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K Jhamandas

Publications and source records attributed to K Jhamandas.

At least 73 records · Page 4Linked to original sources
PubMed1991

Characteristics of precipitated withdrawal from spinal morphine: changes in [Met5]enkephalin levels.

This investigation was carried out to study the development of physical dependence on spinally administered morphine, and it was determined if this phenomenon is associated with altered levels of [Met5]enkephalin. Morphine was infused continuously into the intrathecal space of rats for three or six days. In morphine-dependent animals, an intrathecal naloxone challenge produced increased reaction to nociceptive stimuli, hypertension, hyperthermia, decreased urinary output, and loss of body weight. Chronic spinal infusion of morphine alone failed to alter levels of [Met5]enkephalin in sacral and lumbar spinal cord. However, 24 h after the naloxone challenge, there was a significant increase in spinal enkephalin levels in morphine-dependent animals. It is concluded that spinal morphine treatment leads to the development of physical dependence. Certain characteristics of this phenomenon, as reflected in the naloxone-precipitated withdrawal signs, differ from those associated with dependence on systemic morphine.

Analgesics↗
PubMed1991

Dynorphin A-(1-13)-Tyr14-Leu15-Phe16-Asn17-Gly18-Pro19 : a potent and selective kappa opioid peptide.

Dynorphin A-(1-13)-Tyr14-Leu15-Phe16-Asn17-Gly18-Pro19+ ++ (dynorphin Ia: a peptide derived from the structure of adrenal dynorphin I) was synthesized by the solid-phase procedure. The product was purified and compared with dynorphin A-(1-13) and [D-Pro10]dynorphin A-(1-11) for its ability to inhibit the electrically evoked contractions of the guinea pig ileum (GPI) and mouse vas deferens (MVD) and to compete with the binding of [3H]ethylketocyclazocine (kappa ligand), [3H][D-Ala2,MePhe4,Glyol5]enkephalin (mu ligand) and [3H][D-Ser2,Thr6]Leu-enkephalin (delta ligand) to membrane preparations of the guinea pig cerebellum or rat brain. Additionally, the antinociceptive effects of the synthetic peptide were assessed in rat paw-pressure and tail-flick tests. In the GPI, dynorphin Ia possessed a relative potency (IC50 0.5 nM) that was comparable to that of [D-Pro10]dynorphin A-(1-11) (IC50 0.5 nM) or dynorphin A-(1-13) (IC50 0.7 nM). In the delta specific MVD assay, dynorphin Ia displayed a reduced potency (IC50 235 nM) as compared with that of dynorphin A-(1-13) (IC50 20 nM) or [D-Pro10]dynorphin A-(1-11) (IC50 46 nM). The affinity of dynorphin Ia for the kappa site in the guinea pig cerebellum (Ki 0.25 nM) was comparable to those of dynorphin A-(1-13) (Ki 0.11 nM) and [D-Pro10]dynorphin A-(1-11) (Ki 0.10 nM). However, the peptide possessed reduced affinities for the mu (Ki 6.7 nM) and delta (Ki 71 nM) opioid receptors as compared with [D-Pro10]dynorphin A-(1-11) (Ki 1.7 and 1.5 nM) an dynorphin A-(1-13) (Ki 0.5 and 4.4 nM, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

Quisqualate lesions of rat NBM: selective effects on working memory in a double Y-maze.

Some authors have reported that quisqualic acid lesions of the nucleus basalis magnocellularis (NBM), although producing large cortical cholinergic losses, have little effect on memory. The purpose of the present study was to investigate the effects of quisqualic acid lesions of the NBM on working and reference memory in a double Y-maze. Each trial started with placement into one of the two end arms of the first Y-maze, and the correct response was to go down the stem (reference memory). Access was then given to the second Y-maze, the correct response being conditional upon the side of the first Y-maze from which that trial had begun (working memory). Rats were trained to an 88% correct criterion and were then given either bilateral quisqualic acid (60 nM, 0.5 microliters) or sham lesions (0.9% saline, 0.5 microliters) of the NBM. One week postsurgery, rats were tested on the double Y-maze task with delays of 0, 5 or 30 seconds being introduced prior to both the working and reference memory choice. NBM lesions produced a 63.2 +/- 6.2% decrease of cortical choline acetyltransferase (ChAT) compared to unoperated controls. Delays affected only the working memory of the sham group. Rats with lesions showed a significant impairment of working memory at all delays, but no change in reference memory. Results indicate that quisqualic acid lesions of the NBM that produce significant reductions in cortical ChAT selectively impair working memory.

Animals↗
PubMed1991

The K(+)-evoked release of [3H]acetylcholine from slices of rat globus pallidus: modulation by delta-opioid receptors.

Previous investigations have shown that the activation of delta-opioid receptors depresses the release of acetylcholine (ACh) in the rat caudate putamen. This finding raised the possibility that the release of ACh is similarly modulated in the globus pallidus, a region containing a distinct population of cholinergic neurons and enriched in enkephalinergic nerve terminals. In the present study the pallidal release of ACh was characterized and the effects of delta-opioid receptor activation on this release were examined. The results show that this release is stimulated by high K+ in a concentration- and Ca(2+)-dependent manner. D-Pen2,L-Pen5-enkephalin (0.1-10 microM), a selective delta-opioid receptor agonist, produced a dose-related inhibition of the 25 mM K(+)-evoked tritium release. The maximal inhibitory effect, representing a 34% decrease in the K(+)-induced tritium release, was observed at a concentration of 1 microM. This opioid effect was attenuated by the selective delta-opioid receptor antagonist, ICI 174864 (1 microM). These findings support the role of a delta-opioid receptor in the modulation of ACh release in the rat globus pallidus.

Acetylcholine↗
PubMed1991

Met-enkephalin release from slices of the rat striatum and globus pallidus: stimulation by excitatory amino acids.

The present study evaluated the effects of high K+ and four excitatory amino acids (EAAs) on the release of met-enkephalin-like immunoreactivity (ME-i.r.) from slices of the rat striatum and globus pallidus. High K+ (15-50 mM) increased the release of ME-i.r. in a concentration-dependent manner in both regions, the release response in the globus pallidus being consistently greater than in the striatum. This release was highly Ca(++)-dependent and was significantly enhanced in the absence of external Mg++. D-2-Amino-7-phosphonoheptanoic acid (0.5 mM), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, did not alter this enhanced action of K+, suggesting that the activation of NMDA receptors by an endogenous agonist did not contribute to the enhancement. Exposure of pallidal or striatal slices to four EAA receptor agonists, NMDA, L-glutamate, kainate (KA) and quisqualate, increased the release of ME-i.r. above the base line, an effect that was Ca(++)-dependent. Both L-glutamate and NMDA, at concentrations of 1 and 5 mM, produced a graded increase in the ME-i.r. release, but a higher concentration (10 mM) produced a lower release. In both regions the NMDA (5 mM)-evoked release was effectively inhibited by Mg++ (1.2 mM), 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (5 microM), a competitive NMDA receptor antagonist and thienylcyclohexylpiperidine (10 microM), a noncompetitive NMDA receptor antagonist. Tetrodotoxin (0.3 microM), a Na+ channel blocker, did not affect the NMDA-evoked release of ME-i.r. in the striatum, but decreased it by 52% in the globus pallidus.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1990

Elevation of Met-enkephalin-like immunoreactivity in the rat striatum and globus pallidus following the focal injection of excitotoxins.

The present study examined the effects of excitotoxins which activate distinct excitatory amino acid (EAA) receptor subtypes on the levels of Methionine-enkephalin-like immunoreactivity (ME-i.r.) in the striatum and globus pallidus, with a view to developing a model of the striatopallidal enkephalin deficit that prevails in Huntington's disease (HD). Each of the 4 excitotoxins, N-methyl-D-aspartate (NMDA, 50-150 nmol), quisqualate (QUIS, 26.5-102 nmol), kainate (KA, 0.5-7 nmol) and quinolinate (QUIN, 18-288 nmol), were unilaterally infused into the right striatum under halothane anaesthesia. Seven days after the injection, levels of ME-i.r. in the ipsilateral and contralateral striatum or globus pallidus were measured by radioimmunoassay (RIA). Injection of each of the 4 excitotoxins produced dose-related and bilateral elevations in ME-i.r. in both brain regions. Generally, the excitotoxin-induced contralateral response mirrored that on the ipsilateral side and the globus pallidus showed a greater change in ME-i.r. levels than did the striatum. The rank order of apparent efficacy for these 4 agents, based on the magnitude of the maximal effect produced by the excitotoxin, was QUIN = KA greater than NMDA = QUIS. In contrast, the rank order of apparent potency, based on the doses producing a maximal effect, was KA greater than QUIS greater than QUIN greater than NMDA. Histological examination of brain sections revealed that in all cases of excitotoxin injection, the dose producing a maximal increase in ME-i.r. was associated with tissue damage in the injection area. However, no tissue damage was apparent in the globus pallidus or the contralateral striatum. To determine the involvement of EAA receptors in the observed elevations of ME-i.r., the action of 3 EAA antagonists was evaluated in co-injection experiments. Kynurenate (KYN), but not CNQX, antagonized the actions of QUIS on pallidal ME-i.r. levels. Both KYN and CPP, a potent NMDA receptor antagonist, blocked the effect of QUIN. The possibility that contralateral changes in the striatum or globus pallidus were due to mobilization of an endogenous EAA was investigated by injection of CPP into the striatum contralateral to the QUIN infusion. This injection of CPP (1.8-3.6 nmol) did not block the QUIN-induced contralateral response, but reduced the elevation in ME-i.r. in the ipsilateral pallidum. Although the excitotoxin-induced changes in ME-i.r. levels do not appear to correspond to the enkephalin deficit seen in HD, such a deficit may be discernible in different parameters of enkephalinergic cell function.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolites.

Certain products of tryptophan metabolism interact with excitatory amino acid receptors to produce or protect against excitotoxicity. In this study, the action of several tryptophan metabolites, yielded by the kynurenine pathway, on cortical cholinergic toxicity was evaluated following focal injection into the rat nucleus basalis magnocellularis (nbM). Metabolites were injected singly or in combination with a fixed dose of quinolinic acid (QUIN). Cholinergic toxicity, or protection against it, was evaluated by measurements of choline acetyltransferase (ChAT) activity or potassium-evoked release of [3H]acetylcholine [( 3H]ACh) from slices of the frontoparietal cortex, from the injected and uninjected sides. Focal injections of QUIN and 3-hydroxyanthranilic, but not kynurenic, picolinic, quinaldic or anthranilic acid, produced a dose-related decrease in ChAT activity, with QUIN being more potent. Kynurenic, picolinic, quinaldic and anthranilic acid, co-injected into the nbM with QUIN (120 nmol), produced dose-related antagonism of the neurotoxicity associated with QUIN alone. Picolinic acid also prevented the reduction in cortical [3H]ACh release induced by injections of QUIN. Kynurenic and picolinic acid produced a complete blockade of QUIN's effect on cortical ChAT activity, while quinaldic and anthranilic acid produced a partial blockade. The order of effectiveness against QUIN was kynurenic greater than picolinic greater than quinalidic or anthranilic acid. Evaluation of thin sections following Cresyl violet staining indicated that injections of QUIN produced neuronal loss and glial proliferation, while co-injections of picolinic or quinaldic acid with QUIN protected neurons. These findings show that several tryptophan metabolites have the potential to either produce or antagonize cholinergic toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxyanthranilic Acid↗
PubMed1990

Reexamination of dopamine as the prolactin-release inhibiting factor (PIF): supplementary agent may be required for dopamine to function as the physiological PIF.

A large number of studies have been performed concerning dopamine's inhibitory effect on prolactin release, but many of these studies have examined the effect of dopamine dissolved in a solution containing ascorbic acid. Ascorbic acid, routinely used to protect dopamine from oxidation, alone does not stimulate or inhibit prolactin release, but it can potentiate the inhibitory effect of dopamine in a static monolayer culture system by approximately 100 times. We have closely examined the inhibitory effect of dopamine on prolactin release in the absence of ascorbic acid using a perifusion system. Male rat adenohypophyses were dispersed with trypsin and cultured in a Petri dish to form cell clusters. Inhibition of prolactin release by dopamine (1 mumol/L) in the absence of ascorbic acid was sustained for only 63 min during the 2-h perifusion period. Following a 2-h period of incubation of dopamine in the same experimental solution, the dopamine concentration was reduced from 1 to 0.18 mumol/L, yet this "2-h-old dopamine" was still effective in inhibiting prolactin release (approximately 30 min). This result suggests that the lactotrophs may be desensitized by chronic exposure to a high concentration of dopamine in the absence of ascorbic acid. In contrast, when a low concentration of dopamine (3 nmol/L) containing ascorbic acid (0.1 mmol/L) was perifused, inhibition of prolactin release was sustained for the entire 2-h perifusion period. Although there may be a large number of explanations for dopamine's transient inhibitory effect on prolactin release, the present results suggest that dopamine may require supplementary agent(s) to effectively inhibit prolactin release and thus function as the prolactin release inhibitory factor (PIF).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Actions of beta-endorphin and related peptide fragments on a pressor response induced by cholinergic stimulation.

The present study examined the antagonist potential of shorter beta-EP1-31 related peptide fragments in an opioid-sensitive model of blood pressure. In urethane-anesthetized rats, pretreated with methyl atropine, physostigmine (25-200 micrograms/kg i.v.) produced a pressor response that was stereoselectively depressed by i.c.v. levorphanol, an action reversed by naloxone. beta-EP1-31 and beta-EP1-27(H) (5-20 micrograms i.c.v.) also depressed the physostigmine-induced pressor response in a naloxone-reversible manner. However, injections of beta-EP1-27(O) or beta-EP1-26(H) failed to influence this response or to reverse the depressor action of levorphanol. These findings show that shorter fragments of beta-EP1-31 do not mimic the action of naloxone in an opioid-sensitive model of blood pressure.

Animals↗
PubMed1989

Cortical muscarinic receptor function following quinolinic acid-induced lesion of the nucleus basalis magnocellularis.

Phosphatidylinositol metabolism, linked to muscarinic receptor activation, was studied in rat cortical slices after a unilateral quinolinic acid lesion to the nucleus basalis magnocellularis (nbM) or the cortex itself. The incorporation of [3H]inositol into inositol phosphate was measured in the presence of LiCl, followed by anion exchange chromatography to separate inositol phosphates. Carbachol produced a dose-related increase in the amount of inositol phosphate in both the control and the cortex from rats with lesions to the nbM. No significant difference in the accumulation of inositol phosphate was observed between the two groups. Destruction of cortical cells with quinolinic acid almost completely eliminated the activation of phosphatidylinositol metabolism by carbachol. These results suggest that muscarinic receptors linked to phosphatidylinositol metabolism in the cortex are localized on intrinsic cortical neurons and not on afferent terminals from basal forebrain cholinergic neurons.

Animals↗
PubMed1989

Kynurenic acid protects against the neurochemical and behavioral effects of unilateral quinolinic acid injections into the nucleus basalis of rats.

It has recently been demonstrated that kynurenic acid (KYN), an endogenous tryptophan metabolite, provides almost complete protection against the neurotoxic and mnemonic effects of another tryptophan metabolite quinolinic acid (QUIN) on the cell bodies of the nucleus basalis magnocellularis (nbm). The present study further investigated whether unilateral coinjections of KYN and QUIN into the rat nbm antagonized the effects of QUIN alone. Food-deprived rats were pretrained on an eight-arm radial maze, with four arms baited, until choice accuracy stabilized to greater than or equal to 87% correct. Postoperatively, rats were tested on the radial maze for 32 consecutive days. Feeding behavior and locomotor activity were also measured to determine if nonassociative factors accounted for any observed behavioral deficits. QUIN lesions resulted in significantly more working and reference memory errors compared with sham-operated and coinjected animals, which did not differ significantly from each other. There were no reliable group differences in amount of food eaten or locomotor activity. The QUIN group had a reliable decrease in cortical choline acetyltransferase, with no significant changes for the sham and coinjected groups. Results confirm that KYN antagonizes the neurotoxic and mnemonic effects of QUIN alone and suggest that the memory deficits induced by nbm lesions cannot be solely attributed to changes in feeding or locomotor activity.

Animals↗
PubMed1989

Characterization of L-glutamate action on the release of endogenous dopamine from the rat caudate-putamen.

In the present study the effect of L-glutamic acid (L-Glu), N-methyl-D-aspartic acid (NMDA), kainic acid (KA) and quisqualic acid (QUIS) on the release of endogenous dopamine (DA) from slices of the rat caudate-putamen was investigated. DA was measured by high-performance liquid chromatography coupled to an electrochemical detector. L-Glu, NMDA, KA and QUIS, in the absence of Mg++, produced a dose-related, Ca++-dependent increase in DA release. The order of agonist efficacy was L-Glu greater than NMDA greater than KA = QUIS. D-2-amino-7-phosphonoheptanoic acid (0.5 mM), but not L-2-amino-7-phosphonoheptanoic acid, antagonized the action of L-Glu and NMDA, but did not modify the effect of KA or QUIS. Tetrodotoxin (0.1 microM) partially inhibited the stimulatory effect of KA and QUIS, but not that of L-Glu or NMDA. Mg++ (1.2 mM) abolished the excitatory effect of NMDA, significantly reduced the action of L-Glu, but did not influence the action of KA or QUIS. The inhibitory action of Mg++ on the L-Glu-induced DA release was reversed when L-Glu was coupled to high concentrations of K+. N-allylnormetazocine (SKF-10,047), a benzmorphan agent, produced a stereospecific inhibition of L-Glu-induced DA release. This inhibition was also produced by 1-[1-(2-thienyl)cyclohexyl]piperidine, a phencyclidine receptor ligand, but not by 1,3-di-O-tolylguanidine, a sigma receptor-selective ligand. The results of this study show that L-Glu increases DA release predominantly by activation of the NMDA receptor located presynaptically on dopaminergic afferents.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1989

Animal studies of brain acetylcholine and memory.

Memory loss is a common feature of aging in the human but not all memories are equally lost. Usually the loss is more severe for the memory of recent events and information rather than the memory of remote events and information. Associated with memory losses of this type is a reduction in levels of cortical acetylcholine and a loss of cholinergic cells of the nucleus basalis magnocellularis. In the rat it is possible to assess two types of memory analogous to recent and remote memories in humans. Reference memory would refer to information concerning the task that is invariant from trial to trial. Working memory would refer to information that changes from trial to trial. In support of the hypothesis that decreases in cholinergic function lead to a differential impairment of working memory, rats trained in this task and given scopolamine showed a specific increase in working memory errors. In more recent studies rats have been trained in a task and then given unilateral neurotoxic lesions of the NBM. These results raise the intriguing possibility that degeneration of the NBM and associated memory impairment seen in aging and in Alzheimer's disease may be related to a change in the ratio of these or related endogenous tryptophan metabolites.

Acetylcholine↗
PubMed1988

Effects of a kappa-receptor agonist, U-50,488H, on the release of endogenous brain dopamine.

The potential interaction between kappa-opiate receptors and dopamine activity was examined in this study by monitoring the effect of U-50,488H on the release of endogenous dopamine from rat striatal slices in both the absence and presence of 10 microM nomifensine, a potent dopamine uptake inhibitor. Basal dopamine release was increased 10-fold in the presence of nomifensine, and the normally steady base line was observed to increase gradually under these conditions. U-50,488H, a potent kappa-agonist, enhanced the spontaneous release of dopamine, but only at relatively high concentrations (40.0 microM) and only in the absence of nomifensine. Likewise, nomifensine and U-50,488H (40.0 microM) each significantly inhibited the synaptosomal uptake of [3H]dopamine. As with basal release, nomifensine markedly enhanced the potassium-evoked release of dopamine, and this evoked release was significantly attenuated by U-50,488H (0.4 and 40.0 microM) in both the absence and presence of nomifensine. This opiate-mediated inhibition of evoked dopamine release was antagonized in a time-dependent manner by the putative kappa-antagonist, WIN 44,441-3, suggesting that striatal kappa-receptor activation modulates dopamine release.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1988

Morphine can stimulate prolactin release independent of a dopaminergic mechanism.

Prolactin release is controlled by prolactin-release inhibiting factor (PIF), possibly dopamine, and an unidentified putative hypothalamic prolactin-releasing factor (PRF). Morphine and related opioids may indirectly stimulate prolactin release by inhibiting PIF release and (or) by stimulating putative PRF release. In the present study, we have completely blocked the dopaminergic receptors in normal male rats by pretreatment with a large dose of pimozide (3 mg/kg) to demonstrate if putative PRF has a role in morphine-induced prolactin release. Morphine sulfate (10 mg/kg) was still able to stimulate prolactin release in the rat without any functional dopaminergic PIF receptors. When naloxone (3 mg/kg) was injected 20 min before the morphine in the pimozide-treated rat, plasma prolactin concentration was not affected by morphine indicating that the stimulatory effect of this opioid on prolactin release in the pimozide-pretreated rat was mediated by mu-receptors. We can conclude that morphine can stimulate prolactin release through a mechanism apparently independent of dopaminergic receptors, one possible route being through a putative PRF.

Animals↗