2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Pain

The ionotropic glutamate receptorantagonists include two types: MK-801, antagonist of N-methyl-D-asparticacid (NMDA) receptor, and NBQX, antagonist of non-NMDA receptor.The above-mentioned ionotropic antagonists can block the glutamate and its corresponding receptor binding to produce analgesic effect. The objective of this research was to study two antagonists in analgesic effect on rat behavior,as well as to investigate the down-regulation and up-regulation of cyclooxygenase-2 (COX-2) and Janus-activated kinase (Jak3) in collagen-induced arthritis (CIA) rat serum and tissue fluid after the application of these antagonists, that is, the effect on molecular biology.. This study used the ionotropic glutamate receptors as the target and established CIA rat model. Vivo studies were used to observe changes in behavior and molecular biology of the CIA rat.Behavioral assessment includedmechanical allodynia and joint swelling in the CIA rat,where themechanical allodynia was measured using the paw-withdrawal threshold (PWT) with VonFrey filaments according to the "Up-Down" method,and the drainage volume was used to assess joint swelling. Then the blood samples taken from the heart of the rat and the tissue homogenate were collected to detect the down-regulation and up-regulation of COX-2 and Jak3 in the serum and tissue fluid after the antagonists wereused.. Using MK-801, NBQX alone or using the combination of these two antagonists,these three methods all could alleviate pain(P<0.01).The analgesic effect lasted more than 24 h.Both antagonists reached the peak of analgesia at the end of 4 hours post-injection. NBQX had stronger analgesic effect than MK-801 (P<0.05).Whether alone or combined use of these two antagonists,could not change the CIA rats' swelling of the joint (P>0.05). MK-801 could decrease the expression of COX-2 (P<0.01).At the same time, NBQX did not have this effect (P>0.05). Using MK-801, NBQX alone or combination of these two antagonists could not affect the increased expression of Jak3 caused by the CIA (P>0.05).. MK-801 and NBQX could both alleviate pain, NBQX was much better than MK-801. Neither MK-801 nor NBQX had the effect on the swelling of the joint. NMDA receptor and COX-2 inflammatory pathways had certain interactions. For Jak3, it could not be found to have cross-function with ionotropic glutamate signaling pathways by this experiment.

Topics: Analgesics; Animals; Arthritis, Experimental; Cyclooxygenase 2; Dizocilpine Maleate; Edema; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Hyperalgesia; Janus Kinase 3; Male; Pain; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate

Synovial fluid glutamate concentrations increase in arthritis. Activation of kainate (KA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors (GluRs) increase interleukin-6 (IL-6) release and cause arthritic pain, respectively. We hypothesised that AMPA and KA GluRs are expressed in human arthritis, and that intra-articular NBQX (AMPA/KA GluR antagonist) prevents pain and pathology in antigen-induced arthritis (AIA).. GluR immunohistochemistry was related to synovial inflammation and degradation in osteoarthritis (OA) and rheumatoid arthritis (RA). A single intra-articular NBQX injection was given at induction, and knee swelling and gait of AIA and AIA+NBQX rats compared over 21 days, before imaging, RT-qPCR, histology and immunohistochemistry of joints. Effects of NBQX on human primary osteoblast (HOB) activity were determined.. AMPAR2 and KA1 immunolocalised to remodelling bone, cartilage and synovial cells in human OA and RA, and rat AIA. All arthritic tissues showed degradation and synovial inflammation. NBQX reduced GluR abundance, knee swelling (p<0.001, days 1-21), gait abnormalities (days 1-2), end-stage joint destruction (p<0.001), synovial inflammation (p<0.001), and messenger RNA expression of meniscal IL-6 (p<0.05) and whole joint cathepsin K (p<0.01). X-ray and MRI revealed fewer cartilage and bone erosions, and less inflammation after NBQX treatment. NBQX reduced HOB number and prevented mineralisation.. AMPA/KA GluRs are expressed in human OA and RA, and in AIA, where a single intra-articular injection of NBQX reduced swelling by 33%, and inflammation and degeneration scores by 34% and 27%, respectively, exceeding the efficacy of approved drugs in the same model. AMPA/KA GluR antagonists represent a potential treatment for arthritis.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Behavior, Animal; Cartilage, Articular; Excitatory Amino Acid Antagonists; Humans; Immunohistochemistry; Inflammation; Interleukin-6; Knee Joint; Male; Menisci, Tibial; Osteoarthritis; Osteoblasts; Pain; Quinoxalines; Radiography; Rats; Receptors, AMPA; Receptors, Kainic Acid; Synovial Membrane

Ascending nociceptive control is a novel spino-striato-rostral ventral medulla pain modulation pathway that mediates heterosegmental pain-induced analgesia, i.e., noxious stimulus-induced antinociception. In this study, we used the dorsal immobility response in rats as a model of the defensive responses. We demonstrated that the activation of ascending nociceptive control by peripheral noxious stimulation and spinal AMPA and mGluR1 receptor blockade significantly potentiated the duration of the dorsal immobility response in rats via an opioid-dependent mechanism in the nucleus accumbens. These results demonstrated the functional role of ascending nociceptive control in the modulation of defensive responses and spinal glutamatergic receptors in the dorsal immobility response. The immobility response is an antipredator behavior that reflects the underlying state of fear, and ascending nociceptive control may modulate fear.

Topics: Animals; Benzoates; Excitatory Amino Acid Antagonists; Glycine; Immobility Response, Tonic; Male; Motor Activity; Neural Pathways; Nociception; Nucleus Accumbens; Pain; Quinoxalines; Rats; Rats, Wistar; Somatostatin

Allodynia or hyperalgesia induced by peripheral nerve injury may be involved in changes in the sensitivity of neurotransmitters at the spinal cord level. In order to clarify the functional role of neurotransmitters in peripheral nerve injury, we used rats with nerve injury induced by chronic constriction of the sciatic nerve (CCI rat model) and estimated the effects of the intrathecal injection of drugs known to affect glutamate and tachykinin receptors. In sham-operated rats, the NMDA receptor agonist NMDA and AMPA-kinate receptor agonist RS-(5)-bromowillardin reduced withdrawal latency. The non-competitive NMDA receptor antagonist MK-801, competitive NMDA receptor antagonist AP-5 and AMPA-kinate receptor antagonist NBQX increased withdrawal latency. Substance P (SP) increased the withdrawal latency but only transitorily. The NK1 receptor antagonist RP67580 increased withdrawal latency, but the NK2 receptor antagonist SR48968 did not show an effect. In CCI rats, RS-(5)-bromowillardin reduced withdrawal latency, but NMDA did not show an effect. NBQX increased withdrawal latency, while MK-801 and AP-5 showed little or no effect. SP reduced withdrawal latency, and both RP67580 and SR48968 increased it. These results indicate that the alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in the spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain.

Topics: Alanine; Analgesics; Animals; Behavior, Animal; Benzamides; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Indoles; Isoindoles; Male; N-Methylaspartate; Pain; Pain Measurement; Piperidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Kainic Acid; Receptors, Tachykinin; Sciatic Nerve; Spinal Cord; Substance P; Valine

Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Amino Acids; Analgesics; Animals; Biological Availability; Cell Line; Disease Models, Animal; Humans; Hyperalgesia; Pain; Rats; Receptors, AMPA; Receptors, Kainic Acid; Recombinant Proteins; Spinal Cord

Adenosine and excitatory amino acids have been known to be involved in modulating nociceptive transmission at the spinal level. The authors assessed the characteristics of the interaction of the adenosine-excitatory amino acid antagonist combinations in the spinal cord of rats on the formalin-induced nociception. Intrathecal NMDA antagonist ((5R, 10S)-(+)-5-methyl-10,11-dihydro-(5)H-dibenzo[a[,]d]cyclohepten-5,10-imine hydrogen maleate, MK801, 30 microg) and AMPA antagonist (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[F]quinoxaline-7-sulfonamide, NBQX, 3 microg) decreased the total number of flinches during both phases in the formalin test. Intrathecal adenosine (300 microg) had little effect on the phase 1 flinching response, but decreased the phase 2 response. The fixed dose analysis and the isobolographic analysis revealed that adenosine interacts additively with MK801 and NBQX in the spinal cord.

Topics: Adenosine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Disease Models, Animal; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Formaldehyde; Injections, Spinal; Male; N-Methylaspartate; Pain; Quinoxalines; Rats; Rats, Sprague-Dawley

1. Ingestion of a poisonous mushroom Clitocybe acromelalga is known to cause severe tactile pain (allodynia) in the extremities for a month and acromelic acid (ACRO), a kainate analogue isolated from the mushroom, produces selective damage of interneurons of the rat lower spinal cord when injected either systemically or intrathecally. Since ACRO has two isomers, ACRO-A and ACRO-B, here we examined their acute and late effects on induction of allodynia. 2. Intrathecal administration of ACRO-A and ACRO-B provoked marked allodynia by the first stimulus 5 min after injection, which lasted over the 50-min experimental period. Dose-dependency of the acute effect of ACRO-A on induction of allodynia showed a bell-shaped pattern from 50 ag x kg(-1) to 0.5 pg x kg(-1) and the maximum effect was observed at 50 fg x kg(-1). On the other hand, ACRO-B induced allodynia in a dose-dependent manner from 50 pg x kg(-1) to 50 ng x kg(-1). 3. N-methyl-d-aspartate (NMDA) receptor antagonists and Joro spider toxin, a Ca(2+)-permeable AMPA receptor antagonist, inhibited the allodynia induced by ACRO-A, but not by ACRO-B. However, other AMPA/kainate antagonists did not affect the allodynia induced by ACRO. 4. Whereas no neuronal damage was observed in the spinal cord in ACRO-A-treated mice, induction of allodynia by ACRO-A (50 fg x kg(-1)) and ACRO-B (50 ng x kg(-1)) was selectively lost 1 week after i.t. injection of a sublethal dose of ACRO-A (50 ng x kg(-1)) or ACRO-B (250 ng x kg(-1)). Higher doses of ACRO-A, however, could evoke allodynia dose-dependently from 50 pg x kg(-1) to 500 ng x kg(-1) in the ACRO-A-treated mice. The allodynia induced by ACRO-A (500 ng x kg(-1)) was not inhibited by Joro spider toxin or NMDA receptor antagonists. These properties of the late allodynia induced by ACRO-A were quite similar to those of the acute allodynia induced by ACRO-B. 5. ACRO-A could increase [Ca(2+)](i) in the deeper laminae, rather than in the superficial laminae, of the spinal cord. This increase was not blocked by the AMPA-preferring antagonist GYKI52466 and Joro spider toxin. 6. Taken together, these results demonstrate the stereospecificity of ACRO for the induction of allodynia and suggest the presence of a receptor specific to ACRO.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Basidiomycota; Benzodiazepines; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glutamates; Heterocyclic Compounds; Indoles; Injections, Spinal; Japan; Kainic Acid; Lumbosacral Region; Male; Mice; Mice, Inbred Strains; Mushroom Poisoning; Oximes; Pain; Quinoxalines; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Spider Venoms; Spinal Cord; Stereoisomerism; Structure-Activity Relationship; Time Factors

The latero-capsular division of the central nucleus of the amygdala (CeA) is now defined as the 'nociceptive amygdala' because of its high content of neurons activated exclusively or preferentially by noxious stimuli. Multireceptive (MR) neurons that respond to innocuous and, more strongly, to noxious stimuli become sensitized in arthritis pain. This form of nociceptive plasticity involves presynaptic group I metabotropic glutamate receptors, which increase glutamate release. Here we address the role of N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Extracellular single-unit recordings were made from 25 CeA neurons in anesthetized rats. The neurons' responses to graded brief (15 s) mechanical stimuli, background activity, receptive field size and threshold were measured before and after the induction of kaolin/carrageenan arthritis in one knee and before and during drug applications into the CeA by microdialysis. All neurons examined received excitatory input from the knee(s) and were MR neurons. A selective NMDA receptor antagonist (AP5) inhibited responses to noxious stimuli more potently in the arthritic pain state (n = 6) than under control conditions before arthritis (n = 8) AP5 also inhibited the enhanced background activity and increased responses to normally innocuous stimuli in arthritis, but had no significant effects on these parameters under control conditions. A selective non-NMDA receptor antagonist (NBQX) inhibited background activity and evoked responses under normal control conditions (n = 6) and in arthritis (n = 8) These data suggest that activation of both NMDA and non-NMDA receptors contributes to pain-related sensitization of amygdala neurons.

Topics: 2-Amino-5-phosphonovalerate; Action Potentials; Amygdala; Analysis of Variance; Animals; Arthritis; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Kaolin; Male; Neural Inhibition; Neurons; Nociceptors; Pain; Pain Measurement; Physical Stimulation; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

The effects of systemic administration of the novel AMPA/GluR5 selective receptor antagonist NS1209 in animal models of experimental pain have been tested and compared with the AMPA receptor antagonist NBQX and the opiate morphine. In the mouse hot plate test, NS1209 (3-30 mg/kg, s.c. and i.p.) and morphine (3-30 mg/kg, s.c.) significantly increased the nociceptive response latency, whereas NBQX (3-30 mg/kg, i.p.) was ineffective. In the rat formalin test, a model of persistent pain, NS1209 (3 and 6 mg/kg, i.p.) and morphine (0.5 and 3 mg/kg, s.c.) produced dose-dependent reductions in second phase nociceptive behaviours, although NBQX (10 and 20 mg/kg, i.p.) was without effect. In the chronic constriction injury model of neuropathic pain, NS1209 (3 and 6 mg/kg, i.p.), NBQX (10 and 20 mg/kg, i.p.) and morphine (3 and 6 mg/kg, s.c.) all reduced mechanical allodynia and hyperalgesia responses to von Frey hair and pin prick stimulation of the injured hindpaw. NS1209 and morphine also reduced cold hypersensitivity in response to ethyl chloride stimulation of the injured hindpaw. At the doses associated with anti-nociceptive actions, no effects on motor performance as determined by the rotarod test were observed for any of the drugs tested. Thus, systemic administration of NS1209 at non-ataxic doses has marked analgesic actions comparable to those of morphine in a range of animal models of experimental pain.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Excitatory Amino Acid Antagonists; Male; Morphine; Narcotics; Pain; Pain Measurement; Pain Threshold; Peripheral Nervous System Diseases; Pyrroles; Quinoxalines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Kainic Acid; Tetrahydroisoquinolines; Time Factors

To determine whether both the N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the knee joint contribute to the induction and/or maintenance of arthritic pain, we examined the effects of intra-articular injection of NMDA receptor antagonist dizocilpine (MK-801) and non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX) on the decrease in weight load induced by carrageenan injection into the knee joint cavity in rats. Injection of MK-801 (0.75 and 1.5 mM) and NBQX (0.25, 0.625 and 2.5 mM) immediately prior to carrageenan injection (2%, 40 microl) significantly prevented the pain-related behavior. However, injection of MK-801 (0.75 and 1.5 mM) and NBQX (0.625 and 2.5 mM) 5 h after carrageenan injection had no effect on pain-related behavior. These results suggest that both the NMDA and non-NMDA receptors in the knee joint are involved in the induction, but not maintenance, of arthritic pain.

Topics: Animals; Arthritis, Experimental; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Joints; Male; Pain; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Time Factors

Intraspinal injection of quisqualic acid, a mixed kainic acid/2-amino-3(3-hydroxy-5-methylisoxazol-4-yl)propionic acid and metabotropic glutamate receptor agonist, produces an excitotoxic injury that leads to the onset of both spontaneous and evoked pain behavior as well as changes in spinal and cortical expression of opioid peptide mRNA, preprodynorphin and preproenkephalin. What characteristics of the quisqualic acid-induced injury are attributable to activation of each receptor subtype is unknown. This study attempted to define the role of activation of the kainic acid/2-amino-3(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and metabotropic glutamate receptor subtypes in the regulation of opioid peptide expression and the onset of spontaneous and evoked pain-related behavior following excitotoxic spinal cord injury by comparing quisqualic acid-induced changes with those created by co-injection of quisqualic acid and the kainic acid/AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline, (NBQX) or the metabotropic antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA). Therefore, 42 male Long-Evans adult rats were divided into seven treatment groups and received intraspinal microinjections of saline (sham), 0.5% dimethylsulphoxide (sham), quisqualic acid (1.2 microl, 125 mM), NBQX (1.2 microl, 60 microM), AIDA (1.2 microl, 250 microM), quisqualic acid/NBQX (1.2 microl, 125 mM/60 microM), or quisqualic acid/AIDA (1.2 microl, 125 mM/250 microM) directed at spinal levels thoracic 12-lumbar 2. Behavioral observations of spontaneous and evoked pain responses were completed following surgery. After a 10-day survival period, animals were killed and brain and spinal cord tissues were removed and processed for histologic analysis and in situ hybridization. Both AIDA and NBQX affected the quisqualic acid-induced total lesion volume but only AIDA caused a decrease in the percent tissue damage at the lesion epicenter. Preprodynorphin and preproenkephalin expression is increased in both spinal and cortical areas in quisqualic acid-injected animals versus sham-, NBQX or AIDA-injected animals. NBQX did not affect quisqualic acid-induced spinal or cortical expression of preprodynorphin or preproenkephalin except for a significant decrease in preproenkephalin expression in the spinal cord. In contrast, AIDA significantly decreases quisqualic acid-induced preprodynorphin and preproenkephalin expression within the spinal cord and cortex. AIDA, b

Topics: Animals; Behavior, Animal; Dynorphins; Enkephalins; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Grooming; Indans; Male; Nerve Degeneration; Neurons; Neurotoxins; Opioid Peptides; Pain; Pain Measurement; Protein Precursors; Quinoxalines; Rats; Rats, Long-Evans; Receptors, AMPA; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, Metabotropic Glutamate; RNA, Messenger; Spinal Cord; Spinal Cord Injuries

The aim of the present in vivo microdialysis study was to determine the possible contribution of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) receptors to capsaicin-induced release of substance P-like immunoreactivity (SP-LI) in the dorsal horn of the rat. Perfusion of a microdialysis probe with capsaicin (50 or 100 microM) induced a significant eight-fold increase of the extracellular SP-LI level. The capsaicin (50 microM)-evoked release of SP-LI was blocked by spinal administration of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (D-APV; 5 mM), but not by the AMPA/KA antagonist 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione disodium (NBQX; 0.5 mM). In contrast, the SP-LI release induced by 100 microM capsaicin could not be prevented by D-APV (10 mM) or NBQX (0.5 mM). The data suggest that the spinal SP-LI release induced by a moderate concentration of capsaicin is in part dependent on the release of glutamate acting on NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; Animals; Capsaicin; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Microdialysis; Nerve Fibers; Nociceptors; Pain; Posterior Horn Cells; Quinoxalines; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Substance P; Synapses; Synaptic Transmission

Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and thermal allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of thermal allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the thermal allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.

Topics: Animals; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hyperalgesia; Injections, Spinal; Male; Motor Activity; Pain; Physical Stimulation; Quinoxalines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Cord Injuries; Valine

To examine the involvement of different ionotropic glutamate receptors in the mediation of responses evoked by noxious cutaneous stimulation, single unit recordings were made from 31 neurons in the primary somatosensory (SI) cortex of rats anesthetized with urethane. To compare synaptic receptor pharmacology across somatosensory submodalities, 13 of the neurons were also tested with an innocuous, cutaneous air jet stimulus. Mechanical (HT) responses, evoked by a 5-s noxious pinch, decayed gradually upon termination of the stimulus and lasted on average for 15.1+/-1.9 s (+/-SEM; n=10). An increase in baseline activity was also observed during noxious stimulus trials of 5-min stimulus intervals. A correlation between increase in mechanical or thermal HT responses and baseline activity was found for some neurons. However, the normalized ratios of the mechanical or thermal HT response to baseline activity during iontophoretic application of (RS)-3-(2-carboxypiperazine-4-yl)-propyl-l-phosphonic acid (CPP), an N-methyl-D-aspartic acid (NMDA) receptor antagonist (0.6+/-0.1; n=11, or 6-nitro-7-sulfamoylbenz[f]quinoxaline-2,3-dione (NBQX), an (RS)-alpha-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist (0.8+/-0.1; n=11), suggest that the reductions in baseline activity did not account for the reductions of the mechanical or thermal HT responses observed, which were reduced proportionally more than the baseline activity. A 10-ms air jet evoked a biphasic increase in action potentials above an average background activity of 7+/-2 spikes/s (n=13). The early phase of this low-threshold (LT) response was within two or three 10-ms bins and had an average firing rate of 74+/-11 spikes/s evoked in the first 10-ms bin (n=13). In eight neurons, the early LT response was followed by a lower frequency excitatory component lasting an average of 415+/-92 ms. Iontophoretic application of CPP reduced responses evoked by a noxious pinch (21+/-10% of control responses; n=19) and a noxious thermal stimulus (24+/-18%; n=5). The fast component of the LT responses was only reduced to 85+/-4% (n=12). A slower component of the LT responses, when present, was also reduced by CPP (15+/-19%; n=4). Iontophoretic application of NBQX reduced responses evoked by a noxious pinch (42+/-12%; n=19) and a noxious thermal stimulus (63+/-16%; n=8). The fast component of the LT responses was reduced to 43+/-6% (n=12) and the slower component to 32+/-20% (n=6). These d

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Excitatory Amino Acid Antagonists; Hot Temperature; Male; N-Methylaspartate; Neurons; Pain; Piperazines; Quinoxalines; Rats; Rats, Wistar; Reaction Time; Receptors, Glutamate; Skin; Somatosensory Cortex; Synapses; Time Factors

LTP is often studied as a model of synaptic plasticity. Plasticity in pain control systems may involve mechanisms similar to those involved in learning. We recently reported LTP of both the A beta and C-fibre evoked responses of single dorsal horn neurons after a tetanic stimulation of the sciatic nerve, lasting for at least 6 h. In the present paper we show that identical stimulation induced LTP only of the C-fibre evoked response after blockade of muscular contractions during the tetanus. The C-fibre evoked response increased significantly less after pretreatment with either the AMPA antagonist NBQX or the NMDA antagonist D-AP5 (mean increase 33%) than in untreated animals (105%, p < 0.001), indicating that both AMPA and NMDA receptor stimulation are involved in the induction of LTP.

Topics: 2-Amino-5-phosphonovalerate; Analysis of Variance; Animals; Excitatory Amino Acid Antagonists; Female; Long-Term Potentiation; Muscle Contraction; Pain; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Spinal Cord

1. Rats develop tactile allodynia to stimulation of the plantar surface of the hindpaw with von Frey filaments within days of the onset of streptozotocin-induced diabetes. This is prevented by insulin and alleviated by systemic lignocaine, but the aetiology is unknown. 2. Using indwelling lumbar intrathecal catheters to deliver pharmacological agents, we have investigated whether tactile allodynia in streptozotocin-diabetic rats is dependent on mechanisms associated with spinal sensitization, by assessing the efficacy of agents that inhibit specific components of spinal nociceptive processing. 3. Dose-dependent inhibition of tactile allodynia in diabetic rats was noted with the N-type calcium channel antagonist SNX 239, the alpha2-adrenoceptor agonist dexmedetomidine, the mu-opioid receptor agonist morphine, the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 and the non-NMDA receptor antagonist NBQX. 4. No effect on tactile allodynia was noted after intrathecal administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), the cyclo-oxygenase inhibitor ketorolac, the L-type calcium channel inhibitor diltiazem or any vehicle. 5. These data suggest that the tactile allodynia of diabetic rats involves spinal glutamatergic pathways but is not associated with spinal release of nitric oxide or prostaglandins.

Topics: 2-Amino-5-phosphonovalerate; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Anti-Bacterial Agents; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Imidazoles; Injections, Spinal; Medetomidine; Morphine; Pain; Quinoxalines; Rats; Rats, Sprague-Dawley; Spinal Cord; Streptozocin

Touch-evoked allodynia, an important symptom of clinical neural injury pain, can be modelled acutely and reversibly in the urethane-anesthetized rat using intrathecal (i.t.) strychnine (STR). Allodynia, after i.t. STR (40 micrograms), is manifest as a significant enhancement of cardiovascular and motor responses evoked by normally innocuous brushing of the hair (hair deflection), as compared to responses evoked by either hair deflection after i.t. saline (SAL), or to i.t. STR (40 micrograms) with no tactile stimulus. The present study investigated: (1) the pharmacology of afferent neural inputs involved in STR-dependent allodynia using neonatal capsaicin and the non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX); and (2) the effect of i.t. STR on responses evoked by peripheral noxious stimulation. Neonatal capsaicin (25 mg/kg, s.c., post-natal day (PND) 1, and 50 mg/kg, s.c., PND 2, 3, 4, 11, 25, 55 and 85) significantly attenuated the responses evoked by noxious mechanical, thermal or chemical stimuli, but had no effect on STR-dependent allodynia. All hair deflection-evoked, STR-dependent responses were dose-dependently inhibited by i.t. NBQX. The ED50 values and 95% confidence intervals were 10.4 micrograms (5.5-19.6) for the motor withdrawal response, 14.4 micrograms (8.6-24.0) for changes in MAP and 12.2 micrograms (6.8-21.8) for changes in HR. Cortical EEG synchrony was unchanged by i.t. NBQX confirming its spinal locus of action. Intrathecal STR neither reduced nor enhanced the responses elicited by noxious stimuli in capsaicin- or vehicle-pretreated rats. These results indicate that STR-dependent allodynia is initiated by primary afferents not normally involved in nociception (possibly A beta-fibers), and that STR-sensitive modulation in the spinal cord is selective for non-noxious sensory input. The sensitivity of STR-dependent allodynia to non-NMDA receptor antagonists, and the failure of i.t. STR to produce hyperalgesia to mechanical, thermal or chemical noxious stimuli, confirm the independence of nociceptive pathways and STR-sensitive afferent inputs in this model.

Topics: Anesthesia, General; Animals; Animals, Newborn; Blood Pressure; Capsaicin; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Injections, Spinal; Male; Nerve Fibers; Pain; Physical Stimulation; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Strychnine

We have previously reported that transient spinal cord ischemia induced a behavioral hypersensitivity (allodynia) to innocuous cutaneous mechanical stimulation in rats. The spinal ischemia-induced allodynia was not relieved by morphine, but it was relieved by the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen, indicating that the allodynia may be related to dysfunction of the spinal GABA-ergic inhibitory system. In the present study we report that systemic application of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor for excitatory amino acids, dose-dependently relieved allodynia after spinal cord ischemia. The analgesic effect of NBQX at a low dose (7.5 mg/kg) was not accompanied by motor deficits or sedation. On the other hand, the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) only partially alleviated allodynia, even at doses that produced severe motor deficits. It is suggested that the abnormal, possibly painful, sensations elicited by innocuous mechanical stimulation observed after spinal cord ischemia may be mediated by excitatory amino acids, acting mainly on the AMPA receptor. Antagonists of excitatory amino acid receptors, especially at the AMPA site, may be effective in treating pain conditions where input from low threshold afferents triggers painful sensations.

Topics: Animals; Dizocilpine Maleate; Female; Pain; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Reperfusion Injury; Skin Physiological Phenomena; Spinal Cord; Vocalization, Animal

In urethane-anesthetized rats, xylene applied locally to the skin of the hind paws was shown to induce reflex increases of blood pressure (33%) and heart rate (37%). The blood pressure elevation was dose dependently inhibited by the NMDA antagonist, MK-801 (0.3-1.0 mg/kg i.v.), and by the AMPA (D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxalonepropionic acid) antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline 0.1-1.0 mg/kg per min). In contrast, only the latter compound was shown to block dose dependently the observed increase in heart rate. The results suggest that the two glutamate antagonists inhibit nociceptive impulse traffic at distinct anatomical sites and/or by different modes of actions.

Topics: Animals; Blood Pressure; Cardiovascular Physiological Phenomena; Cardiovascular System; Dizocilpine Maleate; Female; Heart Rate; Pain; Propranolol; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, AMPA; Receptors, Neurotransmitter; Reflex; Skin; Skin Physiological Phenomena