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K Jhamandas

Publications and source records attributed to K Jhamandas.

At least 109 records · Page 6Linked to original sources
PubMed1984

Morphine diesters. I. Synthesis and action on guinea pig ileum.

3,6-Dipropanoylmorphine (DPM), 3,6-dibutanoylmorphine (DBM), and 3,6-dihexanoylmorphine (DHM) were prepared as prospective long-acting narcotic analgesics. The purity and structure of these compounds were authenticated by high pressure liquid chromatography and direct probe mass spectrometry. In aqueous solution the stability of the HCI salts of these compounds decreased with increasing alkyl chain length such that DHM underwent rapid hydrolysis to 6-monohexanoylmorphine (MHM). A comparison of DPM, DBM, and MHM with morphine (MO) and 3,6-diacetylmorphine (DAM, heroin) in the electrically stimulated guinea pig ileum myenteric plexus longitudinal muscle strip preparation (GUPIL) revealed similar potencies and efficacies for all compounds, but marked differences in the onset of drug action (MO greater than DAM greater than MHM greater than DPM greater than DBM, faster to slower). In a periodically washed GUPIL preparation DBM and MHM were five times longer acting than MO, DAM or DPM.

Animals↗
PubMed1984

Stability of dopamine in an in vitro incubation system using Medium 199.

This study investigated the stability of exogenous dopamine (DA) in vitro in a commercially available medium (Medium 199), with and without additional ascorbic acid, during incubation with pituitary halves in prolactin secretion experiments. After a 3-h incubation period, 26 and 15% of the starting concentrations of DA were degraded in the absence and presence of 1 mM ascorbic acid, respectively; in the absence of pituitary tissue, these reductions in DA concentration were 19% and 0%, respectively. In contrast, 98% of DA was degraded after 3 h of incubation in Krebs-Henseleit bicarbonate buffer which contained no tissue or no antioxidants. A number of antioxidants (including a low concentration of ascorbic acid) which are already present in Medium 199 are most likely responsible for the relative stability of DA in this medium. The loss of DA during incubation in Medium 199 is considered small for this type of study, and additional ascorbic acid only marginally improves DA stability in this medium. We have concluded that there is no need to be overly concerned about the degradation of exogenous DA in vitro for some incubation experiments using Medium 199, and the addition of extra ascorbic acid (which may be deleterious) is not necessary.

Animals↗
PubMed1984

Kainic acid evoked release of D-[3H]aspartate from rat striatum in vitro: characterization and pharmacological modulation.

A presynaptic stimulatory action of kainic acid (KA) on the release of glutamate from corticostriatal neurons is thought to contribute to the toxic effect of KA on cell bodies of neurons in the striatum. To characterize the action of KA on the presynaptic amino acid release, its effect was evaluated on the spontaneous efflux of D-[3H]aspartate (D-[3H]Asp), a marker for glutamatergic neurons, from slices of rat striatum in superfusion experiments. In the concentration range 0.5-10.0 mM, KA significantly increased the spontaneous efflux of D-[3H]Asp. Under similar conditions potassium (K+, 25 mM), veratridine, D-aspartic acid (D-Asp), and N-methyl-D-L-aspartic acid (NMDLA) also induced the efflux of the radiolabelled amino acid. The stimulatory effect of KA, like that of K+, was partly calcium dependent. The action of veratridine, D-Asp, and NMDA was not calcium dependent. Tetrodotoxin (TTX) blocked the action of veratridine on D-[3H]Asp efflux but did not affect the action of KA. In a sodium-free perfusion medium the action of KA was greatly reduced. Dihydrokainic acid produced an effect on D-[3H]Asp efflux comparable in magnitude with that produced by KA. The latter, at a dose of 5 mM, also stimulated the efflux of D-[3H]Asp from the cortex, hippocampus and the septum but its effect on these regions was weaker than its striatal effect. The action of several agents, which previously have been found to depress transmitter release in other systems and (or) to modify the neurotoxic action of KA in vivo, was evaluated on the KA-evoked D-[3H]Asp efflux from striatal slices.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Studies on the release by somatic stimulation from rat and cat spinal cord of active materials which displace dihydromorphine in an opiate-binding assay.

Using the spinal superfusion procedure, in anesthetized rats and cats, the presence of active factors which displace dihydromorphine in brain opiate binding studies, has been observed. Separation of this activity on a Sephadex G-10 column reveals the presence of two fractions which occur before (Fraction I) and after (Fraction II) the salt peak which account for over 70% of the observed dihydromorphine-displacing activity. The ratio of activity in Fraction II/Fraction I is 33 and 21, in the resting spinal perfusates of the rat and cat, respectively. High intensity, bilateral stimulation of the sciatic nerve in cats, results in a 30- and 5.4-fold increase in the levels of Fraction I and Fraction II, respectively, over pre-stimulation levels. In rat, bilateral stimulation of the hind paws, resulted in a frequency-dependent increase in the levels of Fraction I (1.9- and 3.2-fold at 5 and 50 Hz, respectively). Dynorphin 1-13 fragment elutes at least partly in Fraction I. With regard to Fraction II, the peak co-chromatographs with hexapeptide derivatives of enkephalin. Met- and Leu-enkephalin (Fraction III), elute off the column at a point where opiate receptor displacing activity is relatively small. Electrophoretic separation of Fraction I radioreceptor activity of alkaline and acid pH on agarose columns revealed two principle peaks which co-migrated with alpha-neoendorphin and dynorphin 1-13. Fraction II activity appeared primarily in a single peak which was isographic with enkephalin hexapeptides. Using radioimmunoassays, detectable levels of dynorphin and Met-enkephalin were observed and sciatic nerve stimulation resulted in significant increases. Neither column-coupled radioreceptor assays nor radioimmunoassays revealed the presence of beta-endorphin. The present experiments demonstrate the releasability by high intensity somatic stimulation of a variety of opioid peptides present in spinal terminals. Significantly, however, the majority of this activity appears to be found in fractions different from those of the pentapeptide enkephalins.

Animals↗
PubMed1983

Stereospecific enhancement of evoked release of brain acetylcholine by narcotic antagonists.

1--Electrical stimulation of nerves in the forepaw of anaesthetized rats caused an increase in the release of acetylcholine (ACh) from the cerebral cortex in vivo. Actions of naloxone (Nal) enantiomers and naltrexone (Ntx) were tested on this release in normal animals and those lacking pituitary gland for 3 weeks. 2--In normal animals systemic administration of (-)-Nal or Ntx, but not (+)-Nal caused a significant increase in the evoked release of ACh. Spinally administered (-)-Nal did not produce this effect. Cortical application of (-)-Nal produced a smaller increase in the evoked release of ACh. 3--In hypophysectomized rats the stimulatory action of (-)-Nal or Ntx on ACh release was significantly reduced. The ability of (-)-Nal to reverse inhibitory action of morphine or the enkephalin (FK 33,824) was not affected by hypophysectomy. 4--It is suggested that (-)-Nal and Ntx increase the stimulated release of cortical ACh by blocking the inhibitory action of an endogenous opioid at a subcortical site. An intact pituitary appears essential for a full expression of the Nal effect on evoked ACh release.

Acetylcholine↗
PubMed1983

Antagonism of enkephalin action on acetylcholine release by methylxanthines: lack of a purine link.

Theophylline (Theo) and caffeine antagonized the inhibitory effect of methionine (Met)-enkephalin, leucine (Leu)-enkephalin and morphine on the twitch height of the field stimulated myenteric plexus longitudinal muscle (MPLM) preparation of the guinea-pig ileum. Antagonism by Theo was observed only in tissues stimulated submaximally, but that by caffeine was observed in tissues stimulated submaximally and supramaximally. Injection of Theo (20, 40 mg kg-1) or caffeine (40 mg kg-1) reversed or blocked the inhibitory effects of Leu-enkephalin (50 micrograms i.c.v.) and a systemically active enkephalin FK 33,824 (0.5 mg kg-1) on the release of acetylcholine (ACh) from the rat cortex in vivo. Injections of morphine (2.5, 5.0 mg kg-1 i.v.) did not modify the in vivo release of radiolabelled purines from the cerebral cortex prelabelled with [3H]-adenosine (2.8 X 10(-7) M). Application of K+ (60 mM) to the cortex readily stimulated this release. Injection of morphine (5.0 mg kg-1 i.v.) increased the spontaneous release of radiolabelled purines from the cortex prelabelled with a higher concentration of [3H]-adenosine (10(-4) M) in six out of eleven experiments. Under similar conditions neither Leu-enkephalin (50 micrograms i.c.v.) nor FK 33,824 (0.5 mg kg-1 i.v.) stimulated purine release. It is concluded that methylxanthines can antagonize the inhibitory action of opioids on the peripheral and central release of ACh. However, this antagonism does not reflect an intermediary purine step in the action of opioids on the release of ACh.

Acetylcholine↗
PubMed1983

Regional release of [3H]dopamine from rat brain in vitro: effects of opioids on release induced by potassium, nicotine, and L-glutamic acid.

Previous studies have suggested that the release of dopamine (DA) in the rat brain may be sensitive to modulation by opioid agents, including the endogenous opioid peptides (enkephalins and endorphins). The present study examined the effects of morphine and the enkephalin analogue D-Ala2-Met5-enkephalinamide (DALA) on the release of radiolabeled DA from superfused slices of rat brain regions. The release of preloaded [3H]DA was evoked from slices of the caudate-putamen (CP) by application of potassium (K+), nicotine (NIC), or L-glutamic acid (L-GLU). The release of [3H]DA from slices of the nucleus accumbens (NA), olfactory tubercle (OT), and substantia nigra (SN) was evoked by L-GLU. Both K+ and NIC evoked a concentration-related release of [3H]DA from CP slices. K+-induced release was only partially dependent on calcium (Ca2+), while NIC-evoked release was completely Ca2+ independent. Neither morphine nor DALA influenced the release of [3H]DA evoked by K+ or NIC. L-GLU produced a concentration-dependent release of [3H]DA from slices of CP, NA, OT, and SN. In all four brain regions, this release was (a) Ca2+-dependent, (b) strongly inhibited by low concentrations of magnesium (Mg2+), (c) greater than the release evoked by D-GLU, (d) attenuated by the putative L-GLU receptor antagonist glutamic acid diethylester (GDEE), and (e) insensitive to tetrodotoxin (TTX) except in the SN. Morphine produced a significant inhibition of L-GLU-evoked [3H]DA release from all four regions. Naloxone, which by itself had no significant effect on the L-GLU-evoked release of [3H]DA, blocked the inhibitory effect of morphine on this release in the CP but not in the other regions. Levorphanol and dextrorphan were equipotent in reducing the glutamate-stimulated release of [3H]DA from CP slices. DALA had no effect on L-GLU-induced release in any of the brain regions examined. The results indicate that L-GLU provokes regional release of DA by acting at a Mg2+-sensitive glutamate receptor. This release is selectively modified by morphine through a mechanism which is insensitive to naloxone.

Animals↗
PubMed1981

Opiatelike actions of eseroline, an eserine derivative.

Eseroline, an eserine derivative without anticholinesterase activity, was tested in several systems for opiatelike activity. Eseroline depressed the twitch of the field-stimulated guinea pig ileum myenteric plexus longitudinal muscle preparation but failed to depress the twitch of the rat vas deferens. Intraperitoneal injections of eseroline in rats induced naloxone-antagonizable analgesia and catalepsy. Eseroline failed to influence the release of acetylcholine from the cortex of anesthetized rats. These observations have implications for studies in which eserine is used as a pharmacological tool.

Acetylcholine↗
PubMed1980

Action of coenzyme A on adenine derivative receptors in isolated tissues.

The action of Coenzyme A (CoA) was investigated on the mechanical activity of four isolated tissues known to possess adenine derivative (AD) receptors that are sensitive, or resistant to blockade by theophylline. CoA produced a dose-related inhibition of the electrically stimulated myenteric plexus longitudinal muscle of the guinea pig ileum, and of the spontaneously contracting rabbit ileum. This effect was competitively antagonized by theophylline in both tissues. CoA caused a dose-related relaxation of the rat ileum. Low doses of CoA were not antagonized by theophylline but higher doses were antagonized by this drug. The rabbit detrusor, which was contracted by ATP and ADP, was not affected by CoA. Differences in the action of CoA at AD receptors in these four tissues, and in its antagonism by theophylline reflect a heterogeneity of these receptors. It is suggested that the simple sub-division of adenine derivative receptors into two types may be inappropriate.

Adenine↗
PubMed1980

Action of enkephalin analogues and morphine on brain acetylcholine release: differential reversal by naloxone and an opiate pentapeptide.

1 Methionine (Met)-enkephalin, leucine (Leu)-enkephalin and their synthetic analogues were tested for effects on the spontaneous release of cortical acetylcholine (ACh) in vivo. The ability of naloxone to reverse the action of enkephalins on ACh release was compared with its action against morphine. An enkephalin analogue, structurally related to Met-enkephalin, was tested for opiate antagonistic activity in ACh release experiments. 2 Intraventricular administration of Met-enkephalin, Leu-enkephalin, D-Ala2-Met5-enkephalinamide (DALA) and D-Ala2-D-Leu5-enkephalin (DALEU) produced a dose-related inhibition of cortical ACh release. Met- and Leu-enkephalin were very similar both in their potency and the time course of their action on ACh release. Both DALA and DALEU were more potent and had a longer duration of action than Leu-enkephalin. Systemic injections of two pentapeptides, D-Met2-Pro5-enkephalinamide and D-Ala2-MePhe4-Met5(O)-ol-enkephalin (33,824), produced a sustained inhibition of cortical ACh release. 3 Naloxone, administered systemically following the depression of ACh release induced by either intraventricular injections of enkephalins (DALA or DALEU), or systemic injections of enkephalins (D-Met2-Pro5-enkephalinamide or 33,824), reversed this depression and restored the release to baseline levels. The effect of D-Met2-Pro5-enkephalinamide on the release of ACh was reversed by naloxone with difficulty. Naloxone also reversed the inhibitory effect of systemic morphine and this reversal was associated with a large overshoot of ACh release. The latter was never observed in the enkephalin experiments. 4 Intraventricular injection of the pentapeptide, D-Ala2-D-Ala3-Met5-enkephalinamide (TAAPM), at doses that did not influence the basal ACh release, blocked or reversed the inhibitory effect of morphine on this release. This peptide did not block the effect of the non-opiate, chlorpromazine, under similar conditions. In two experiments TAAPM failed to reverse the inhibition of ACh release produced by systemically injected enkephalin, D-Met2-Pro5-enkephalinamide. 5 Effects of morphine and enkephalin on ACh release are discussed in terms of their action on difference opiate receptors.

Acetylcholine↗
PubMed1980

Investigation of action of enkephalin on the spontaneous and evoked release of acetylcholine from rat cortical and striatal slices.

1 The effects of two synthetic enkephalins, D-Ala2-Met5-enkephalinamide (DALA) and D-Ala2-MePhe4-Met5-(0)-ol-enkephalin (33,824) were tested on the spontaneous and stimulated release of acetylcholine (ACh) from rat cortical and striatal slices. 2 DALA, but not 33,824, caused a modest increase in spontaneous cortical ACh release. Neither enkephalin affected the release of cortical ACh induced by high potassium (25 mM) or veratridine (20 microM). 3 DALA had no effect on the release of ACh from striatal slices occurring spontaneously or in the presence of potassium (25 mM), veratridine (5 microM) or ouabain (10 microM). The enkephalin 33,824 also had no significant action on the striatal ACh release except that it caused a slight enhancement of veratridine-evoked release. 4 It is suggested that enkephalins have no significant action on release of ACh from the cortex or striatum in vitro. Their action on ACh release from the cortex in vivo, seen in previous studies, may be exerted at a subcortical level.

Acetylcholine↗
PubMed1980

Regional release of [3H]adenosine derivatives from rat brain in vivo: effect of excitatory amino acids, opiate agonists, and benzodiazepines.

Previous studies have suggested that the theophylline-sensitive actions of (a) glutamic acid and related excitatory amino acids, (b) opiate agonists, and (c) benzodiazepines may be mediated by adenosine and its derivatives (AD). In this study the effects of these theophylline-sensitive agents on the in vivo release of labelled AD from the rat cerebral cortex and cerebellum were examined. Application of L-glutamate (L-Glu) to the cortex or cerebellum, preloaded with [3H]adenosine or [3H]adenine, markedly stimulated the release of [3H]adenosine derivatives ([3H]AD) from these regions. This effect was also produced by L-aspartate (L-Asp), kainate (Kai), and two "non-amino-acid" depolarizing agents, veratridine and potassium (56 mM). In the cerebral cortex the excitatory action of L-Glu or L-Asp was stronger than that of Kai but in the cerebellum all of these agents produced a similar effect on the release of [3H]AD. Pretreatment of the cortex with glutamic acid diethylester, HA966, 2-amino-4-phosphonobutyrate, and 2,3-diaminopropionate, but not theophylline, selectively antagonized the releasing action of L-Glu. This action of L-Glu was also reduced by EGTA added to a Ca-free physiological medium. In the cortex and cerebellum the excitatory action of L-Glu on the release of [3H]AD was attenuated by tetrodotoxin (TTX). TTX also antagonized the action of veratridine, but not potassium, on the cortical output of [3H]AD. Chromatographic analysis of release samples showed that about 60% of the total radioactivity released by L-Glu was associated with pharmacologically active AD, adenosine, and adenine nucleotides. The opiate agonists morphine and D-Met2-Pro5-enkephalinamide by themselves did not influence the spontaneous release of [3H]AD from the cortex but both agents very effectively inhibited the release evoked by L-Glu. This inhibitory action was antagonized by naloxone. At a low dose levorphanol, but not dextrorphan, inhibited the L-Glu-evoked release of [3H]AD. Both of these agents suppressed this release at a higher dose. Topical application or systemic administration of two benzodiazepines, flurazepam or diazepam, stimulated the release of [3H]AD from the cerebral cortex but in the cerebellum only flurazepam produced this effect. Except for topically applied flurazepam, in comparative tests these agents did not modify the release of gamma-[3H]aminobutyric acid derivatives. The results suggest that the theophylline-sensitive actions of glutamic acid, related depolarizing agents, and benzodiazepines may be expressed through release of AD from brain regions. Such actions of opiates cannot be explained on the basis of AD release.

Adenosine↗
PubMed1980

Comparative effects of somatostatin and enkephalins on the guinea pig ileum and the rat vas deferens.

The action of somatostatin (SRIF (somatotrophin release inhibiting factor)) was compared with that of Met-enkephalin (Tyr-Gly-Gly-Phe-Met) in the electrically stimulated guinea pig ileum myenteric plexus longitudinal muscle and with that of an enkephalin analogue (FK 33-824 (Tyr-D-Ala-Gly-MePhe-Met-(O)-ol)) in the rat vas deferens. In both tissues SRIF produced a twitch inhibition which was not antagonized by naloxone and which showed a long-lasting tachyphylaxis. The enkephalins tested produced a naloxone-antagonizable inhibition of twitch in both tissues but no tachyphylaxis. Therefore we conclude that SRIF is not acting at opiate receptors in these tissues.

Animals↗
PubMed1979

Interactions of methylxanthines, nonxanthine phosphodiesterase inhibitors, and calcium with morphine in the guinea pig myenteric plexus.

In an earlier study, theophylline was shown to antagonize the morphine-induced inhibition of electrically induced contractions of the longitudinal muscle-myenteric plexus preparation from the guinea pig ileum. In the present study, acetylcholine (ACh) released from the myenteric plexus was measured directly using a radioenzymatic assay. Theophylline antagonized the morphine-induced inhibiton of ACh release. A similar antagonism was also observed with caffeine and 3-isobutyl-l-methylxanthine (IBMX). All three methylxanthines also increased ACh release. The nonxanthine phosphodiesterase (PDE) inhibitors 4-(3-butoxy-4-methoxy)-2-imidazolidinone (Ro 20-1724) and l-ethyl-4-isopropylidenehydrazino-1 H-pyrozolo(3,4-b)-pyridine-5-carboxylate, ethylester, HCl (SQ 20,009) generally did not antagonize the morphine-induced inhibiton of ACh release. The PDE inhibitor SQ 20,009 but not Ro 20-1724, enhanced the release of ACh. Both high calcium concentration and the divalent cation ionophore A23187 antagonized the inhibitory action of morphine on ACh release. These observations suggest that alteration in calcium fluxes rather than the inhibiton of PDE mediate the methylxanthine-induced antagonism of morphine in this preparation.

Acetylcholine↗
PubMed1978

Antagonism of morphine action on brain acetylcholine release by methylxanthines and calcium.

The inhibitory effect of morphine on the release of acetylcholine (ACh) from the rat cerebral cortex was antagonized by theophylline, caffeine and 3-isobutyl-1-methylxanthine (IBMX). Theophylline antagonism of morphine action was dose related and this agent failed to influence a comparable action of chlorpromazine on the release of ACh. Intraventricular injection of calcium also antagonized the anti-release effect of morphine. Neither methylxanthines nor calcium modified the spontaneous release of ACh in the absence of morphine. It is suggested that methylxanthine antagonism of morphine action is selective and that it could be related to the ability of methylxanthines to mobilize bound calcium.

Acetylcholine↗