Search PubMed⌕ Search

Biomedical subjects

I K Ho

Publications and source records attributed to I K Ho.

At least 217 records · Page 12Linked to original sources
PubMed1984

Analgesic cross-tolerance between morphine and opioid peptides.

The analgesic effect of intracerebroventricular administration of morphine, ketocyclazocine, [D-ala2]-methionine enkephalinamide (DAM), [D-ala2-D-leu5]-enkephalin (DADLE), leuenkephalin, metenkephalin, and beta-endorphin on acetic acid-induced abdominal writhing (AAW) was investigated in naive and morphine-tolerant mice. It was found that the relative potencies of a series of opioids are different in naive and morphine-tolerant groups. In naive animals, the order of potency (ED50, nmol) was beta-endorphin greater than morphine = DAM greater than DADLE greater than ketocyclazocine = leuenkephalin = metenkephalin. The morphine-tolerant animals were cross-tolerant to ketocyclazocine and to all the peptides studied; DAM and beta-endorphin exhibited the highest degree of tolerance. In morphine-tolerant animals, the order of potency was morphine = DADLE = beta-endorphin greater than DAM = ketocyclazocine = metenkephalin greater than leuenkephalin. The results indicate that endogenous opioid systems may be affected by tolerance development to morphine.

Analgesics↗
PubMed1984

Antinociceptive and gastrointestinal effects of opiates: an analysis of the nature of the involvement of mu and delta receptors of the central nervous system in morphine-tolerant and non-tolerant mice.

This study attempted to distinguish between mu (morphine) and delta [(D-Ala2-D-Leu5)-enkephalin; DADLE] receptors, with regard to both in vivo effects (analgesia and gastrointestinal motility) and the location of binding activity in the brain. Analgesia and motility are distinguishable both by dose (intracerebroventricular) and by ligand selectivity with mu ligands more potent for the former and delta for the latter. Tolerance and cross-tolerance are exhibited for both effects, with the relationships between mu and delta ligand potencies preserved. In vitro receptor binding revealed an affinity decrease for delta in medulla and an increase in medulla and diencephalon for mu receptors after tolerance development to morphine. The results indicate that the mu receptors in medulla and diencephalon mediate analgesia, while medullary delta receptors control motility.

Analgesia↗
PubMed1984

Effect on striatal dopamine metabolism and differential motor behavioral tolerance following chronic cholinesterase inhibition with diisopropylfluorophosphate.

Rats were treated with diisopropylfluorophosphate (DFP), using 1 or 2 mg/kg acutely, or with 1 mg/kg daily for 4, 14 or 28 days. Their behaviors and striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels were studied. The behaviors: tremors, chewing-movements and hind-limb abduction induced by DFP increased in a steeply dose-dependent manner. Chronic treatment for up to 28 days produced biphasic patterns of change for all the behavioral parameters. Tremor occurred in a complex spectrum of slow to intense fast types. Except for chewing, tolerance developed for these parameters, but at different rates. After acute treatment striatal DA and DOPAC levels were altered and the DOPAC/DA ratios were consistently increased within about the first two hr, suggesting an increased turnover of DA. After chronic treatment for 4 and 14 but not 28 days, both DA and DOPAC levels were decreased without a change in their ratios. It is suggested that the changes in DA metabolism arose secondarily to an elevation of brain acetylcholine following cholinesterase inhibition. A prolonged change in the levels or turnover of DA could be responsible for increase of postsynaptic DA receptor density previously found by us [36], which might then partly mediate the behavioral tolerance to DFP.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

An assessment of comparative acute toxicity of diisopropyl-fluorophosphate, tabun, sarin, and soman in relation to cholinergic and GABAergic enzyme activities in rats.

The sc LD50s (mumol/kg) in rats for diisopropylfluorophosphate (DFP), Tabun, Sarin, and Soman were 14.5, 1.9, 1.4, and 0.88, respectively. The relative potency was as follows: DFP less than Tabun less than Sarin less than Soman (1:7.6:10.4:16.4). The relative potencies correlated with the in vitro acetylcholinesterase (AChE) inhibition (in terms of the IC50) by these compounds, in whole brain homogenates or the purified bovine erythrocyte AChE. There was a dose versus time for mortality relationship for all four compounds; the average time for death decreased with increase in dose. However, there was no correlation between time for death and the extent of AChE inhibition. The striatal as well as other regional (medulla, diencephalon, cortex, and cerebellum) AChE activity was inhibited over 90% of the control, by the lethal doses of these compounds. None of the lethal or sublethal doses had any apparent effect on choline acetyltransferase (CAT) or GABA-transaminase activities. Glutamic acid decarboxylase activity was increased by Soman, Sarin, and Tabun at certain lethal doses but was not affected by DFP even at the lethal dose. The results indicate that (a) the acute toxicity of organophosphate acetylcholinesterase inhibitors is directly related to the inhibition of AChE though there is a wide difference in their potency; (b) a substantial inhibition of AChE activity (over 90% of control) is necessary for lethality to ensue after an acute exposure and the margins between lethal and nonlethal doses are extremely small; and (c) qualitative differences seem to exist among the various organophosphates in affecting noncholinergic neurotransmitter enzymes.

4-Aminobutyrate Transaminase↗
PubMed1984

Effects of diisopropylfluorophosphate (DFP) on renal function in the rat.

Numerous studies have suggested a role for the nervous system in renal function. Several cholinergic agents have been examined for effects in vivo and in renal slices. Effects mediated through the vascular system and also direct effects have been reported. In this study an irreversible cholinesterase inhibitor, diisopropylfluorophosphate (DFP) in doses of 1-4 mg/kg, was tested on renal function. A single dose of DFP (2, 3 or 4 mg/kg) caused an increased flow of urine of low osmolality over the 6 h after the administration of the drug with essentially a return to control status by 24 h after either of the lower doses. Twenty-four hours after 4 mg/kg, urine volume was less and urine osmolality greater than control. Renal and brain cholinesterases remained depressed 24 h after DFP. In acute experiments on anesthetized animals, inulin clearance was increased by the lower doses and decreased by the highest dose of DFP. Renal blood flow measured with an electromagnetic flow meter showed a similar dose-response relationship. However, urine flow increased at all doses. The increased urine flow associated with decreased inulin clearance (4 mg/kg) and renal blood flow (3 or 4 mg/kg) suggest a direct effect of DFP on renal tubular function. These effects do not appear to be related to inhibition of cholinesterase.

Animals↗
PubMed1984

Design of a phencyclidine implantation pellet; suitable for tolerance development.

When using laboratory animals (e.g., mice) for phencyclidine (PCP) tolerance studies, an essential part of the procedure is to administer the PCP in such a way that the animals received adequate doses of the drug at frequent enough intervals to reach and maintain the desired levels of tolerance or employ a osmotic minipump which is either suitable or convenient to develop a high degree of tolerance to PCP in a large number of animals in a short period. However, these methods are unfit for routine work because of repeated daily injections consume too much time and osmotic minipump comes expensive. Therefore, in this paper we attempted to develop PCP pellet suitable for tolerance development. The s.c. implantation of a 10 or 20 mg PCP pellet in the back of a conscious mouse resulted in a much more rapid development of tolerance to PCP than that produced in mice receiving daily i.p. injection of, 10 or 20 mg/kg, PCP-HCl. Assessment of and degree of tolerance to PCP by PCP pellet implantation and daily injection of PCP-HCl were evidenced by a degree of decrease in the duration of motor incoordination after the challenge with, 20 mg/kg, PCP-HCl 24 h after removal of PCP pellets or a last injection of PCP-HCl. These studies may demonstrate a substantial methodological improvement in producing a high degree of tolerance to PCP in a short period of time by means of the s.c. pellet implantation technique.

Animals↗
PubMed1983

GABAergic drugs, morphine and morphine tolerance: a study in relation to nociception and gastrointestinal transit in mice.

Agonists and antagonists of gamma-aminobutyric acid, i.e. GABAergic drugs, such as muscimol, baclofen or bicuculline, alone or in combination, exhibited analgesic effects per se and enhanced the analgesia induced by morphine. The analgesic effects of GABAergic drugs were unaffected by administration of naloxone in a dose which antagonized the analgesia induced by morphine. The ED50 for the antinociceptive effect of muscimol, bicuculline, picrotoxin, gabaculline or aminooxyacetic acid (AOAA) was not affected in the morphine-tolerant group as compared to the control group, in contrast to the increase in the ED50 for morphine under similar conditions; this indicated that there was no development of cross-tolerance between morphine and GABAergic drugs. Muscimol suppressed the abrupt withdrawal-jumping induced by morphine and enhanced the suppression of this phenomenon by morphine. The GABAergic drugs also shared with morphine the property of inhibiting gastrointestinal (GIT) motility. Naloxone reversed the inhibition of motility induced by morphine but failed to influence that induced by GABAergic drugs. In the morphine-tolerant state, the sensitivity of gastrointestinal motility to morphine decreased, whereas, the sensitivity to GABAergic drugs remained unaltered. The results indicate that GABAergic drugs share some of the classical properties of morphine, such as analgesia and inhibition of gastrointestinal motility, but they probably do so by different mechanisms.

Aminooxyacetic Acid↗
PubMed1983

Effect of acute and chronic cholinesterase inhibition with diisopropylfluorophosphate on muscarinic, dopamine, and GABA receptors of the rat striatum.

The effects of acute and chronic administration of diisopropylfluorophosphate (DFP) to rats on acetylcholinesterase (AChE) activity (in striatum, medulla, diencephalon, cortex, and medulla) and muscarinic, dopamine (DA), and gamma-aminobutyric acid (GABA) receptor characteristics (in striatum) were investigated. After a single injection of (acute exposure to) DFP, striatal region was found to have the highest degree of AChE inhibition. After daily DFP injections (chronic treatment), all brain regions had the same degree of AChE inhibition, which remained at a steady level despite the regression of the DFP-induced cholinergic overactivity. Acute administration of DFP increased the number of DA and GABA receptors without affecting the muscarinic receptor characteristics. Whereas chronic administration of DFP for either 4 or 14 days reduced the number of muscarinic sites without affecting their affinity, the DFP treatment caused increase in the number of DA and GABA receptors only after 14 days of treatment; however, the increase was considerably lower than that observed after the acute treatment. The in vitro addition of DFP to striatal membranes did not affect DA, GABA, or muscarinic receptors. The results indicate an involvement of GABAergic and dopaminergic systems in the actions of DFP. It is suggested that the GABAergic and dopaminergic involvement may be a part of a compensatory inhibitory process to counteract the excessive cholinergic activity produced by DFP.

Acetylcholinesterase↗
PubMed1983

Variation of commercial diisopropyl fluorophosphate preparations in toxicological studies.

The variation of three diisopropyl fluorophosphate (DFP) lots obtained from two sources was investigated. The effects of different lots of DFP on body weight, mortality, and brain acetylcholinesterase activity in rats varied significantly. The in vitro effects of these DFP preparations on brain acetylcholinesterase activity also were markedly different. It appears that different commercial preparations of DFP possess different potencies and that the same apparent doses of different DFP preparations will not produce the same effects upon any physiological system under study.

Acetylcholinesterase↗
PubMed1983

Diisopropylfluorophosphate and GABA synaptic function: effect on levels, enzymes, release and uptake in the rat striatum.

The present study revealed that diisopropylfluorophosphate increased the GABA and glutamate levels, decreased the uptake of GABA, decreased the spontaneous release of GABA and did not exhibit its effects on the metabolic enzymes of GABA, glutamic acid decarboxylase and GABA-transaminase. These results, together with our previous finding that the postsynaptic GABA receptor population is increased by DFP treatment, indicate that GABA transmission is affected by DFP. An overall enhancement of GABA function appears to be involved in DFP poisoning; it is suggested that this may be a compensatory mechanism to counteract the cholinergic hyperactivity.

4-Aminobutyrate Transaminase↗
PubMed1983

Effect of morphine on the responses to and disposition of phencyclidine in mice. I. Enhancement of phencyclidine effects by acute morphine administration.

Morphine elicited a dose-related increase in the duration of phencyclidine (PCP)-induced motor incoordination. In the open field behavioral observations, morphine enhanced the PCP-induced decrease in the number of ambulation and rearing. Morphine potentiated the PCP-induced decrease in body temperature. The LD50 of PCP was significantly decreased in the presence of morphine. An opiate antagonist, naloxone, antagonized the morphine-induced effects without influencing the pharmacological actions of PCP itself. The levels of hepatic microsomal cytochrome P-450 and cytochrome b5 and the activities of NADPH dehydrogenase and NADPH cytochrome c reductase were unaffected by morphine treatment. The half-lives of PCP in serum and brain were increased by the concurrent administration of morphine. The ratio of the liver weight to body weight and aniline hydroxylase activity in hepatic microsomal fraction were decreased in the morphine-treated group compared with the control group; this is indicative of a possible reduction in the oxidative metabolism of PCP. The results indicate that acute administration of morphine enhances a variety of pharmacological effects of PCP; an inhibition of PCP disposition by morphine may be a mechanism involved in this process.

Aniline Compounds↗
PubMed1983

Assessment of diisopropylfluorophosphate (DFP) toxicity and tolerance in rats.

Single s.c. injection of 1, 2, 3 or 4 mg/kg of DFP in saline was given to male rats. Control rats received saline. Beginning 24 hr after injections, body weights and food and water consumption were measured at 24 hr intervals. The 1 and 2 mg/kg DFP-treated group maintained these parameters at levels equal to those of the controls. The other DFP-treatment groups showed significant depressions in body weights and in food and water consumption, but these groups recovered 48 and 72 hrs after DFP administration of 3 mg/kg or 4 mg/kg, respectively. Daily injections of 2, 3 or 4 mg/kg of DFP, s.c., caused significant depressions of all three parameters, with only 75% of the 2 mg/kg group showing recovery over the 14 day treatment period. Of the 2 mg/kg group, 25% died following the 6th injection, 100% of the 3 mg/kg group were dead following the 4th injection and 100% of the 4 mg/kg group were dead following the 3rd injection. Prior to deaths in all DFP-treatment groups, the decreases in body weights and in food and water consumption were progressive and dose-dependent. The data show dose-dependency of general toxicity during acute and subacute exposure to DFP and of tolerance during subacute exposure.

Animals↗
PubMed1982

Acute and chronic effects of pentobarbital in relation to postsynaptic GABA receptors: a study with muscimol.

Muscimol, a GABA agonist, enhanced pentobarbital sleeping time in a dose-dependent manner. The GABA antagonists such as bicuculline and picrotoxin, and the CNS stimulant such as pentylenetetrazol, inhibited pentobarbital sleeping time; however, all except picrotoxin produced less than 35% maximum inhibition. Picrotoxin, and agent which blocks the chloride ionophore of GABA-receptor complex, exhibited a parallel dose-response curve with respect to muscimol. Chronic administration of pentobarbital by pellet implantation induced tolerance as evidenced by decreased sleeping time; the tolerance receded gradually upon abrupt withdrawal. Muscimol enhanced pentobarbital sleeping time both in tolerant and withdrawal mice. Na+-independent GABA-receptor binding, using [3H]muscimol as a ligand, was increased after acute and chronic pentobarbital administration; withdrawal of the pentobarbital reversed the increase in receptor population. None of the treatments altered the affinity of [3H]muscimol binding. These results support the contention that pentobarbital (a) directly acts on the postsynaptic chloride ionophore and (b) augments GABA-mediated postsynaptic effects. The functional significance of the increase in GABA receptor population after pentobarbital treatment is unclear.

Animals↗
PubMed1982

Development of dispositional tolerance to phencyclidine by osmotic minipump in the mouse.

Development of tolerance to phencyclidine (PCP) was assessed in male ICR mice, using motor incoordination as a parameter. The implantation of a PCP (1-3 mg/day/mouse for 1-5 days)-containing osmotic minipump, induced tolerance, as evidenced by a gradual reduction of the duration of motor incoordination. The degree of tolerance exhibited dose and time dependency. Even after the removal of the PCP pump (1 mg/day/mouse for 5 days), the tolerance remained to the same degree for at least 4 days. The hepatic microsomal cytochrome P-450, cytochrome b5 and nicotinamide adenine dinucleotide phosphatase (NADPH)-cytochrome c reductase activities were found to be elevated in tolerant mice (2 mg/day/mouse for 5 days). The half-life of PCP in the brains of tolerant mice was likewise decreased. These data indicate a dispositional tolerance for PCP. It appears that the administration of PCP by the osmotic minipump offers a convenient method for inducing PCP tolerance.

Animals↗