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)

Chronic tension-type headache may be caused by prolonged painful input from pericranial myofacial tissues, for example tender points, resulting in central sensitisation (increased excitability of neurons in the central nervous system). Animal studies have shown that sensitisation of pain pathways may be caused by or associated with the activation of neuronal nitric oxide synthase and the generation of nitric oxide. Furthermore, it has been shown that nitric oxide synthase inhibitors reduce central sensitisation in animal models of persistent pain. On the basis of this information, the analgesic effect of the nitric oxide synthase inhibitor L-N(G) methyl arginine hydrochloride was investigated. This drug significantly reduced headache and myofacial factors in patients with chronic tension-type headache. These studies show that nitric oxide plays a crucial role in the pathophysiology of tension-type headache. The analgesic effect of nitric oxide synthase inhibition in patients with chronic tension-type headache is probably due to a reduction in central sensitisation at the level of the spinal dorsal horn, trigeminal nucleus or both. Furthermore, inhibition of nitric oxide synthase may become a novel principle in the future treatment of chronic headache.
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PMID:Nitric oxide synthase inhibitors for the treatment of chronic tension-type headache. 1193 42

Adenosine can reduce pain and allodynia in animals and man, probably via spinal adenosine A1 receptors. In the present study, we investigate the distribution of the adenosine A1 receptor in the rat spinal cord dorsal horn using immunohistochemistry, in situ hybridization, radioligand binding, and confocal microscopy. In the lumbar cord dorsal horn, dense immunoreactivity was seen in the inner part of lamina II. This was unaltered by dorsal root section or thoracic cord hemisection. Confocal microscopy of the dorsal horn revealed close anatomical relationships but no or only minor overlap between A1 receptors and immunoreactivity for markers associated with primary afferent central endings: calcitonin gene-related peptide, or isolectin B4, or with neuronal subpopulations: mu-opioid receptor, neuronal nitric oxide synthase, met-enkephalin, parvalbumin, or protein kinase Cgamma, or with glial cells: glial fibrillary acidic protein. A few adenosine A1 receptor positive structures were double-labeled with alpha-amino-3-hydroxy-5-methyl-4-isoaxolepropionic acid glutamate receptor subunits 1 and 2/3. The results indicate that most of the adenosine A1 receptors in the dorsal horn are located in inner lamina II postsynaptic neuronal cell bodies and processes whose functional and neurochemical identity is so far unknown. Many adenosine A1 receptor positive structures are in close contact with isolectin B4 positive C-fiber primary afferents and/or postsynaptic structures containing components of importance for the modulation of nociceptive information.
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PMID:Distribution of antinociceptive adenosine A1 receptors in the spinal cord dorsal horn, and relationship to primary afferents and neuronal subpopulations. 1458 Sep 41

The processing of sensory, including nociceptive, information in spinal dorsal horn is critically modulated by spinal GABAergic neurones. For example, blockade of spinal GABA(A) receptors leads to pain evoked by normally innocuous tactile stimulation (tactile allodynia) in rats. GABAergic dorsal horn neurones have been classified neurochemically and morphologically, but little is known about their physiological properties. We used a transgenic mouse strain coexpressing enhanced green fluorescent protein (EGFP) and the GABA-synthesizing enzyme GAD67 to investigate the properties of a subgroup of GABAergic neurones. Immunohistochemistry showed that EGFP-expressing neurones accounted for about one-third of the GABAergic neurones in lamina II of the spinal dorsal horn. They constituted a neurochemically rather heterogeneous group where 27% of the neurones coexpressed glycine, 23% coexpressed parvalbumin and 14% coexpressed neuronal nitric oxide synthase (nNOS). We found almost no expression of protein kinase Cgamma (PKCgamma) in EGFP-labelled neurones but a high costaining with PKCbetaII (78%). The whole-cell patch-clamp technique was used to intracellularly label and physiologically characterize EGFP- and non-EGFP-expressing lamina II neurones in spinal cord slices. Sixty-two per cent of the EGFP-labelled neurones were islet cells while the morphology of non-EGFP-labelled neurones was more variable. When stimulated by rectangular current injections, EGFP-expressing neurones typically exhibited an initial bursting firing pattern while non-EGFP-expressing neurones were either of the gap or the delayed firing type. EGFP-expressing neurones received a greater proportion of monosynaptic input from the dorsal root, especially from primary afferent C-fibres. In conclusion, EGFP expression defined a substantial but, with respect to the measured parameters, rather inhomogeneous subgroup of GABAergic neurones in spinal lamina II. These results provide a base to elucidate the functional roles of this subgroup of GABAergic lamina II neurones, e.g. for nociception.
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PMID:Physiological, neurochemical and morphological properties of a subgroup of GABAergic spinal lamina II neurones identified by expression of green fluorescent protein in mice. 1528 47

Snakebites are a relevant public health problem in Central and South America. Snake bite envenomations cause intense pain, not relieved by anti-venom. The fangs of many species are short, causing subcutaneous injection. Fangs of larger species inflict subcutaneous or intramuscular envenomation. To understand pain induced by subcutaneous venom, this study examined spinal mechanisms involved in pain-enhancing effects of subcutaneous Lys49 and Asp49 secretory phospholipase-A(2) (sPLA2), two components of Bothrops asper snake venom showing highly different enzymatic activities. Unilateral intraplantar sPLA2-Lys49 (catalytically inactive) or sPLA2-Asp49 (catalytically active) into rat hindpaws each induced mechanical hyperalgesia (Randall-Selitto test), whereas only catalytically active sPLA2-Asp49 caused mechanical allodynia (von Frey test). Effects induced by both sPLA2s were inhibited by intrathecal fluorocitrate, a reversible glial metabolic inhibitor. In support, immunohistochemical analysis revealed activation of dorsal horn astrocytes and microglia after intraplantar injection of either sPLA2. Spinal proinflammatory cytokines, nitric oxide, and prostanoids each appear to be involved in the pain-enhancing effects of these sPLA2s. Blockade of interleukin-1 (IL1) inhibited hyperalgesia induced by both sPLA2s, while leaving allodynia unaffected. Blockade of tumor necrosis factor reduced responses to sPLA2-Asp49. An inhibitor of neuronal nitric oxide synthase, 7-nitroindazole (7-NI), inhibited hyperalgesia induced by both sPLA2s, without interfering with allodynia induced by sPLA2-Asp49. On the other hand, L-N(6)-(1-iminoethyl)lysine (L-NI), an inhibitor of the inducible nitric oxide synthase, did not alter any sPLA2-induced effect. Lastly, celecoxib, an inhibitor of cyclooxygenase-2, attenuated sPLA2 actions. These data provide the first evidence of spinal mediators involved in pain facilitation induced by subcutaneous venoms.
Pain 2004 Sep
PMID:Snake venom components enhance pain upon subcutaneous injection: an initial examination of spinal cord mediators. 1532 10

The present study investigated the role of neuronal nitric oxide synthase (nNOS) in carrageenan-induced inflammatory pain by combining genomic and pharmacological strategies. Intrathecal injection of the nNOS inhibitor 7-nitroindazole dose-dependently inhibited carrageenan-induced thermal hyperalgesia in both early and late phases in wild-type mice. However in nNOS knockout mice, carrageenan-induced thermal hyperalgesia remained intact in the early phase but was reduced in the late phase. Spinal Ca2+ -dependent nitric oxide synthase (NOS) activity in nNOS knockout mice was significantly lower than that in wild-type mice. Following carrageenan injection, although the spinal Ca2+ -dependent NOS activity in both wild-type and knockout mice increased, the enzyme activity in nNOS knockout mice reached a level similar to that in wild-type mice. On the other hand, no significant difference in spinal Ca2+ -independent NOS activity was noted between wild-type and nNOS knockout mice before and after carrageenan injection. Furthermore, intrathecal administration of the endothelial NOS (eNOS) inhibitor L-N5-(1-iminoethyl)-ornithinein nNOS knockout mice inhibited the thermal hyperalgesia in both early and late phases, though this inhibitor had no effect in wild-type mice. Meanwhile, Western blot showed that eNOS expression in the spinal cord of nNOS knockout mice was up-regulated compared with wild-type mice; immunohistochemical staining showed that the spinal eNOS was mainly distributed in superficial laminae of the dorsal horn. Finally, double staining with confocal analysis showed that the enhanced spinal eNOS was expressed in astrocytes, but not in neurons. Our current results indicate that nNOS plays different roles in the two phases of carrageenan-induced inflammatory pain. In this model, enhanced spinal eNOS appears to compensate for the role of nNOS in nNOS knockout mice.
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PMID:Differential roles of neuronal and endothelial nitric oxide synthases during carrageenan-induced inflammatory hyperalgesia. 1535 Jun 52

Diabetic neuropathy is one of the most frequent peripheral neuropathies associated with hyperalgesia and hyperesthesia. Besides alteration in the levels of neurotransmitter, alteration in the neuronal nitric oxide synthase (nNOS) is a key factor in the pathogenesis of diabetic neuropathy. The present study was aimed at evaluating the role of PDE-5 inhibitor on nociception in streptozotocin-induced diabetes in animal models of nociception (writhing assay in mice and paw hyperalgesia test in rats). Diabetic animals showed a significant decrease in pain threshold as compared to non-diabetic animals in both tests, indicating diabetes induced hyperalgesia in mice and rats. The PDE-5 inhibitor, sildenafil, significantly increased the pain threshold in both diabetic and non-diabetic animals. However, L-NAME, a non-specific NOS inhibitor and methylene blue (MB), a guanylate cyclase inhibitor blocked the antinociceptive effect. The per se administration of L-NAME or MB augmented the hyperalgesic response in diabetic animals with little or no effect in non-diabetic animals, indicating the alteration of NO-cGMP pathway in diabetes. The results in the present study demonstrate that the decreased nNOS-cGMP system may play a crucial role in the pathogenesis of diabetic neuropathy.
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PMID:Modulatory effect of the PDE-5 inhibitor sildenafil in diabetic neuropathy. 1545 68

Myristoylated alanine-rich C-kinase substrate (MARCKS) is a major in vivo substrate for protein kinase C in the brain and has been implicated in cellular processes associated with cytoskeletal restructuring such as synaptic trafficking and neurotransmitter release. A phosphorylation-site specific antibody against Ser159-phospho-MARCKS (pS159-Mar-Ab) revealed that MARCKS is phosphorylated at Ser159 by Rho-kinase and that its phosphorylation is inhibited by the Rho-kinase specific inhibitor H-1152. Since the function of MARCKS is regulated by phosphorylation at multiple sites, here we examined the involvement of Rho-kinase in relation to phosphorylation of MARCKS at Ser159 in inflammatory and neuropathic pain by H-1152. When intrathecally administered 10 min before s.c. injection of formalin, H-1152 at 10 and 100 ng attenuated the second-phase, but not the first-phase, pain-like behaviors in the formalin test. Neuropathic pain induced by selective L5 spinal nerve transection was also relieved by intrathecal injection of H-1152. Nitric oxide synthase activity visualized by NADPH diaphorase histochemistry increased in the superficial layer of the spinal cord 30 min after formalin injection and 7 days after nerve transection, which were blocked by H-1152. Phosphorylation of MARCKS at Ser159 was detected in the spinal cord by pS159-Mar-Ab and the level of phosphorylation increased in the superficial layer after nerve transection. In contrast, immunoreactivities of neuronal nitric oxide synthase and MARCKS did not change significantly in the spinal cord before and after nerve transection. Taken together, the present study demonstrates that Rho-kinase is involved in inflammatory pain and the maintenance of neuropathic pain through phosphorylation of MARCKS at Ser159.
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PMID:Involvement of Rho-kinase in inflammatory and neuropathic pain through phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS). 1570 90

Tolerance and dependence are the most important side effects of opioid-mediated pain therapies. However, the mechanisms through which these phenomena are produced still remain unknown. Among the opioid receptors, the kappa-opioid receptor has been the focus of strong research efforts, since it contributes to the reversal of morphine-induced tolerance and dependence. Parallel to this, neuronal nitric oxide synthase has been shown to play a key role in the development of these unwanted effects. Both the kappa-opioid receptor and neuronal nitric oxide synthase are abundantly located in the CNS. One of the areas where these cellular agents are best represented is a key encephalic nucleus in the development of tolerance to the analgesic action of opioid drugs, the periaqueductal gray. In this work, we studied whether morphine-induced tolerance and dependence causes changes (a) in the activity of neuronal nitric oxide synthase and (b) in kappa-opioid receptor expression in the rat periaqueductal gray. Besides, we examined the colocalization of both molecules. Our results point to an involvement of KOR and nNOS in the same intracellular network that controls the development of morphine tolerance and dependence.
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PMID:Evidence of involvement of the nNOS and the kappa-opioid receptor in the same intracellular network of the rat periaqueductal gray that controls morphine tolerance and dependence. 1595 Jul 75

Despite abundant evidence implicating the importance of N-methyl-D-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.
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PMID:Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain. 1619 Aug 98

Nitric oxide (NO) acts as a neurotransmitter or neuromodulator involving in the modulation of thermal and/or inflammatory hyperalgesia. The neuronal nitric oxide synthase (nNOS) is a key enzyme for NO production in normal neuronal tissues, but its functional role in chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical pain hypersensitivity during the maintenance (but not the development) of inflammatory pain, while it failed to attenuate either development or maintenance of CFA-induced thermal pain hypersensitivity. Intraperitoneal administration of L-N(G)-nitro-arginine methyl ester (L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical pain hypersensitivity at both development (2h) and maintenance (24h) phase in wild type mice, but had no effect in the knockout mice. Furthermore, intrathecal injection of either L-NAME or 7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical pain hypersensitivity at both 2 and 24h after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical pain hypersensitivity and that it may also be sufficient for the development of mechanical pain hypersensitivity and for the development and maintenance of thermal pain hypersensitivity after chronic inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory pain.
Pain 2005 Dec 15
PMID:Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain. 1629 60


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