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Biomedical subjects

R A Johns

Publications and source records attributed to R A Johns.

At least 19 recordsLinked to original sources
PubMed2006

A comparison of cyclizine and granisetron alone and in combination for the prevention of postoperative nausea and vomiting.

We conducted a randomised double-blinded study of 960 women undergoing day-case surgery to determine whether combination anti-emetic therapy of granisetron and cyclizine was more effective at decreasing the incidence of postoperative nausea and vomiting than these agents used alone. The women were randomly allocated to three groups to receive intravenous granisetron 1 mg, cyclizine 50 mg or both before induction of general anaesthesia. The incidence of postoperative nausea and vomiting was 77/322 (24%) in the granisetron group, 73/316 (23%) in the cyclizine group and 53/322 (17%) in those women given both drugs (p = 0.04). There was no difference in the requirement for rescue anti-emetic drugs. There were no differences in the anaesthetic techniques used in the three groups. We conclude that the risk of postoperative nausea and vomiting is less with cyclizine and granisetron given together than with either given alone.

Adult↗
PubMed2004

Knockdown of spinal cord postsynaptic density protein-95 prevents the development of morphine tolerance in rats.

The activation of spinal cord N-methyl-D-aspartate (NMDA) receptors and subsequent intracellular cascades play a pivotal role in the development of opioid tolerance. Postsynaptic density protein-95 (PSD-95), a molecular scaffolding protein, assembles a specific set of signaling proteins around NMDA receptors at neuronal synapses. The current study investigated the possible involvement of PSD-95 in the development of opioid tolerance. Opioid tolerance was induced by intrathecal injection of morphine sulfate (20 microg/10 microl) twice a day for 4 consecutive days. Co-administration of morphine twice daily and PSD-95 antisense oligodeoxynucleotide (50 microg/10 microl) once daily for 4 days not only markedly reduced the PSD-95 expression and its binding to NMDA receptors in spinal cord but also significantly prevented the development of morphine tolerance. In contrast, co-administration of morphine twice daily and PSD-95 missense oligodeoxynucleotide (50 microg/10 microl) once daily for 4 days did not produce these effects. The PSD-95 antisense oligodeoxynucleotide at the doses we used did not affect baseline response to noxious thermal stimulation or locomotor function. The present study indicates that the deficiency of spinal cord PSD-95 attenuates the development of opioid tolerance. These results suggest that PSD-95 might be involved in the central mechanisms of opioid tolerance and provide a possible new target for prevention of development of opioid tolerance.

Animals↗
PubMed2004

Evidence of neuronal excitatory amino acid carrier 1 expression in rat dorsal root ganglion neurons and their central terminals.

The expression and distribution of the neuronal glutamate transporter, excitatory amino acid carrier-1 (EAAC1), are demonstrated in the dorsal root ganglion neurons and their central terminals. Reverse transcriptase-polymerase chain reaction shows expression of EAAC1 mRNA in the dorsal root ganglion. Immunoblotting analysis further confirms existence of EAAC1 protein in this region. Immunocytochemistry reveals that approximately 46.6% of the dorsal root ganglion neurons are EAAC1-positive. Most EAAC1-positive neurons are small and around 250-750 microm2 in surface area, and some co-label with calcitonin gene-related peptide (CGRP) or isolectin IB4. In the spinal cord, EAAC-1 immunoreactive small dot- or patch-like structures are mainly localized in the superficial dorsal horn, and some are positive for CGRP or labeled by isolectin IB4. Unilateral dorsal rhizotomy experiments further show that EAAC1 immunoreactivity is less intense in superficial dorsal horn on the side ipsilateral to the dorsal rhizotomy than on the contralateral side. The results indicate the presence of EAAC1 in the dorsal root ganglion neurons and their central terminals. Our findings suggest that EAAC1 might play an important role in transmission and modulation of nociceptive information via the regulation of pre-synaptically released glutamate.

Amino Acid Transport System X-AG↗
PubMed2004

Differential roles of neuronal and endothelial nitric oxide synthases during carrageenan-induced inflammatory hyperalgesia.

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.

Animals↗
PubMed2003

Role of postsynaptic density protein-95 in the maintenance of peripheral nerve injury-induced neuropathic pain in rats.

Our previous work has demonstrated that postsynaptic density protein-95, a molecular scaffolding protein that binds and clusters N-methyl-D-aspartate receptors at neuronal synapses, plays an important role in the development of peripheral nerve injury-induced neuropathic pain. The current study further investigated the possible involvement of postsynaptic density protein-95 in the maintenance of neuropathic pain. Mechanical and thermal hyperalgesia were induced within 3 days and maintained for 15 days or longer after unilateral injury to the fifth lumbar spinal nerve. The rats injected intrathecally with postsynaptic density protein-95 antisense oligodeoxynucleotide every 24 h for 4 days from day 7 to day 10 post-surgery exhibited not only a marked decrease in spinal cord postsynaptic density protein-95 protein expression but also a significant reduction in mechanical and thermal hyperalgesia on day 11 post-surgery. The rats injected with sense oligodeoxynucleotide did not display these changes. However, in the rats without nerve injury, postsynaptic density protein-95 antisense oligodeoxynucleotide given intrathecally every 24 h for 4 days did not affect responses to mechanical and thermal stimulation. In addition, postsynaptic density protein-95 antisense oligodeoxynucleotide did not change locomotor activity of experimental animals. Our results indicate that the deficiency of postsynaptic density protein-95 protein in the spinal cord significantly attenuates nerve injury-induced mechanical and thermal hyperalgesia during both the development and maintenance of chronic neuropathic pain. These results suggest that postsynaptic density protein-95 might be involved in the central mechanisms of chronic neuropathic pain and provide a novel target for development of new pain therapies.

Animals↗
PubMed2003

Intact carrageenan-induced thermal hyperalgesia in mice lacking inducible nitric oxide synthase.

To date, the exact role of inducible nitric oxide synthase (iNOS) in inflammatory pain remains controversial. In the present study, we combined a pharmacological strategy (using a selective iNOS inhibitor) with a genomic strategy (using mice lacking the iNOS gene) to address the function of iNOS in the central mechanism of carrageenan-induced persistent inflammatory pain. In the wild type mice, intrathecal administration of L-N(6)-(1-iminoethyl)-lysine, a selective iNOS inhibitor, significantly inhibited thermal hyperalgesia in the late phase but not in the early phase of carrageenan inflammation. Moreover, iNOS mRNA expression in the lumbar enlargement segments of the spinal cord was dramatically induced at 24 h (late phase) after injection of carrageenan into a hind paw. Interestingly, targeted disruption of iNOS gene did not affect carrageenan-induced thermal hyperalgesia in either the early (2-6 h) or late phase. In the lumbar enlargement segments of iNOS knockout mice, nitric oxide synthase (NOS) enzyme activity remained at a similar level to that of the wild type mice at 24 h after carrageenan injection. We found that intrathecal administration of 7-nitroindazole (a selective neuronal NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (a selective endothelial NOS inhibitor), significantly reduced carrageenan-induced thermal hyperalgesia in both the early phase and the late phase in iNOS knockout mice. We also found that expression of neuronal NOS but not endothelial NOS in the lumbar enlargement segments was significantly increased in iNOS knockout mice compared with wild type mice at 24 h after carrageenan injection. Our results indicate that neuronal NOS might compensate for the function of iNOS in the late phase of carrageenan-induced inflammatory pain in iNOS knockout mice. This suggests that iNOS may be sufficient, but not essential, for the late phase of the carrageenan-induced thermal hyperalgesia.

Animals↗
PubMed2002

Activation and up-regulation of spinal cord nitric oxide receptor, soluble guanylate cyclase, after formalin injection into the rat hind paw.

Nitric oxide synthase is expressed abundantly in the spinal cord, and nitric oxide (NO) has been shown to play important roles in the central mechanism of inflammatory hyperalgesia. However, the expression and function of the NO receptor, soluble guanylate cyclase, is not fully understood in this processing at the spinal cord level. In the present study, we report that the soluble guanylate cyclase alpha(1) subunit but not the beta(1) subunit was expressed in rat spinal cord, particularly in the dorsal horn. We showed that intrathecal administration of a selective inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, produced a significant anti-nociception demonstrated by the decrease in the number of flinches and shakes in the formalin-induced inflammatory pain model. This was accompanied by a marked reduction in formalin-induced c-fos expression in the spinal cord. During formalin-induced long-lasting inflammation, we found that the expression of the alpha(1) subunit of soluble guanylate cyclase was dramatically increased in the lumbar spinal cord on the second and fourth days after formalin injection into the dorsal side of a hind paw. Intraperitoneal pretreatment with an N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine maleate (MK-801), and a neuronal NO synthase inhibitor, 7-nitroindazole, not only significantly blocked formalin-induced secondary thermal hyperalgesia but also suppressed formalin-produced increase in the alpha(1) subunit of soluble guanylate cyclase in the spinal cord. The present results indicate that peripheral inflammation not only initially activates but also later up-regulates soluble guanylate cyclase expression via the NMDA receptor-NO signaling pathway, suggesting that soluble guanylate cyclase might be involved in the central mechanism of formalin-induced inflammatory hyperalgesia in the spinal cord.

Animals↗
PubMed2001

Knockdown of PSD-95/SAP90 delays the development of neuropathic pain in rats.

Our previous work has shown that PSD-95/SAP90 is required for NMDA receptor-mediated thermal hyperalgesia. To address the role of PSD-95/SAP90 in chronic pain, the present study investigated the effect of the deficiency of PSD-95/SAP90 on nerve injury-induced neuropathic pain. Following unilateral L5 spinal nerve injury, mechanical and thermal hyperalgesia developed within 3 days and persisted for 9 days or longer on the injured side. The intrathecal administration of antisense oligodeoxynucleotide specifically against PSD-95/SAP90, but not sense or missense oligodeoxynucleotide, dose-dependently delayed the onset of tactile allodynia and thermal hyperalgesia. These results suggest that PSD-95/SAP90 might be involved in the central mechanisms of the development of chronic neuropathic pain.

Animals↗
PubMed2001

Chronic hypoxia induces apoptosis in cardiac myocytes: a possible role for Bcl-2-like proteins.

The effect of prolonged hypoxia as well as the molecular mechanisms on cardiac cell death is not well established. A possible role of Bcl-2 and Bax in hypoxia-induced apoptosis in different cell types has been proposed. Here we demonstrate the effect of hypoxia on the induction of apoptosis and the expression of Bcl-2-like proteins in vivo and in vitro. Hearts from rats exposed to chronic hypoxia (n = 4) showed an increased rate of apoptosis compared to normoxic hearts (n = 4). The induction of apoptosis in hypoxic hearts correlated with a significant decrease of Bcl-2 protein level, whereas Bax protein expression was increased. Exposure of isolated neonatal rat cardiac myocytes to hypoxia also resulted in a significant increase in apoptosis. However, Bcl-2 and Bax protein levels essentially remained unchanged. Our results may suggest a different molecular mechanism of hypoxia-induced apoptosis in vivo and in vitro.

Animals↗
PubMed2001

Effect of the deficiency of spinal PSD-95/SAP90 on the minimum alveolar anesthetic concentration of isoflurane in rats.

BACKGROUND: Spinal N-methyl-D-aspartate (NMDA) receptor activation has been demonstrated to play an important role in the processing of spinal nociceptive information and in the determination of the minimum alveolar anesthetic concentration (MAC) of inhalational anesthetics. Postsynaptic density-95 (PSD-95)/synapse-associated protein-90 (SAP90), a molecular scaffolding protein that binds and clusters the NMDA receptor perferentially at synapses, was implicated in NMDA-induced thermal hyperalgesia. The current study investigated the possible involvement of PSD-95/SAP9O in determining MAC for isoflurane anesthesia. METHODS: Sprague-Dawley rats were pretreated intrathecally with PSD-95/SAP90 antisense oligodeoxyribonucleotide (ODN), sense ODN, missense ODN, or saline every 24 h for 4 days. After initial baseline determination of the MAC, NMDA or saline was injected intrathecally. Ten minutes later, MAC measurement was repeated. The rats also were evaluated for the presence of locomotor dysfunction by intrathecal administration of NMDA or saline in the saline- and ODN-treated rats. RESULTS: In the groups treated with antisense ODNs, but not in those treated with sense or missense ODNs, there was a significant decrease in isoflurane MAC that was not accompanied by marked changes in either blood pressure or heart rate. In the saline-treated group, intrathecal NMDA caused an increase in isoflurane MAC. In contrast, in the antisense ODN-treated group, intrathecal NMDA did not produce a significant change in isoflurane MAC. An NMDA-induced increase in blood pressure but not heart rate was found in both saline- and antisense ODN-treated groups. Locomotor activity was not changed in any of the treated animals. CONCLUSION: The results indicate not only a significant decrease in MAC for isoflurane but also an attenuation in the NMDA-induced increase in isoflurane MAC in the PSD-95/SAP90 antisense-treated animals, which suggests that PSD-95/SAP90 may mediate the role of the NMDA receptor in determining the MAC of inhalational anesthetics.

Anesthetics, Inhalation↗
PubMed2001

Neuronal nitric oxide synthase: expression in rat parietal cells.

Nitric oxide synthases (NOS) are enzymes that catalyze the generation of nitric oxide (NO) from L-arginine and require nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor. At least three isoforms of NOS have been identified: neuronal NOS (nNOS or NOS I), inducible NOS (iNOS or NOS II), and endothelial NOS (eNOS or NOS II). Recent studies implicate NO in the regulation of gastric acid secretion. The aim of the present study was to localize the cellular distribution and characterize the isoform of NOS present in oxyntic mucosa. Oxyntic mucosal segments from rat stomach were stained by the NADPH-diaphorase reaction and with isoform-specific NOS antibodies. The expression of NOS in isolated, highly enriched (>98%) rat parietal cells was examined by immunohistochemistry, Western blot analysis, and RT-PCR. In oxyntic mucosa, histochemical staining revealed NADPH-diaphorase and nNOS immunoreactivity in cells in the midportion of the glands, which were identified as parietal cells in hematoxylin and eosin-stained step sections. In isolated parietal cells, decisive evidence for nNOS expression was obtained by specific immunohistochemistry, Western blotting, and RT-PCR. Cloning and sequence analysis of the PCR product confirmed it to be nNOS (100% identity). Expression of nNOS in parietal cells suggests that endogenous NO, acting as an intracellular signaling molecule, may participate in the regulation of gastric acid secretion.

Animals↗
PubMed2001

Upregulation of lung soluble guanylate cyclase during chronic hypoxia is prevented by deletion of eNOS.

Hypoxia upregulates endothelial (e) nitric oxide synthase (NOS), but how eNOS affects soluble guanylate cyclase (sGC) protein expression in hypoxia-induced pulmonary hypertension is unknown. Wild-type (WT), eNOS-deficient [eNOS(-/-)], and inducible NOS (iNOS)-deficient [iNOS(-/-)] mice were used to investigate the effects of lack of NO from different NOS isoforms on sGC activity and protein expression and its relationship to the muscularization of the pulmonary vasculature. After 6 days of hypoxic exposure (10% O2), the ratios of the right ventricle to left ventricle + septum weight (RV/LV+S) and right ventricle weight to body weight, the lung sGC activity, and vascular muscularization were determined, and protein analysis for eNOS, iNOS, and sGC was performed. Results demonstrated that there were significant increases of RV/LV+S in all animals treated with hypoxia. In hypoxic WT and iNOS(-/-) mice, eNOS and sGC alpha1- and beta1-protein increased twofold; cGMP levels and the number of muscularized vessels also increased compared with hypoxic eNOS(-/-) mice. There was a twofold increase of iNOS protein in WT and eNOS(-/-) mice, and the basal iNOS protein concentration was higher in eNOS(-/-) mice than in WT mice. In contrast, the eNOS(-/-) mouse lung showed no eNOS protein expression, lower cGMP concentrations, and no change of sGC protein levels after hypoxic exposure compared with its normoxic controls (P > 0.34). These results suggest that eNOS, but not iNOS, is a major regulator of sGC activity and protein expression in the pulmonary vasculature.

Animals↗
PubMed2000

Synaptic relationship of the neurons containing a metabotropic glutamate receptor, MGluR5, with nociceptive primary afferent and GABAergic terminals in rat spinal superficial laminae.

Recent pharmacological evidence showed that metabotropic glutamate receptors (mGluRs), particularly mGluRs1/5, had a potential role in spinal nociceptive processing. However, previous morphological studies on mGluRs have been limited mainly to their distribution in the spinal cord. In the present study, electron microscopic immunocytochemistry was employed to identify the synaptic relationship of the neurons containing mGluR5, with nociceptive primary afferent and gamma-aminobutyric acid-ergic (GABAergic) terminals in the superficial dorsal horn of the spinal cord. Nociceptive C- and A(delta)-primary afferent terminals selectively labeled with horseradish peroxidase conjugated to wheat-germ agglutinin were in asymmetric synaptic contacts with or in direct apposition to mGluR5 positive dendritic profiles. The double-labeling studies revealed that mGluR5 immunoreactive dendrites also received symmetric synaptic contacts from axon terminals labeled with immunogold particles indicating GABA. The present demonstration of mGluR5 neurons receiving inputs from both nociceptive primary afferents and GABAergic terminals of presumed interneurons further supports the involvement of mGluR5 in the transmission and modulation of nociceptive information in the spinal cord.

Animals↗
PubMed2000

Activation of cGMP-dependent protein kinase Ialpha is required for N-methyl-D-aspartate- or nitric oxide-produced spinal thermal hyperalgesia.

The effect of a selective cyclic guanocine 3',5'-monophosphate (cGMP)-dependent protein kinase Ialpha inhibitor, Rp-8-[(4-chlorophenyl)thio]-cGMPS triethylamine (Rp-8-p-CPT-CGMPS), on either N-methyl-D-aspartate (NMDA)- or N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)ethanamine (NOC-12, a nitric oxide (NO) donor)-produced thermal hyperalgesia was examined in the rat. Intrathecal administration of NMDA (15 pg/10 microl) or NOC-12 (10, 20 and 30 microg/10 microl) produced a marked curtailment of the tail-flick latency. Maximal NMDA- or NOC-12-produced facilitation of the tail-flick reflex was significantly and dose-dependently blocked by intrathecal pretreatment with Rp-8-p-CPT-CGMPS (7.5, 15 and 30 microg/10 microl). Rp-8-p-CPT-CGMPS given alone did not markedly alter baseline tail-flick latency. These results suggest that the activation of cGMP-dependent protein kinase Ialpha is required for NMDA- or NO-produced facilitation of thermal hyperalgesia at the spinal cord level.

Animals↗
PubMed2000

Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes.

The relationship between hypoxia and regulation of nitric oxide synthase (NOS) in myocardial tissue is not well understood. We investigated the role of hypoxia inducible factor-1 (HIF-1) on expression of the inducible NOS (iNOS) in myocardial cells in vivo and in vitro. In situ hybridization in myocardial tissue from rats exposed to hypoxia for 3 weeks demonstrated increased iNOS mRNA expression. Northern analysis of RNA from hearts of those animals and from cells exposed to hypoxia for 12 hours in vitro demonstrated an increase of HIF-1 RNA expression. Electrophoretic mobility shift assays using oligonucleotides containing the iNOS HIF-1 DNA binding site and nuclear extracts from cardiac myocytes showed induction of specific DNA binding in cells subjected to hypoxia. Transient transfection of cardiac myocytes using the murine iNOS promoter resulted in a 3.43-fold increase in promoter activity under hypoxia compared with normoxia. Mutation or deletion of the HIF-1 site eliminated the hypoxic response. As cytokines have been shown to regulate iNOS expression in myocardial cells, cultured neonatal cardiac myocytes were stimulated with interleukin-1beta causing a dramatic induction of iNOS protein expression under normoxia, with further augmentation under hypoxia. Transient transfection of cells stimulated with interleukin-1beta showed an increased iNOS promoter activity under normoxic conditions compared with unstimulated cells, with a further increase in response to hypoxia, which was dependent on HIF-1. These results demonstrate that hypoxia causes an increase in iNOS expression in cardiac myocytes and that HIF-1 is essential for the hypoxic regulation of iNOS gene expression.

Animals↗
PubMed2000

Expression of PSD-95/SAP90 is critical for N-methyl-D-aspartate receptor-mediated thermal hyperalgesia in the spinal cord.

PSD-95/SAP90, a molecular scaffold protein, attaches the N-methyl-D-aspartate receptor to cellular signaling pathways through PSD-95/DLG/Z0-1 domain interactions at neuronal synapses.(5,9) This suggests that PSD-95/SAP90 might be involved in many physiological and pathophysiological actions triggered via the N-methyl-D-aspartate receptor in the central nervous system. Here, we present evidence that suppression of the expression of PSD-95/SAP90 in the spinal cord significantly attenuated facilitation of the tail-flick reflex triggered through N-methyl-D-aspartate receptor activation but not baseline tail-flick reflex latency. Moreover, PSD-95/SAP90's messenger RNA and protein were enriched in the spinal cord and selectively distributed in the superficial dorsal horn, where PSD-95/SAP90 overlapped with the N-methyl-D-aspartate receptor. In spinal cord neurons, PSD-95/SAP90 interacted with the N-methyl-D-aspartate receptor subunits 2A/2B. It is indicated that activation of the N-methyl-D-aspartate receptor in spinal hyperalgesia results in association of the N-methyl-D-aspartate receptor with PSD-95/SAP90 and that PSD-95/SAP90 is required for noxious thermal hyperalgesia triggered via the N-methyl-D-aspartate receptor at the spinal cord level. The present findings may provide novel insights into the mechanisms for persistent sensitization of the somatosensory system.

Animals↗
PubMed2000

Expression and action of cyclic GMP-dependent protein kinase Ialpha in inflammatory hyperalgesia in rat spinal cord.

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.

Animals↗