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Biomedical subjects

A A Larson

Publications and source records attributed to A A Larson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Manipulations of zinc in the spinal cord, by intrathecal injection of zinc chloride, disodium-calcium-EDTA, or dipicolinic acid, alter nociceptive activity in mice.

Zinc is concentrated in the dorsal horn of the spinal cord and has been proposed to alter excitability of primary afferent C-fibers, structures believed to be important in nociceptive transmission. Based on the inhibitory effect of zinc on the activity of various other neurotransmitters that play a role in nociception, we tested the hypothesis that zinc modulates pain transmission. To test this, we examined the effect of exogenous zinc, administered intrathecally (i.t.), on nociception in the mouse. We also assessed the impact of decreased concentrations of endogenously occurring zinc in the extracellular fluid brought about by an i.t. injection of either ethylenediaminetetraacetic acid disodium-calcium salt (Ca++EDTA), a calcium-saturated, membrane-impermeable chelator of divalent cations, or of dipicolinic acid, a zinc chelator. Injection of zinc produced a dose-related antinociceptive effect, optimal at 90 min in the writhing assay, but had no effect on tail-flick response latencies. In contrast, injection of either Ca++EDTA or dipicolinic acid produced a dose-related hyperalgesia in the tail-flick assay at 90 min after injection. Responses induced in the writhing assay were unaffected by Ca++EDTA. Although zinc had no effect on thermal nociception, the hyperalgesic effect of Ca++EDTA was antagonized by coadministration of Ca++EDTA with zinc. Similarly, the antinociceptive effect of zinc on writhing responses was attenuated when coadministered with Ca++EDTA. Zinc also inhibited primary afferent C-fiber activity because 10 ng of zinc i.t. inhibited the behavioral response induced by injection i.t. of 1 nmol of capsaicin. Neither zinc nor Ca++EDTA altered writhing or tail-flick latencies, respectively, when injected intracerebroventricularly. These findings support the hypothesis that endogenous zinc, localized in the dorsal horn of the spinal cord, plays a role in the regulation of pain.

Analgesics↗
PubMed1997

Mutual antagonism between nerve growth factor and substance P N-terminal activity on nociceptive activity in mice.

Nerve growth factor (NGF) induces a relatively long-term hyperalgesia in rats, whereas substance P (SP) N-terminal fragments, like SP(1-7), produce a long-lasting antinociception in mice. We used various nociceptive assays to compare the effects of these compounds on pain transmission when injected intrathecally (i.t.) in mice, and to determine whether either compound affects the action of the other. NGF produced thermal hyperalgesia when injected i.t. in mice 24 and 48 hr before testing by the tail-flick assay. During this same interval, NGF elicited no effect on the response to von Frey fibers or on chemically induced nociception measured by the writhing assay. In contrast to NGF, SP(1-7) had no effect on tail-flick latencies but induced antinociception in the writhing assay 24 hr after injection. When administered 2 hr before NGF, SP(1-7) antagonized the thermal hyperalgesic effect of NGF in a dose-related fashion, despite the inability of SP(1-7) to alter tail-flick latency when administered alone. NGF, in turn, antagonized the antinociceptive effects of SP(1-7) in the writhing assay. The D-amino acid-substituted analog, D-SP(1-7), failed to mimic the antinociceptive effect of SP(1-7) or to alter the hyperalgesic effect of NGF, which indicated a stereoselective action of SP(1-7). D-SP(1-7), that inhibits SP(1-7) binding, did reverse the ability of SP(1-7) to antagonize NGF-induced hyperalgesia, consistent with its action as a SP N-terminal antagonist. Mutual antagonism between NGF and SP may reflect modulatory roles of these endogenously occurring peptides during chronic pain when N-terminal metabolites of SP may accumulate.

Analgesics↗
PubMed1996

Simultaneous assessment of loss of heterozygosity at multiple microsatellite loci using semi-automated fluorescence-based detection: subregional mapping of chromosome 4 in cervical carcinoma.

Detection of loss of heterozygosity (LOH) by comparison of normal and tumor genotypes using PCR-based microsatellite loci provides considerable advantages over traditional Southern blotting-based approaches. However, current methodologies are limited by several factors, including the numbers of loci that can be evaluated for LOH in a single experiment, the discrimination of true alleles versus "stutter bands," and the use of radionucleotides in detecting PCR products. Here we describe methods for high throughput simultaneous assessment of LOH at multiple loci in human tumors; these methods rely on the detection of amplified microsatellite loci by fluorescence-based DNA sequencing technology. Data generated by this approach are processed by several computer software programs that enable the automated linear quantitation and calculation of allelic ratios, allowing rapid ascertainment of LOH. As a test of this approach, genotypes at a series of loci on chromosome 4 were determined for 58 carcinomas of the uterine cervix. The results underscore the efficacy, sensitivity, and remarkable reproducibility of this approach to LOH detection and provide subchromosomal localization of two regions of chromosome 4 commonly altered in cervical tumors.

Chromosome Deletion↗
PubMed1996

Evidence that the NH2-terminus of substance P modulates N-methyl-D-aspartate-induced activity by an action involving sigma receptors.

Behaviors induced in mice by intrathecal injections of either N-methyl-D-aspartate (NMDA) or kainic acid are modulated by NH2-terminal fragments of substance P, such as substance P-(1-7). The action of substance P-(1-7) on kainic acid depends on sigma receptor activity. The present study was designed to test the hypothesis that sigma receptor activity is also necessary for modulation of NMDA by substance P-(1-7). Intrathecal injection of mice with NMDA results in a brief burst of biting and scratching behaviors which decrease in intensity when NMDA is injected repeatedly at 2 min intervals. Pretreatment with 1,3-di-O-tolylguanidine (DTG), a ligand at both sigma 1 and sigma 2 sites, converted NMDA-induced desensitization to sensitization, thereby enhancing tonic NMDA receptor activity. Although haloperidol (30 min) alone was without effect, the potentiation of NMDA-induced activity by DTG was abolished by haloperidol but unaffected by an equimolar dose of either spiperone or thiothixine, two dopamine receptor antagonists. When mice received substance P-(1-7), NMDA-induced behaviors were initially inhibited but then potentiated. Pretreatment with haloperidol prevented both inhibitory and potentiative effects of substance P-(1-7) whereas thiothixine did not, suggesting inhibitory as well as potentiative modulation of NMDA by sigma receptor activity. Endogenous sigma 1 receptor activity may enhance NMDA receptor activity as a treatment regimen that down-regulates sigma 1 binding also inhibited responses to NMDA. In contrast, pretreatment with haloperidol just 5 min prior to challenge, which blocks both sigma 1 and sigma 2 receptor activity, increased responses to NMDA suggesting an inhibitory effect of sigma 2 receptor activity. In summary, modulation of NMDA by substance P-(1-7) appears to depend on activity at sigma sites as substance P-(1-7) mimicked the potentiative effects of DTG, while haloperidol inhibited the effects of both DTG and substance P-(1-7).

Analysis of Variance↗
PubMed1996

Analysis of replication error (RER+) phenotypes in cervical carcinoma.

Infection of epithelial cells with human papillomavirus is an important early event in the development of cervical dysplasia. However, progression to overt malignancy appears dependent upon further genetic and/or epigenetic events. We have recently developed methodologies for the simultaneous analysis of loss of heterozygosity (LOH) at multiple PCR-based microsatellite loci using semiautomated fluorescent DNA sequencing technology to determine the locations of tumor suppressor genes which are inactivated during tumor progression. While examining 30 microsatellite loci for LOH on chromosomes 3p, 4, and 11q, we detected novel tumor-specific alleles indicative of microsatellite instability (MI). The methodology allowed rapid and accurate comparison of over 3000 genotypes from 89 primary tumors and 10 cervical carcinoma-derived cell lines and showed that five tumors (5.6%) and one human papillomavirus-negative cell line, C33A, had genetic features consistent with a replication error (RER+) phenotype as defined by MI at two or more loci. In each of the RER+ tumors, LOH was also observed at one or more loci on each of the three chromosomes examined. These findings suggest that defects in DNA repair-associated genes are rarely acquired and do not supersede allelic loss during cervical carcinogenesis. In addition, the semiautomated multiplex approach has proven unequivocal in the detection and interpretation of MI and should greatly accelerate the rapidity and accuracy of analysis of such defects in tumors. Moreover, the number of loci that can be relatively easily examined in this way will also allow a detailed statistical consideration of the importance of such events.

Chromosomes, Human, Pair 11↗
PubMed1996

Role of substance P in the modulation of C-fiber-evoked responses of spinal dorsal horn neurons.

Substance P (SP) as well as excitatory amino acids (EAAs) appear to be released in response to stimulation of primary afferent C-fibers. Activity at N-methyl-D-aspartate (NMDA) receptors is essential for wind-up (the progressive potentiation of C-fiber-evoked responses of single neurons in response to an electrical stimulation), however, the role of SP in wind-up is unclear. To address this, the effects of iontophoretically applied CP-99,994 (a NK-1 receptor antagonist), SP and SP(1-7) (an N-terminal breakdown product of SP), were compared on responses of spinal dorsal horn wide dynamic range (WDR) neurons of the rat. Post-stimulus time histograms (PSTH) were summed over 12 responses to low frequency (0.5 Hz) electrical stimulation of the cutaneous receptive field. Changes in responses of dorsal horn neurons were evaluated by monitoring C-fiber input, wind-up, and the total number of spikes evoked by C-fiber activity in response to the 12 stimuli. The NK-1 receptor antagonist CP-99,994 significantly inhibited the total number of C-spikes and caused a significant reduction in wind-up without changing the C-fiber input, indicating the involvement of NK-1 receptors in wind-up. Application of SP led to an overall increase in the total number of C-fiber evoked responses of dorsal horn neurons and C-fiber input, however, wind-up, as defined, was significantly decreased following SP. In contrast, substance P(1-7) evoked a long-lasting increase in the total number of C-fiber-related spikes which was initially sustained by a transient increase in the input followed by a longer lasting increase in wind-up, an effect opposite that of CP-99,994. As NMDA activity has been previously shown to be inhibited and then potentiated by SP N-terminal activity over a similar time interval, the present data are consistent with the mediation of wind-up by NMDA and its modulation by SP N-terminal activity. Release of SP in response to noxious stimulation may, therefore, increase primary afferent C-fiber activity (input) whereas an accumulation of SP N-terminal metabolites appears to potentiate wind-up, perhaps via positive modulation of EAA activity.

Animals↗
PubMed1996

Nitric oxide mediates long-term hyperalgesic and antinociceptive effects of the N-terminus of substance P in the formalin assay in mice.

Conditions such as hyperalgesia can occur days or months after the noxious insult. Substance P (SP) is released in response to noxious stimuli. Given the long-term effects of the N-terminus of SP on putative nociceptive transmitters, we investigated changes in formalin-induced nociception following an accumulation of SP N-terminal metabolites in mice. Pre-treatment with the N-terminal metabolite of SP, SP(1-7), was without effect when injected intrathecally (i.t.) 5 or 30 min before formalin. However, at 24 h, SP(1-7) increased behaviors during Phase 1, indicating hyperalgesia, and attenuated Phase 2 responses, consistent with antinociception. The nitric oxide (NO) synthase inhibitor, N omega-nitro-L-arginine methyl ester HCl (L-NAME), blocked both hyperalgesic and antinociceptive effects when co-injected with SP(1-7). Consistent with a NO-mediated pathway, L-arginine (L-arg), the N-terminal amino acid of SP and precursor to NO, mimicked the antinociceptive effect of SP(1-7) on Phase 2. The hyperalgesic effect of SP(1-7) in Phase 1, which was not mimicked by L-arg, was prevented by D-SP(1-7), a SP(1-7) antagonist. Thus, SP(1-7) modulates nociception via two distinct NO-mediated pathways. When injected for 7 days, tolerance developed to the antinociceptive effect of SP(1-7) on Phase 2, but not to the hyperalgesic effect on Phase 1. Intraperitoneally injected SP(1-7) also produced hyperalgesia during Phase 1, to which tolerance developed following seven daily injections. Together, these data support the hypothesis that an accumulation of SP N-terminal metabolites, either peripherally or within the spinal cord area, is sufficient for long-term modulation of multiple types of nociception with hyperalgesic responses being most persistent.

Analgesics↗
PubMed1996

The substance P amino-terminal metabolite substance P(1-7), administered peripherally, prevents the development of acute morphine tolerance and attenuates the expression of withdrawal in mice.

Acute opioid tolerance and dependence develop within hours of a single injection of morphine. We tested the hypothesis that substance P (SP) amino-terminal metabolites, originating in the periphery, affect the development of tolerance and dependence just as they modulate opioid dependence when injected intrathecally. The SP amino-terminal fragment SP(1-7) (1, 3 or 30 nmol), injected i.p. 30 min before 100 mg/kg morphine, attenuated the development of acute tolerance (5 hr) to the analgesic effect of morphine (5 mg/kg) when tested in the tail-flick assay. Injection of the D-isomer of SP(1-7), [D-Pro2, D-Phe7]SP(1-7), did not alter tolerance development but antagonized the effect of SP(1-7). Neither SP(1-7) nor [D-Pro2,D-Phe7]SP(1-7) reversed tolerance when injected 30 min before challenge with 5 mg/kg morphine. Pretreatment with SP(1-7) i.p. 30 min before 100 mg/kg morphine treatment also increased the number of withdrawal jumps induced by naloxone 3.5 hr later. In contrast, SP(1-7) given 30 min before naloxone inhibited withdrawal. [D-Pro2,D-Phe7]SP(1-7) induced an effect opposite that of SP(1-7) and antagonized the effect of SP(1-7) when coadministered. Thus, SP amino-terminal fragments have the unique characteristic of inhibiting the development of tolerance and potentiating the development but inhibiting the expression of withdrawal. These results suggest a possible mechanism by which pain-evoked release of SP may sustain opioid analgesia by attenuating the development of tolerance and inhibiting the expression of withdrawal.

Animals↗
PubMed1995

Discrepancies in characterization of sigma sites in the mouse central nervous system.

The characteristics of [3H](+)-pentazocine and [3H]1,3-di(2-tolyl) guanidine (DTG) binding to mouse whole brain, cortex, cerebellum and spinal cord membranes were investigated in radioreceptor assays. [3H](+)-Pentazocine bound to a single, high affinity site (Kd = 1.2-1.6 nM) with increasing density along the neuraxis from the cortex (Bmax = 543 fmol/mg protein) to the spinal cord (Bmax = 886 fmol/mg protein). Hot saturation studies resolved the presence of one binding site for [3H]DTG showing no tissue variations in terms of density (Bmax = 1075-1264 fmol/mg protein) or affinity (Kd = 16.6-22.3 nM). Incubation with 100 nM (+)-pentazocine revealed two classes of high affinity [3H]DTG labeled binding sites corresponding to sigma 1 and sigma 2 subtypes. A preponderance of sigma 2 sites was revealed in all investigated tissues. Different pharmacological profiles were demonstrated for the sigma 2 sites in mouse whole bain compared to mouse spinal cord. However, competition studies indicated that the whole brain and spinal [3H](+)-pentazocine labeled sigma 1 binding sites exhibited similar pharmacological properties. The density of [3H](+)-pentazocine labeled sigma 1 population was found not to match that of [3H]DTG labeled sigma 1 site throughout the mouse central nervous system. The presence of low affinity [3H]DTG labeled sites was demonstrated in cold saturation experiments. Equilibrium binding data for the low affinity [3H]DTG binding site resulted in an increasing density (Bmax = 1973-11,369 fmol/mg protein) with a decreasing affinity (Kd = 242-943 nM) in mouse cortex through the spinal cord.

Animals↗
PubMed1995

Effects of nitric oxide availability on responses of spinal wide dynamic range neurons to excitatory amino acids.

The role of nitric oxide (NO) in responses of spinal dorsal horn neurons to excitatory amino acids and to cutaneous mechanical stimuli was examined. Extracellular recordings were made from wide dynamic range neurons excited with iontophoretically applied excitatory amino acid agonists, N-methyl-D-aspartate (NMDA) and (R,S)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or kainic acid. Nitric oxide availability was decreased by iontrophoretic application of NO synthase inhibitors, N omega-nitro-L-arginine methyl ester (L-NAME) or L-N5-(1-iminoethyl)ornithine (L-NIO), or elevated by the NO donating compound, S-nitroso-N-penicillamine (SNAP). When cells were excited with successive application of NMDA and non-NMDA excitatory amino acid receptor agonists, application of NO synthase inhibitors led to a decrease in responses to NMDA in 60% of neurons. In more than a third of the cells tested, inhibition of NO synthase caused reciprocal changes in responses to glutamate receptor agonists: NMDA-evoked responses were significantly decreased whereas responses to the non-NMDA receptor agonists (AMPA or kainic acid) were increased. Application of the NO donating compound, S-nitroso-N-penicillamine, revealed an opposite tendency, increasing responses to NMDA in more than half of the neurons tested. In approximately 40% of the cells, reciprocal changes in responses to excitatory amino acid receptor agonists of NMDA versus non-NMDA types were observed after application of S-nitroso-N-penicillamine, such that the increase in NMDA responses was accompanied by decreases in the responses to kainic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1995

Altered N-methyl-D-aspartate (NMDA) activity in the mouse spinal cord following morphine is mediated by sigma activity.

The present study was designed to determine whether the increase in N-methyl-D-aspartate (NMDA) activity in the mouse spinal cord, unmasked by naloxone in morphine-pretreated mice, is mediated by sigma receptor activity. Behavioral responses to intrathecal injections of NMDA were inhibited by pretreatment (2 h) with morphine (10 mg/kg i.p.) except when NMDA was injected together with 0.1 micrograms of naloxone. This excitatory effect of morphine on NMDA-induced behaviors, unmasked in the presence of naloxone was prevented but not reversed by haloperidol, a sigma ligand and dopamine antagonist, but not by an equivalent dose of spiperone, a dopamine antagonist. Sigma activity also appeared to contribute to morphine withdrawal jumping in mice as haloperidol inhibited naloxone-induced jumping while spiperone did not. Together these data indicate that naloxone unmasks an action of morphine on NMDA and during acute withdrawal, and these effects are each brought about by mechanisms involving sigma receptor activity.

Animals↗
PubMed1995

Sensitization to the behavioral effect of kainic acid in the mouse is mediated by nitric oxide.

Kainic acid (KA)-sensitive receptors are located on primary afferent C-fibers. Behavioral sensitization to each of four repeated injections of KA appears to involve activation of primary afferent C-fibers based on its susceptibility to capsaicin pretreatment. Hyperalgesia, thought to involve transmission along C-fibers, is sensitive to pharmacologic manipulation of nitric oxide (NO). We tested the hypothesis that KA activates C-fibers, either directly or indirectly, by a mechanism that involves NO. Pretreatment with N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, inhibited KA sensitization whereas D-NAME, the inactive isomer, failed to mimic this action. D-Arginine also inhibited sensitization to KA, whereas L-arginine, a NO precursor, was inactive when administered alone but reversed the inhibitory effect of L-NAME. Methylene blue, which inhibits guanylyl cyclase and NO synthase, attenuated KA sensitization, suggesting that cyclic GMP synthesis may also be involved in this phenomenon. Reduced hemoglobin, which sequesters NO in the extracellular space, attenuated KA sensitization, indicating that the effect of NO is brought about in structures adjacent to cells in which it is synthesized. This convergence of data is consistent with the mediation of behavioral sensitization to KA by NO. KA sensitization has been shown to involve an action of the NH2 terminus of substance P (SP) and NO may thus mobilize SP. Consistent with this, in the presence of SP(1-7), methylene blue was no longer able to inhibit sensitization to KA, suggesting that NO evokes, rather than results from, mobilization of SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Increased N-methyl-D-aspartate (NMDA) activity in the mouse spinal cord following morphine does not mediate opioid withdrawal.

N-Methyl-D-aspartate (NMDA) receptors have been proposed to play a role in opioid tolerance and dependence. The present study was designed to determine whether the increased NMDA activity in the spinal cord, unmasked by naloxone in morphine-pretreated mice, reflects activity leading to opioid withdrawal. Behavioral responses to intrathecal injections of NMDA were inhibited by pretreatment (2 h) with morphine (10 mg/kg i.p.), but enhanced following morphine when naloxone was injected together with NMDA. Although injected at doses that inhibited NMDA activity, the excitatory effects of morphine on NMDA-induced behaviors were prevented by dizocilpine (MK-801), a phencyclidine (PCP) ligand, but not by 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1 phosphonic acid (CPP), a competitive NMDA antagonist. MK-801 also inhibited naloxone-induced withdrawal jumping, however, just as CPP failed to affect morphine-induced changes in MMDA-induced behaviors, CPP also failed to inhibit withdrawal jumping. Together these data indicated that withdrawal from acute opioid dependence correlates with, but is not mediated by enhanced NMDA activity.

Analysis of Variance↗
PubMed1994

An N-terminal fragment of substance P, substance P(1-7), down-regulates neurokinin-1 binding in the mouse spinal cord.

Injected intrathecally, substance P (SP) down-regulates neurokinin-1 (NK-1) binding in the spinal cord and desensitizes rats to the behavioral effect of SP. N-terminal fragments of SP, such as SP(1-7), induce antinociception and play a role in desensitization to SP in mice. The goal of this study was to assess the abilities of N- and C-terminal fragments of SP to down-regulate NK-1 binding. Binding of [3H]SP to mouse spinal cord membranes was inhibited by SP, CP-96,345, and to a lesser extent by SP(5-11), but not SP(1-7), consistent with these binding sites being NK-1 receptors. Injection of SP(5-11) intrathecally did not affect the affinity (Kd) or concentration (Bmax) of [3H]SP binding. However, injection of 1 nmol of SP(1-7) decreased the Bmax of [3H]SP binding in the spinal cord at 6 h after its injection just as this dose of SP decreased the Bmax at 24 h. These data suggest that the N-terminus of SP is responsible for down-regulation of NK-1 binding. As SP(5-11) did not down-regulate NK-1 binding, activation of NK-1 sites does not appear necessary or sufficient for down-regulation of SP binding. In contrast, SP(1-7), in spite of its inability to interact with NK-1 sites, did down-regulate SP binding, suggesting an indirect mechanism dissociated from NK-1 receptors.

Animals↗
PubMed1994

Substance P N-terminus inhibits C-fiber-dependent facilitation of the rat flexor reflex.

Substance P injected intrathecally or a conditioning stimulus (1 Hz, 20 s) at C-fiber strength, which releases substance P from intraspinal primary afferent terminals, each enhance the hamstring muscle flexor reflex elicited by electrical stimulation of the sural nerve in decerebrate, spinalized rats. This suggests a role for substance P in pain transmission. Since substance P N-terminal metabolites are biologically active, we examined the effect of the metabolite substance P-(1-7) on the flexor reflex and the enhancement of the flexor reflex following a conditioning stimulus of the sural nerve. In contrast to the excitatory effect of substance P, intrathecal injection of substance P-(1-7) had no effect on the flexor reflex. However, 10 and 30 min after injection, 0.6 or 6 micrograms of substance P-(1-7) attenuated the facilitation of the flexor reflex by the conditioning stimulus. These data indicate that substance P-(1-7) may modulate the expression of nociception involving repetitive firing of C-fibers while having no significant effect on acute or phasic responses.

Animals↗
PubMed1994

Morphine modulates excitatory amino acid-induced activity in the mouse spinal cord: short-term effects on N-methyl-D-aspartate (NMDA) and long-term effects on kainic acid.

Excitatory amino acid (EAA) antagonists and phencyclidine (PCP) ligands inhibit the development of morphine tolerance and dependence. The present study tested the hypothesis that opioids increase EAA-induced activity by monitoring morphine's effect on the caudally-directed biting and scratching behaviors produced in mice by intrathecal (i.t.) injections of either N-methyl-D-aspartate (NMDA) or kainic acid (KA). A single injection of 10 mg/kg of morphine i.p. had no effect on the intensity of behaviors induced 2 h later by KA but inhibited NMDA-induced activity. Pretreatment with 100 mg/kg of morphine i.p. 24 h before testing did not alter NMDA-induced behaviors, but attenuated sensitization to repeated injections of KA, which is thought to reflect activation of primary afferent C-fibers. Coadministration of 0.1 microgram of naloxone with EAAs did not alter responses to either NMDA or KA in control mice, however, 2 h after 10 mg/kg of morphine, inclusion of naloxone potentiated NMDA-induced activity without altering responses to KA. 24 h after 100 mg/kg of morphine, naloxone, coadministered with KA, was also able to reverse the inhibitory effect of morphine pretreatment on KA-induced activity. In summary, morphine produces short-term inhibitory and excitatory effects on NMDA-induced activity, the latter of which is unmasked by naloxone. Morphine has no immediate effect on KA-induced activity but is able to bring about a long-term inhibition of sensitization to KA, an effect that is reversed by naloxone. Activity along pathways activated by NMDA and KA may, therefore, contribute to different aspects of opioid tolerance or withdrawal.

Analysis of Variance↗
PubMed1994

GYKI 52466 inhibits AMPA/kainate and peripheral mechanical sensory activity.

The selectivity of the 2,3-benzodiazepine compound, GYKI 52466, was tested on wide dynamic range (WDR) dorsal horn neurons of the rat spinal cord. Using extracellular recordings, neurons were characterized by stimulation with noxious and innocuous intensities of the receptive field. In most cells, responses to iontophoretically applied (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainic acid (KA), but not N-methyl-D-aspartate (NMDA), were profoundly reduced by iontophoretic ejection of GYKI 52466. The inhibition usually lasted for 5-30 min following application of GYKI 52466. In a few neurons, responses to NMDA were also decreased by GYKI 52466. Responses to both noxious and innocuous mechanical stimulation were reduced in the presence of GYKI 52466. The results provide evidence for the selective inhibition by GYKI 52466 of AMPA/KA receptor-mediated functions and support the involvement of these receptors in spinal mechanical nociception.

Animals↗