(+) channel pathways in rats.
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PMID:Role of nitric oxide/cyclic GMP/K(+) channel pathways in the antinociceptive effect caused by 2,3-bis(mesitylseleno)propenol. 1803 63

A large body of evidence indicates that the release of nitric oxide (NO) is crucial for the central sensitization of pain pathways during both inflammatory and neuropathic pain. Here, we investigated the distribution of NO-sensitive guanylyl cyclase (NO-GC) in the spinal cord and in dorsal root ganglia, and we characterized the nociceptive behavior of mice deficient in NO-GC (GC-KO mice). We show that NO-GC is distinctly expressed in neurons of the mouse dorsal horn, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. GC-KO mice exhibited a considerably reduced nociceptive behavior in models of inflammatory or neuropathic pain, but their responses to acute pain were not impaired. Moreover, GC-KO mice failed to develop pain sensitization induced by intrathecal administration of drugs releasing NO or carbon monoxide. Surprisingly, during spinal nociceptive processing, cGMP produced by NO-GC may activate signaling pathways different from cGMP-dependent protein kinase I (cGKI), whereas cGKI can be activated by natriuretic peptide receptor-B dependent cGMP production. Together, our results provide evidence that NO-GC is crucially involved in the central sensitization of pain pathways during inflammatory and neuropathic pain.
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PMID:cGMP produced by NO-sensitive guanylyl cyclase essentially contributes to inflammatory and neuropathic pain by using targets different from cGMP-dependent protein kinase I. 1871 16


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