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Biomedical subjects

L B Hough

Publications and source records attributed to L B Hough.

At least 19 recordsLinked to original sources
PubMed1996

Tissue distribution of ibogaine after intraperitoneal and subcutaneous administration.

The distribution of the putative anti-addictive substance ibogaine was measured in plasma, brain, kidney, liver and fat after ip and sc administration in rats. One hr after ip dosing (40 mg/kg), drug levels ranged from 106 ng/ml (plasma) to 11,308 ng/g (fat), with significantly higher values after sc administration of the same dose. Drug levels were 10-20 fold lower 12 hr after the same dose. These results suggest that: 1) ibogaine is subject to a substantial "first pass" effect after ip dosing, demonstrated by higher drug levels following the sc route, 2) ibogaine shows a large accumulation in adipose tissue, consistent with its lipophilic nature, and 3) persistence of the drug in fat may contribute to a long duration of action.

Animals↗
PubMed1996

Characterization of the antinociceptive properties of cimetidine and a structural analog.

The antinociceptive and pharmacological properties of the H2 receptor antagonist cimetidine and a novel cimetidine analog, SKF92374, were characterized. On both the hot-plate and tail-flick nociceptive tests, cimetidine and SKF92374 induced complete, dose-related analgesic responses when injected into the lateral ventricle of rats. SKF92374 showed strong similarities to cimetidine in analgesic efficacy, slope of dose-response curves and chemical structure, suggesting that these compounds share a common analgesic mechanism. In contrast, histamine induced submaximal antinociceptive effects, and the H3 antagonist thioperamide, a known HA-releasing drug, had little or no analgesic effects. Compared with cimetidine, SKF92374 showed very weak activity (400-fold lower affinity) on H2 receptors in vitro (isolated guinea pig atrium) and in vivo (rat gastric secretion). In addition, SKF92374 (100 microM) had neither agonist nor antagonist action on guinea pig ileum H1 receptors. SKF92374 was also a weak competitive antagonist of N alpha-methylhistamine-induced inhibition of electrically induced contractions of the guinea pig ileum (Kd = 5.2 microM), an H3 receptor-mediated response. Autoradiographic binding assays in guinea pig brain confirmed a weak antagonism of H3 receptors by SKF92374. The compound (up to 10 microM) also had no effect on unpurified rat brain histamine N-methyltransferase activity. These results support the hypothesis that cimetidine induces analgesia by a novel brain mechanism unrelated to H1, H2 or H3 receptors.

Analgesics, Non-Narcotic↗
PubMed1995

Identification and quantification of the indole alkaloid ibogaine in biological samples by gas chromatography-mass spectrometry.

A sensitive and highly selective analytical chemical method for measuring the indole alkaloid ibogaine in biological samples has been developed. The method utilizes organic extraction, derivatization with trifluoroacetic anhydride, and detection by combined gas chromatography-mass spectrometry. The deuterated analog of ibogaine, O-[Cd3]-ibogaine, was synthesized and used as an internal standard for the method. Standard curves, constructed from variable amounts of ibogaine (50-400 ng) and a fixed amount of internal standard (250 ng) were linear. The method has an approximate detection limit of at least 20 ng/mL of tissue extract (180 ng/g tissue), with a coefficient of variation of 8 to 12.5%. Chemical stability studies with the method found that aqueous ibogaine solutions (1-10 mg/mL) could be stored at 10 degrees for up to 7 months with no more than 10% loss. The method was also used to measure brain ibogaine levels in rats 1 and 19 hr after a single dose of drug (40 mg/kg, i.p.); the results suggest a rapid disappearance of the drug after i.p. dosing. The method will help reveal the pharmacokinetic properties of this putative anti-addictive agent in animals and humans.

Acetic Anhydrides↗
PubMed1995

Importance of histamine H2 receptors in restraint-morphine interactions.

The effects of the brain-penetrating H2 antagonist zolantidine (ZOL, 3 mg/kg, s.c.) were studied on morphine (MOR, 4 mg/kg, s.c.) antinociception (tail flick test) in the presence and absence of previous restraint stress. Animals were handled for 3 days (to reduce handling stress), restrained for 1 hr or handled on day 4, and tested 24 hrs later. As found previously, restraint enhanced the intensity and duration of MOR antinociception. ZOL potentiated MOR antinociception in handled, non-restrained animals, but inhibited MOR action in restrained animals. In contrast, ZOL had no effects on nociceptive responses in either handled or stressed subjects in the absence of MOR. The data suggest that, in the absence of restraint, brain HA acts at the H2 receptor to inhibit MOR antinociception. In contrast, when an animal has been previously restrained, HA enhances MOR antinociception. Thus, brain HA appears to mediate the restraint-induced potentiation of MOR antinociception. Taken with previous results, the present findings suggest that in the presence of MOR, brain HA can provide bidirectional modulation of nociception. The direction of the modulation seems to depend upon the stress experience of the animal.

Analysis of Variance↗
PubMed1995

Modulation of morphine antinociception by the brain-penetrating H2 antagonist zolantidine: detailed characterization in five nociceptive test systems.

Because histamine (HA) in the CNS may be a mediator of antinociception, a detailed investigation of the effects of the brain-penetrating H2 antagonist zolantidine (ZOL) was performed on five nociceptive tests in the presence and absence of morphine (MOR) in rats. ZOL inhibited MOR antinociception on the tail flick test, although a diurnal difference (inhibition in the dark cycle >> light cycle) was found. Similar results were found with the hot plate test, although details of the test procedure were significant. In contrast, ZOL induced opposing effects on MOR antinociception on two nonthermal tests (jump test and tail pinch test); ZOL alone induced moderate antinociception on the former test and mild antinociception on the latter test. Thus, ZOL exerts differential effects on baseline nociception and on MOR antinociception that vary depending on the nociceptive test employed, the light-dark cycle of the subjects, and the degree of stress associated with the nociceptive testing. These complex effects reveal the heterogeneous nature of opiate-induced modulation of nociception, and show that ZOL is a powerful tool for studying the relationships between opiates, HA, and nociceptive mechanisms.

Animals↗
PubMed1995

Pharmacological characterization of GT-2016, a non-thiourea-containing histamine H3 receptor antagonist: in vitro and in vivo studies.

GT-2016, a non-thiourea-containing imidazole, has been developed as a histamine H3 antagonist. In vitro and in vivo studies in rats were conducted to characterize receptor selectivity and autoreceptor functionality for GT-2016. GT-2016 demonstrated high affinity (43.8 +/- 3.0 nM) and selectivity for the histamine H3 receptor in vitro. In vivo, GT-2016 (3, 10 and 30 mg/kg i.p. and p.o.) was shown to cross the blood-brain barrier and dose-dependently bind to cortical histamine H3 receptors. GT-2016 induced dose-dependent increases in histamine turnover at concentrations that exhibited significant histamine H3 receptor occupancy. Also, in vivo microdialysis experiments were conducted in awake, freely moving rats treated with GT-2016. GT-2016 (10 and 30 mg/kg i.p.) increased histamine release by approximately 75% above baseline within 1 hr, and elevated histamine release was observed for up to 2.5 hr after the higher dose. In contrast, GT-2016 was devoid of activity on histamine methyltransferase in vitro at concentrations up to 3 microM. Taken together, the results show that GT-2016 crosses the blood-brain barrier, binds to H3 receptors and increases the release of histamine in the cerebral cortex, consistent with blockade of presynaptic H3 autoreceptors. In summary, these findings allowed us to identify and characterize the in vitro and in vivo biochemical properties of a novel H3 receptor antagonist, GT-2016.

Animals↗
PubMed1994

Histamine-mediated neuronal death in a rat model of Wernicke's encephalopathy.

Three experiments were conducted to examine the role of histamine in neuronal degeneration in a rat model of Wernicke's encephalopathy induced by an acute bout of pyrithiamine-induced thiamine deficiency (PTD). In the first experiment, histamine levels in medial thalamus of freely moving PTD rats measured by microdialysis were increased (180% of controls) at a prelesion stage of thiamine deficiency (treatment day 12) and further elevated 48 hr later (380%) in the same animals when necrosis was evident. Histamine levels in dialysates of the hippocampus collected simultaneously from the same animals were unchanged at either stage of thiamine deficiency. Glutamate levels in microdialysates from the same animals were unchanged at the prelesion stage but were significantly elevated on the second collection day. In a second experiment, separate groups of PTD and pairfed control (CT) rats were infused continuously with either alpha-fluoromethylhistidine (FMH; 80 mg/day, i.p.), an irreversible inhibitor of histamine synthesis, or saline. FMH pretreatment produced a significant protection against PTD-induced neuronal loss within the midline-intralaminar and anteromedial thalamic nuclei, but had no effect on damage to ventrolateral nuclei, anteroventral nucleus, or the mammillary bodies. In a third study, histamine (80 micrograms, free base) or vehicle was directly infused into the same region of medial thalamus dialyzed in experiment 1. Histamine infusion into prelesion PTD but not CT animals resulted in severe neuronal loss and gliosis. Infusion of vehicle into the same regions of PTD and CT rats produced a mild gliosis restricted to the needle tract with no evidence of neuronal loss. These observations together with recent evidence of a histamine enhancement of glutamate receptor activation suggest that early histamine release may contribute significantly to glutamate-N-methyl-D-aspartate (NMDA)-mediated excitotoxic neuronal death in thiamine deficiency-induced Wernicke's encephalopathy.

Animals↗
PubMed1994

Prolonged antinociception following carbon dioxide anesthesia in the laboratory rat.

In the laboratory rat, inhalation (30 s) of high (> 70%) CO2 concentrations resulted in short-term (1-3 min) anesthesia, followed by a prolonged (up to 60 min) mild antinociception. Exposure to 100% CO2 resulted in significant thermal (hot-plate, 52 degrees, and tail-flick) and mechanical (tail-pinch, 886 g force) antinociception. Control animals, placed in the same chamber filled with air, showed no such effects. Rats exposed to 70% CO2 exhibited effects on the hot plate comparable to those seen after inhalation of 100% CO2, indicating that the response is not due to CO2-induced hypoxia. Additionally, recovery from halothane-induced anesthesia of comparable duration did not result in antinociception, confirming that anesthesia alone is not sufficient to produce the effect. Pretreatment with the opiate antagonist naltrexone (0.1-10 mg/kg i.p.) did not diminish the CO2-induced antinociception, suggesting that endogenous opioids are not obligatory in the mechanism of this response. Furthermore, hypophysectomy abolished hot-plate antinociception in animals exposed to 100% CO2 while sham-treated controls exhibited a pattern of hot-plate responses similar to that reported above. Taken together, these findings show that: (1) recovery from CO2-induced anesthesia results in a prolonged mild antinociception, detectable with thermal and mechanical nociceptive tests; and (2) this response may represent a novel from of environmentally induced antinociception, mediated by a non-opiate hormonal substance.

Anesthesia↗
PubMed1994

Histamine does not play an essential role in electrocortical activation during waking behavior.

Intraperitoneal injection of alpha-fluoromethylhistidine (alpha-FMH; 200 mg/kg), a specific inhibitor of histidine decarboxylase produced a severe depletion of neocortical and hippocampal histamine 3 h later as determined by a radioenzymatic assay. This treatment had no obvious effect on either low voltage fast activity (LVFA) in the neocortex or on rhythmical slow activity (RSA) in the hippocampus during an 8 h recording period during the rats' light cycle. Scopolamine-sensitive LVFA, scopolamine-resistant LVFA and scopolamine-resistant hippocampal RSA all appeared unaffected. This suggests that any contribution histamine makes to electrocortical activation is probably indirect, acting via other transmitter systems.

Animals↗
PubMed1994

alpha-Fluoromethylhistidine-induced inhibition of brain histidine decarboxylase. Implications for the CO2-trapping enzymatic method.

The actions of S-alpha-fluoromethylhistidine (FMH), an irreversible inhibitor of the histamine biosynthetic enzyme histidine decarboxylase (HD), were studied on rat brain HD, as measured by a recently developed CO2-trapping enzymatic method. As expected, FMH induced a virtually complete inhibition of HD in the hypothalamus both in vivo and in vitro. In the frontal cortex, however, maximal doses of FMH did not maximally inhibit HD, suggesting the existence of an FMH-resistant form of HD. Careful studies of the conditions under which the assays were performed (homogenate dilution, preincubation times, incubation times, temperatures), as well as experiments with inhibitors of other decarboxylases, were unable to provide an explanation for this. When comparable studies of the effects of FMH in these brain regions were performed by alternative methods for measuring HD activity, no evidence for the existence of an FMH-resistant form of HD could be found. Thus, even though the CO2-trapping method appears to be accurate for measuring HD activity in rat hypothalamic homogenates, the present results show that this method may not be specific when studying brain regions other than the hypothalamus.

Animals↗
PubMed1994

Characterization of basal and morphine-induced histamine release in the rat periaqueductal gray.

Previous studies have shown that antinociceptive doses of systemic morphine increase extracellular histamine (HA) levels in the rat periaqueductal gray (PAG), although the cellular origin of basal and morphine-induced HA release in the PAG is unknown. Treatment with alpha-fluoromethylhistidine (FMH; 100 mg/kg, i.p.), the irreversible inhibitor of histidine decarboxylase, decreased basal HA release by a maximum of 80% and prevented morphine-induced HA release in the PAG. In addition, perfusion of this area with the sodium channel blocker tetrodotoxin (10(-6) M) decreased basal HA release by a maximum of 57% from baseline levels. When the perfusion medium was modified by substitution of magnesium for calcium, extracellular HA levels in the PAG decreased by a maximum of 72%, and morphine-induced HA release was prevented. Thioperamide (5 mg/kg, i.p.), an H3 antagonist, increased HA release in the PAG to a maximum of 249% within the first 30-60-min period. Taken together, these results suggest that basal and morphine-induced HA release in the rat PAG have a neuronal origin.

Animals↗
PubMed1993

Opiates, mast cells and histamine release.

Opiates have long been known to cause the release of histamine from mast cells, resulting in several undesirable effects, such as hypotension, urticaria, pruritus, and tachycardia. The mechanism of this opiate response has remained unclear, although it is known to be non-immunological in nature. A survey of the histamine-releasing properties of a variety of opiates shows that the pharmacology of opiate-induced histamine release from mast cells is distinct from that of known opiate receptors. Although functional opiate receptors may exist on mast cells and may be capable of modulating IgE-mediated histamine release, there is no evidence that these receptors account for opiate-induced histamine release. Since other basic compounds have been suggested to release histamine from mast cells by directly activating G-proteins, it seems possible that morphine and endogenous opiates may also share this mechanism.

Animals↗
PubMed1993

Simultaneous measurement of opiate-induced histamine release in the periaqueductal gray and opiate antinociception: an in vivo microdialysis study.

Histamine release and the subsequent activation of H2 receptors in the periaqueductal gray (PAG) are thought to be important components of morphine antinociception. In vivo microdialysis and antinociceptive testing were simultaneously applied in rats to characterize the effects of morphine on PAG histamine release and determine the relationship between histamine release and antinociception. In the absence of nociceptive (tail pinch) testing, morphine (12.8 mg/kg) induced a delayed, long-lasting release of histamine in the PAG. This effect of morphine was abolished by the opiate antagonist naltrexone (1 mg/kg) but was not mimicked by the mu-preferring agonist fentanyl (0.3 mg/kg), suggesting that activation of an opiate receptor other than, or in addition to, the mu receptor is necessary. In contrast to the findings with fentanyl in untested animals, fentanyl combined with nociceptive testing increased histamine release, even though testing alone had no such effect. Unexpectedly, tail pinch testing inhibited morphine-induced histamine release. These results show that the test procedure alters the action of opiates on histamine release, an effect likely to be the result of the stress of repeated tail pinch testing. Therefore, although histamine release may not be obligatory for all types of opiate antinociception, histamine in the PAG may function as a mediator of stress-induced potentiation of opiate antinociception. Even though the microdialysis technique has been acclaimed for its ability to assess neurochemical and behavioral characteristics simultaneously, the introduction of nociceptive testing clearly can alter the neurochemical systems under study.

Analgesia↗
PubMed1992

Modulation of morphine antinociception by antagonism of H2 receptors in the periaqueductal gray.

To determine the brain site of action of the H2 receptor antagonist tiotidine as an inhibitor of systemic morphine (MOR) antinociception, the effects of intracerebral microinjections of this drug were studied on this response in rats. As assessed on the hot plate test, microinjections of tiotidine (1 ng in 0.5 microliter) into the ventral lateral periaqueductal gray at the level of the dorsal raphe (PAG/DR) attenuated MOR-induced antinociceptive responses 10-15 min later, but potentiated these responses when tested 20-30 min after its administration. This treatment had neither effect in the absence of MOR. In contrast, intracerebral tiotidine had no effects on tail flick responses in the presence or absence of MOR. Intracerebral tiotidine reduced by about 50% the antinociception induced by systemic MOR (5.6 and 10 mg/kg), resulting in a parallel, rightward shift in the MOR dose-response curve. When testing occurred with a fixed dose of MOR at a fixed time interval, tiotidine dose-response curves were U-shaped, an effect postulated to result from the separate inhibitory and stimulatory mechanisms found at different times. Intracerebral mapping studies showed that the attenuation of MOR antinociception by tiotidine given into the PAG/DR was not reproduced by tiotidine injections into adjacent rostral, caudal, dorsal or ventral areas. Taken with previous studies showing that: (1) both MOR and histamine (HA) induce antinociception when given into the PAG/DR, and (2) systemic MOR releases HA in the PAG, the present results strongly suggest that systemic MOR attenuates supraspinally organized responses to phasic, thermal nociceptive stimuli by mechanisms that include PAG HA release and subsequent activation of PAG H2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1992

Differential effects of ibogaine pretreatment on brain levels of morphine and (+)-amphetamine.

Previous studies in rats have shown that ibogaine inhibits neurochemical and behavioral effects of morphine yet potentiates similar effects of (+)-amphetamine. To assess whether these different functional interactions have a metabolic basis, brain levels of morphine and (+)-amphetamine were measured by gas chromatography-mass spectrometry after ibogaine pretreatment (19 h before injection of morphine or (+)-amphetamine). Ibogaine pretreatment had no effect on brain morphine levels, either at 30 min or 2 h after morphine injection; however, ibogaine significantly increased brain amphetamine levels at 30 min and, to a greater extent, at 2 h after (+)-amphetamine injection. These and other data suggest that ibogaine irreversibly inhibits an amphetamine-metabolizing enzyme. The functional interactions between ibogaine and (+)-amphetamine, but not those between ibogaine and morphine, may result from a hepatic drug-drug interaction.

Animals↗
PubMed1992

Inhibition of morphine antinociception by centrally administered histamine H2 receptor antagonists.

The actions of zolantidine dimaleate and five other histamine H2 receptor antagonists, given into the lateral ventricle of rats, were assessed on nociceptive responses in the presence and absence of systemically administered morphine. On the tail flick response, zolantidine induced a time- and dose-dependent inhibition of morphine antinociception, with no effect on responses in the absence of morphine. Zolantidine and another H2 receptor antagonist, tiotidine, also inhibited morphine responses in the hot plate test. Four other H2 receptor antagonists of varying structure, brain-penetrating ability, and H2 potency also induced dose-related inhibition of morphine tail flick responses. Over three orders of magnitude, the potency of these compounds as inhibitors of morphine antinociception was highly correlated with H2 receptor antagonist potency (r = 0.98, P less than 0.005, n = 5). Taken with previous studies showing the selectivity of these compounds for histamine H2 receptors, and the antinociceptive properties of histamine, these results strongly suggest a role for brain histamine H2 receptors in the expression of morphine antinociception.

Animals↗
PubMed1992

Morphine-induced increases of extracellular histamine levels in the periaqueductal grey in vivo: a microdialysis study.

The effect of morphine on extracellular histamine levels in two regions of the rat midbrain was studied in vivo by microdialysis. Morphine (5.6 and 12.8 mg/kg, s.c.) significantly and dose-dependently increased extracellular histamine levels in the periaqueductal grey, while no significant effect was observed in the reticular formation. In addition, no significant effect of sequential saline injections was observed on extracellular histamine levels in the periaqueductal grey. Since morphine has no effect on histamine catabolism, these results suggest that morphine increases histamine release in the rat PAG, a site where morphine and histamine are known to have analgesic action. Taken with earlier studies showing the ability of H2 antagonists to block morphine analgesia, these results support the hypothesis that histamine and H2 receptors are important in mediating morphine analgesia in the rat periaqueductal grey. The cellular origin of the extracellular histamine, and the mechanism of this morphine effect remain to be determined.

Animals↗