Biomedical subjects

A A Larson

Publications and source records attributed to A A Larson.

At least 73 records · Page 4Linked to original sources

PubMed1992

Identification of a novel receptor mediating substance P-induced behavior in the mouse.

To determine whether opioid receptors or the more recently characterized naloxone-sensitive substance P (SP) N-terminal binding sites play a role in desensitization to the behavioral effects of SP, we assessed the effects of selective antagonists at mu-(naloxonazine and beta-funaltrexamine), delta- (naltrindole) and kappa- (nor-binaltorphimine) opioid receptors, as well as the effect of [D-Pro2,D-Leu7]SP-(1-7) D-SP-(1-7) (D-SP (1-7)), an inhibitor of [3H]SP-(1-7) binding, on behaviors induced by intrathecally administered SP in mice. Whereas naloxone, a non-selective opioid antagonist, inhibited the development of behavioral desensitization to SP, the response to repeated SP administration remained unaffected by pretreatment with selective opioid antagonists. Like naloxone, however, the SP-(1-7) antagonist inhibited SP-induced desensitization. The protection against desensitization to SP by D-SP-(1-7), but not by selective antagonists of mu, delta or kappa receptors, suggests that desensitization to the behavioral effects of SP does not appear to be mediated by an action at an opioid receptor but by an action at the SP-(1-7) binding site.

Analysis of Variance↗

PubMed1992

Modulation of N-methyl-D-aspartate and (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) responses of spinal nociceptive neurons by a N-terminal fragment of substance P.

The effects of an N-terminal fragment of substance P, substance P-(1-7) [SP-(1-7)], on the responses of dorsal horn nociceptive neurons to N-methyl-D-aspartate (NMDA) and (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) were tested by combined single-unit extracellular recordings/microiontophoresis. While SP-(1-7) had no effects when applied by itself, it was a potent and long-lasting modulator of both NMDA- and AMPA-mediated excitation of spinal dorsal horn nociceptive neurons. NMDA responses were transiently decreased (by an average of 36% of control at minimum) by SP-(1-7) followed by a more sustained increase (by 76% at maximum). In contrast, AMP responses were only increased by SP-(1-7) (by 81% at maximum). It is hypothesized that the actions of SP-(1-7) on excitatory amino acid (EAA) responses of dorsal horn nociceptive neurons reflect a novel mechanism by which SP and EAAs interact to modulate pain transmission.

Animals↗

PubMed1992

Experimental peripheral neuropathy decreases the dose of substance P required to increase excitatory amino acid release in the CSF of the rat spinal cord.

Partial ligation of the sciatic nerve of rats produces hyperalgesia similar to that seen in humans following nerve injury. In this study, we used microdialysis of the spinal cord cerebral spinal fluid (CSF) to test the hypothesis that hyperalgesia is due to an enhanced release of excitatory amino acids (EAA) in response to substance P (SP). Intrathecal SP caused release of aspartate and glutamate in the CSF of rats with partial sciatic ligation at a dose of SP that did not cause release in sham operated animals. Neonatal capsaicin pretreatment blocked SP-induced EAA release in both sham and sciatic ligated animals. Release of EAAs in ligated animals was not significantly different from release in sham-operated animals following higher doses of SP or chemical nociceptive stimulation. These results demonstrate a partial sciatic ligation-induced decrease in the dose of SP required to initiate EAA release in the CSF of the spinal cord, a change which could play an important role in hyperalgesia.

Amino Acids↗

PubMed1992

Selective potentiation of NMDA-induced activity and release of excitatory amino acids by dynorphin: possible roles in paralysis and neurotoxicity.

Selective antagonists of N-methyl-D-aspartate (NMDA) excitatory amino acid (EAA) receptors have been shown to protect against dynorphin-A (DYN)-induced paralysis and neurotoxicity in the spinal cord. To test the hypothesis that either DYN-induced paralysis or neurotoxicity involves an enhanced release of EAAs, we used microdialysis to monitor aspartate (Asp) and glutamate (Glu) release in both the lumbar spinal cord extracellular fluid (ECF) and the spinal cord cerebral spinal fluid (CSF) of conscious rats in response to DYN (1-13). Injection of 5 nmol of DYN produced temporary paralysis in 8 of 10 animals, but did not significantly change Asp or Glu release in either the ECF or the CSF. Injection of 20 nmol of DYN caused permanent paralysis and neuronal cell loss in all animals tested as well as a significant increase of Asp and Glu in both the ECF and the CSF, and a decrease in glutamine (Gln) release only in the ECF. Pretreatment with 1 mg/kg of the NMDA antagonist MK-801 blocked both paralysis and amino acid changes in the ECF. Pretreatment of animals with 5 mg/kg naloxone inhibited glutamate release in the ECF, but did not block paralysis, Asp release or inhibition of Gln release. As MK-801 sensitive paralysis by DYN was not mediated through enhanced EAA release, we examined whether DYN could act through postsynaptic facilitation of NMDA receptors by testing the ability of DYN to alter the magnitude of a behavioral response produced by intrathecal injection of NMDA in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Enhancement of NMDA-evoked neuronal activity by glycine in the rat spinal cord in vivo.

The effects of iontophoretically administered N-methyl-D-aspartate (NMDA), glycine and strychnine on nociceptive dorsal horn neurons of the rat spinal cord were studied to test the hypothesis that their responses to NMDA are influenced in vivo by glycine acting at a strychnine-insensitive site. Experiments were carried out on 44 dorsal horn neurons responsive to microiontophoretic application of NMDA and peripheral stimulation. Glycine alone either enhanced or inhibited NMDA responses depending upon its dose (151% and 68% of control, respectively). Strychnine alone increased the NMDA-induced neural firing (129%), suggesting the presence of endogenous glycine. When glycine was co-ejected with strychnine, NMDA responses were further elevated (171%) revealing the activation of strychnine-insensitive binding sites. These data provide evidence that glycine can potentiate NMDA responses of nociceptive dorsal horn neurons in vivo and thus that glycine sites on NMDA receptors on these neurons are not saturated.

Animals↗

PubMed1992

Antinociceptive effects of intrathecal taurine and calcium in the mouse.

Taurine (Tau), calcium (Ca+2) and opiates each produce antinociception when injected i.t. in mice. This study was initiated to determine whether there is a common mechanism underlying their antinociceptive effects. Using the abdominal stretch assay, the antinociceptive effects of both Tau (12 nmol) and Ca+2 (72 nmol) were antagonized by i.t. TAG (4.4 nmol), a Tau antagonist, but not by i.p. injection of the opiate antagonist naloxone (5 mg/kg). The antinociceptive effects of Tau and Ca+2 correlated with their ability to inhibit the intensity of caudally-directed biting and scratching behaviors produced by i.t. NMDA or kainic acid. The inhibitory effects of both Tau and Ca+2 on the biting and scratching behaviors behaviors induced by substance P or excitatory amino acids were reversed by TAG, suggesting a common mediation by Tau. These data indicate that the antinociceptive effects of both Tau and Ca+2 appear to be mediated, at least in part, by Tau but not by the release of endogenous opioid compounds. In addition, inhibition of chemical irritant-induced nociception may be produced by a simple blockade of excitatory amino acid activity.

Amino Acids↗

PubMed1992

Fluorogold administration via microdialysis labels neurons terminating within the dialysis region.

The use of microdialysis to monitor the release of neurotransmitters in selected regions of the CNS has increased substantially in the last several years. We describe here a method for retrogradely labeling neurons that terminate within the effective sampling region surrounding the dialysis cannula. This is accomplished by direct infusion of fluorogold through the dialysis cannula. By combining this technique with immunohistochemistry, it is possible to identify neurons that could contribute to the neurotransmitter release measured by microdialysis.

Animals↗

PubMed1992

Amino terminus of substance P potentiates kainic acid-induced activity in the mouse spinal cord.

Sensitization to the behavioral effects produced by repeated injections of kainic acid (KA) into the mouse spinal cord area has been previously shown to be abolished by pretreatment with capsaicin, a neurotoxin of substance P (SP)-containing primary afferent C-fibers. While SP has a variety of well characterized biological actions that are mediated by interactions of its COOH terminus with neurokinin receptors, more recently we have characterized an amino-terminally directed SP binding site. The present studies were initiated to determine whether behavioral sensitization to repeated injections of intrathecally administered KA is mediated by the COOH or NH2 terminal of SP. In the present studies, pretreatment with SP(1-7), an NH2-terminal fragment of SP, but not SP(5-11), a COOH-terminal fragment, potentiated KA-induced behavioral activity in mice. Pretreatment with [D-Pro2,D-Phe7]SP(1-7), an inhibitor of SP NH2-terminal binding, blocked the potentiative effect of SP(1-7) as well as the sensitization to repeated injections of KA. In contrast, [D-Pro2,D-Trp7,9]SP, a neurokinin antagonist, had little effect on behavioral sensitization to KA. The present study suggests that SP has an important modulatory role on excitatory amino acid activity in the spinal cord that is mediated by an action of the NH2 terminal of SP at a non-neurokinin receptor.

Animals↗

PubMed1992

Neurokinin receptors and mucosal ion transport in porcine jejunum.

Neurokinin (NK) peptides such as substance P (SP) may modulate epithelial ion transport in the small intestine. The present study was undertaken to examine the pharmacological mechanisms by which SP and its endogenous homologs NKA and NKB affect active electrolyte transport in the mucosa of porcine jejunum. Neurokinins and NK agonist analogs increased short circuit current, a measure of active ion transport, across sheets of jejunal mucosa-submucosa with the order of potency: SP greater than [beta-Ala8]NKA4-10 greater than or equal to [Sar9,Met(O2)11]SP greater than NKA = Arg-NKB greater than NKB after their addition to the serosal aspect of tissues (SP EC50 = 11 nM). Epithelial responses to SP or NKA underwent rapid autotachyphylaxis and unidirectional cross-tachyphylaxis after repeated peptide administration. The neuronal conduction blocker tetrodotoxin significantly reduced NK efficacy. SP activity was significantly reduced in tissues pretreated with the muscarinic cholinoceptor blocker atropine or the eicosanoid synthesis inhibitor eicosa-5,8,11,14-tetraynoic acid. NK peptides increased contractility in longitudinally oriented strips of jejunal smooth muscle with an order of potency: [Sar9,Met(O2)11]SP greater than SP greater than Arg-NKB = [beta-Ala8]NKA4-10 greater than or equal to NKB = NKA (SP EC50 = 11 nM). SP-induced contractions were reduced by 70 to 80% in tissues pretreated with atropine or the neuronal Ca++ channel blocker, omega-conotoxin. [125I]Bolton-Hunter-substance P (BHSP) bound specifically to a single population of sites in slide-mounted sections of mucosa-submucosa and smooth muscle with Kd = 0.3 and 0.1 nM and Bmax = 18 and 31 fmol/mg protein, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

NMDA-, kainate- and quisqualate-stimulated release of taurine from electrophysiologically monitored rat hippocampal slices.

While excitatory amino acids (EAAs) are known to evoke the release of taurine in the hippocampus, we have found that taurine is localized primarily in dendrites and only to a lesser extent in terminals in this region. To determine whether taurine is released as a neurotransmitter by non-toxic concentrations of EAAs, or exclusively as a neuroprotectant in response to excitotoxicity, we monitored the release of amino acids from hippocampal slices during simultaneous electrophysiological recording in the CA1 region to assess tissue viability. N-methyl-D-aspartate (NMDA) was the most potent of the EAA agonists tested for stimulating release of taurine. Exposure of slices to 120 microM NMDA increased the concentration of taurine in the perfusate to 1325% of its basal value. Kainate (KA) at a concentration of 128 microM increased taurine to 543% of baseline while quisqualate (Quis) at a concentration of 120 microM increase taurine to only 202% of its baseline value. Release of taurine in response to NMDA and KA peaked during the period when the concentration of the agonist was declining in the bath and did not return to its baseline value until 20 min after removal of the agonist. Increases in release of taurine were associated with concentrations of NMDA, KA, and Quis that caused an incomplete recovery of the CA1 field potential. These results suggest that taurine is primarily released by concentrations of glutamate receptor agonists that exhibit evidence of excitotoxicity in the CA1 region.

Animals↗

PubMed1991

Excitatory amino acids are released from rat primary afferent neurons in vitro.

Multiple lines of evidence implicate the excitatory amino acids (EAAs) (L-aspartate (L-Asp) and L-glutamate (L-Glu) as excitatory transmitters in the spinal cord. The specific objective of this study was to determine whether the EAAs are released from primary afferents. Dorsal root ganglia (DRG) from 2 to 18-day-old rats dissected and cultured for 1-2 weeks were washed in modified Ringers recording solution for a period of 1 h to allow equilibration. The mean +/- S.E.M. baseline concentrations of EAAs recovered during a 5 min interval were 533.29 +/- 65.59 nmol for L-Glu and 106.67 +/- 14.05 nmol for L-Asp. Stimulation of DRG organotypic cultures with potassium resulted in a significant concentration-dependent increase in the release of both EAAs. The concentration of Asp increased to 166 +/- 17% and 203 +/- 13% in response to 5 min exposure of the culture to 25 and 50 mM potassium, respectively. The concentration of Glu increased to 155 +/- 12% and 226 +/- 18% of control in response to the same stimuli. In response to application of 50 mM potassium for 25 min, peak concentrations increased to 465 +/- 53% for Asp and 312 +/- 51% for Glu of the basal concentration. Exposure of the cultures to 1 or 10 microM capsaicin also caused release of both EAAs. The concentrations of Asp and Glu significantly increased to 204 +/- 11% and 165 +/- 15% of basal concentrations, respectively, in response to a 5 min exposure to 1 microM capsaicin. High [K+]e failed to increase the release of EAAs from cultures where DRG cell bodies were removed 72 h prior to release experiments. These results confirm results demonstrating release of EAA from mammalian spinal cord tissues and directly demonstrate for the first time that primary afferent fibers are specifically involved in this release.

Afferent Pathways↗

PubMed1991

Spinal seizures evoked by sudden cooling of amphibian isolated spinal cords: involvement of excitatory amino acids.

Sudden cooling of the isolated spinal cord of frogs results in characteristic seizure-like activity in the hind legs. In the present investigation, these spinal seizures induced by sudden cooling (SSSC) were studied to determine whether excitatory amino acids (EAAs) are involved in the mediation of this activity. The nonspecific EAA antagonist, L-glutamic acid diethyl ester and cis-2,3-piperidine dicarboxylic acid inhibited the clonic and tonic phase of SSSC after intralymphatic or intrathecal administration. The antagonist gamma-D-glutamylaminomethylsulfonic acid and gamma-D-glutamyltaurine also suppressed both phases after intrathecal injections. The NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid, DL-2-amino-7-phosphonoheptanoic acid, and 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid were effective inhibitors of the tonic phase and actually prolonged the duration of the clonic phase, an effect similar to that observed after low doses of gamma-D-glutamylglycine. SSSC were resistant to spinal perfusion to tetrodotoxin (1 microM). The concentrations of glutamate, aspartate, and glycine were increased in the Ringer's solution surrounding rapidly cooled spinal cord slices, but only in cords from species that elicited some magnitude of SSSC, not in cords from species resistant to induction of SSSC. Our data support the hypothesis that EAAs play a role in SSSC via activation of quisqualate receptors.

Amino Acids↗

PubMed1991

Changes in extracellular concentrations of glutamate, aspartate, glycine, dopamine, serotonin, and dopamine metabolites after transient global ischemia in the rabbit brain.

Although considerable evidence supports a role for excitatory amino acids in the pathogenesis of ischemic neuronal injury, few in vivo studies have examined the effect of increasing durations of ischemia on the extracellular concentrations of these agents. Recently, other neurotransmitters (e.g., glycine and dopamine) have been implicated in the mechanism of ischemic neuronal injury. Accordingly, this study was undertaken to examine the patterns of changes of extracellular glutamate, aspartate, glycine concentrations in the hippocampus, and dopamine, serotonin, and dopamine metabolites in the caudate nucleus with varying durations (5, 10, or 15 minutes) of transient global cerebral ischemia as evidence to support their pathogenetic roles. Microdialysis was used to sample the brain's extracellular space before, during, and after the ischemic period. Glutamate and aspartate concentrations in the dialysate increased from baseline by 1-, 5-, and 13-fold and by 4-, 9-, and 31-fold, respectively, for the three ischemic durations. The concentrations returned to baseline rapidly after reperfusion. The peak concentrations of glutamate and aspartate were significantly higher with increasing ischemic duration. Dopamine concentrations increased by approximately 700-fold in response to all three ischemic durations and returned to baseline within 10 min of reperfusion. Glycine, in contrast, increased during ischemia by a mean of 4-fold, but remained elevated throughout the 80-min period of reperfusion. The final concentrations of glycine were significantly higher than baseline levels (p = 0.0002, Mann-Whitney test). That glutamate and aspartate concentrations in the hippocampus co-vary with the duration of global ischemia is taken as supportive evidence of their pathogenetic role in ischemic neuronal injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1991

Hypothermia prevents ischemia-induced increases in hippocampal glycine concentrations in rabbits.

We subjected 10 New Zealand White rabbits to 10 minutes of global cerebral ischemia under either normothermic (37 degrees C) or moderately hypothermic (29 degrees C) conditions. Hippocampal concentrations of glutamate, aspartate, and glycine were monitored using in vivo microdialysis. Outcome was assessed by both neurological and neuropathologic criteria. Hypothermia afforded nearly complete protection from ischemic injury. Ischemia-induced increases in the concentrations of glutamate, aspartate, and glycine in the normothermic group (3, 12, and 3 times baseline) were strikingly attenuated in the hypothermic group. In addition, the prolonged postischemic elevation of glycine levels seen in the normothermic group was absent in the hypothermic group. These results suggest that the neuroprotective properties of hypothermia may reside, in part, in their ability to prevent increases in the extracellular concentrations of amino acids that enhance the activity of the N-methyl-D-aspartate receptor complex.

Animals↗

PubMed1991

Behavioral sensitization to kainic acid and quisqualic acid in mice: comparison to NMDA and substance P responses.

Substance P (SP) and the excitatory amino acid (EAA) agonists NMDA, kainic acid (KA), or quisqualic acid (Quis) each produce a transient, caudally directed biting and scratching response (CBS) in mice after their intrathecal injection. We have previously shown that repeated injections of SP result in a decrease in the intensity of CBS, or desensitization. The goals of the present study were (1) to determine whether desensitization also develops to the CBS behavior produced by EAAs in the spinal cord, (2) to characterize the role of interneurons in desensitization, and (3) to examine possible interactions between EAAs and SP. While injection of NMDA at 2 min intervals resulted in desensitization to its CBS behavioral effect, behavioral responses to repeated injections of KA or Quis increased in intensity, exhibiting sensitization. The NMDA antagonist DL-2-amino-5-phosphonovaleric acid failed to alter sensitization to either KA or Quis but inhibited behaviors produced by SP and NMDA, suggesting an NMDA-mediated component in SP-induced behavior. Concanavalin A, which is reported to block desensitization to the electrophysiologic effect of Quis, blocked sensitization to the behavioral effects of both Quis and KA. Strychnine, bicuculline, and 5-aminovaleric acid each inhibited desensitization to SP and NMDA, supporting the notion of recruitment of inhibitory transmitters in the attenuation of NMDA and SP activity. Pretreatment with capsaicin selectively inhibited the development of behavioral sensitization to KA, suggesting an involvement of small-diameter C-fibers in the enhancement of responsivity to KA. Consistent with this, pretreatment with SP selectively potentiated the CBS response to KA. The potentiation of KA effects by SP and dependence of KA behavioral sensitization on C-fiber activity suggest a possible mechanism by which EAAs and SP may be involved in the mediation of pain.

2-Amino-5-phosphonovalerate↗

PubMed1990

Effects of urethane and ketamine on substance P- and excitatory amino acid-induced behavior in mice.

Urethane and ketamine were tested for their ability to alter the caudally directed binding and scratching response elicited by the intrathecal (i.t.) injection of excitatory amino acids (EAAs) or substance P (SP). EAAs, such as N-methyl-D-aspartate (NMDA), kainate acid and quisqualic acid, but not SP, were inhibited by subanesthetic doses of urethane. In contrast, SP was more sensitive than NMDA to the inhibitory effect of (+)-ketamine. (-)-Ketamine produced much less inhibition of the SP-induced behaviors than the (+)isomer. These results have important implications regarding the use of urethane and ketamine as anesthetics for studies in which these excitatory compounds are potential mediators.

2-Amino-5-phosphonovalerate↗

PubMed1990

Seizures induced by fluoroacetic acid and fluorocitric acid may involve chelation of divalent cations in the spinal cord.

Fluoroacetic and fluorocitric acid toxicity is often characterized by seizures, however the mechanism of this activity is unknown. Intrathecal (i.t.) injection of fluorocitrate in mice resulted in seizures after an average latency of 15 s, while intracerebroventricular (i.c.v.) injection produced seizures after 36.5 min, and required higher doses to achieve this effect. This indicates the probable site of fluoroacetate and fluorocitrate neurotoxicity is the spinal cord. To mimic citrate accumulation, characteristic of fluoroacetate and fluorocitrate poisoning, citric acid was injected i.t. and also found to produce seizures. The structurally unrelated compounds EDTA, EGTA, glutamic acid and lactic acid also produced seizures identical to fluorocitrate. The ability of these compounds to chelate Ca2+ correlates well with their ability to cause seizures when administered i.t. and coadministration of calcium greatly attenuated the neurotoxicity of these compounds as well as fluoroacetate and fluorocitrate. In contrast, Ca2+ was unable to inhibit seizures elicited by strychnine, suggesting calcium's ability to inhibit chelators of divalent cations is not due to a general anticonvulsant effect. These results suggest that changes in Ca2+ concentration in the spinal cord may be responsible for some forms of seizure activity.

Animals↗

PubMed1990

Role of substance P amino terminal metabolites in substance P-induced desensitization in mice.

Intrathecal injection of mice with substance P or its C-terminal fragments evokes a well documented behavioral syndrome characterized by caudally-directed biting and scratching. We have previously shown that repeated injections of substance P result in naloxone-sensitive desensitization to this substance P-induced behavior, possibly through interactions of N-terminal fragments of substance P with mu opiate binding sites. The present investigation tests the hypothesis that substance P metabolites play a role in the development of desensitization to substance P by using the biting and scratching behavioral paradigm. While substance P-induced behaviors are produced by as little as 1 pmol of substance P, repeated injections of 7.5 pmol at 60-s intervals was found to be the minimum dose capable of causing desensitization. The C-terminal peptides, substance P3-11 and substance P5-11, elicited substance P-like behaviors, but repeated injection of these compounds did not result in desensitization to this behavior. In contrast to C-terminal fragments, intrathecal injection of N-terminal fragments, (substance P1-4, substance P1-7 and substance P1-9), did not elicit any overt substance P-like behaviors when administered alone, but when co-administered with substance P, decreased the magnitude of substance P-induced behaviors in a dose-related fashion. Various peptidase inhibitors significantly inhibited the catabolism of co-administered substance P. Co-administration of substance P with peptidase inhibitors enhanced and prolonged the substance P-induced behavioral episode, but also prevented the development of substance P-induced desensitization. Together these results support the hypothesis that the accumulation of endogenously generated N-terminal metabolites of substance P mediate desensitization to substance P-induced behaviors in the spinal cord. Substance P metabolism may therefore decrease ongoing substance P activity both by the hydrolysis of the C-terminal portion of substance P as well as by the production of N-terminal metabolites that are capable of inhibiting the effects of substance P.

Aggression↗