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Biomedical subjects

P J Monroe

Publications and source records attributed to P J Monroe.

9 recordsLinked to original sources
PubMed1992

Antinociception from the administration of beta-endorphin into the periaqueductal gray of rat is enhanced while that of morphine is inhibited by barbiturate anesthesia.

Pentobarbital anesthesia causes about a 10-fold increase in the antinociceptive potency of beta-endorphin microinjected into the periaqueductal gray (PAG) region of the rat brain. The antinociceptive response to PAG morphine was markedly attenuated during anesthesia, but returned as the rats regained consciousness. As they recovered from anesthesia, muscular rigidity and body stiffness (catalepsy) also occurred in the pentobarbital treated animals receiving morphine. These results are consistent with the activation of separate and distinct descending pain inhibitory neuronal systems by these two opioid agonists, and the differential modulation of the systems by pentobarbital. They also suggest that the mechanism underlying muscular responses to morphine is sensitive to pentobarbital, and is not shared by beta-endorphin.

Analgesics↗
PubMed1992

Opioid receptors mediating antinociception from beta-endorphin and morphine in the periaqueductal gray.

beta-Endorphin and morphine produce an increase in the latency of the tail-flick reflex when administered into the PAG of awake rats. The antinociceptive effect of both opioid agonists was blocked by the sequential local injection of either CTP (D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2), a selective mu opioid receptor antagonist, naltrexone, or beta-endorphin (1-27), a putative epsilon opioid receptor antagonist, with minimal selectivity. When either CTP or naltrexone was used as the antagonist, the dose-inhibition curves generated for beta-endorphin and morphine were not parallel, suggesting the involvement of separate and distinct receptors. Also, synergism occurred when a dose of morphine producing submaximum antinociception was administered simultaneously with either a submaximal or ineffective dose of beta-endorphin. Inhibition of the antinociceptive response to beta-endorphin by mu antagonists and the non-selective antagonism of both beta-endorphin and morphine by beta-endorphin (1-27) suggested that epsilon opioid receptors were not involved. Additionally, a mu/delta opioid receptor complex was not involved, since ICI 174,864 (Allyl2-Tyr-Aib-Aib-Phe-Leu-OH), a selective delta opioid receptor antagonist, did not alter the response to beta-endorphin. Thus, although additional characterization is required, beta-endorphin and morphine appear to act (at least in part) through different opioid receptors, demonstrable using selected mu opioid receptor antagonists.

Amino Acid Sequence↗
PubMed1991

Evaluation of the interactions of serotonergic and adrenergic drugs with mu, delta, and kappa opioid binding sites.

Several serotonergic and adrenergic agents were tested for an ability to interact with mu, delta, and kappa opioid binding sites. Spiroxatrine interacted nearly equipotently with all three opioid subtypes, yielding Ki values near 110 nM. A number of other serotonergic and adrenergic agents interacted with affinities in the 1-50 microM range. Most of the other compounds tested in this study were found to compete for opioid binding to some degree, though not achieving a 50% inhibition of binding at concentrations up to 100 microM. If this interaction between monoaminergic agents and opioid receptors is found to have functional significance, it must be considered in the interpretation of results from studies using these agents to evaluate the contribution of monoaminergic systems to opioid-mediated events.

Animals↗
PubMed1991

Complement C5a receptor assay for high throughput screening.

The complement C5a receptor on U937 cells, a human histiocytic lymphoma cell line, stimulated with dibutyryl-cAMP have been stabilized for at least 3 months at a dilute, ready to use concentration. [125I]-Bolton Hunter labeled C5a, (recombinant, human) has been prepared by reverse phase HPLC to 2200 Ci/mmol. Using a filtration binding assay the Kd from receptor saturation analysis is 10-40 pM and there are 50,000-100,000 receptor sites per cell. These reagents have permitted the development of a reliable, reproducible and convenient drug screening assay, in kit format, for compounds acting at the C5a receptor.

Complement C5a↗
PubMed1987

[3H]spiroxatrine labels a serotonin1A-like site in the rat hippocampus.

[3H]Spiroxatrine was examined as a potential ligand for the labeling of 5-HT1A sites in the rat hippocampus. Analysis of the binding of [3H]spiroxatrine in the absence and presence of varying concentrations of three monoamine neurotransmitters revealed that serotonin (5-HT) had high affinity (IC50 = 20.7 nM for the [3H]spiroxatrine binding sites, consistent with the labeling of 5-HT1 sites, while dopamine and norepinephrine had very low affinity (IC50 = 57600 nM and greater than 10(-4) M respectively). Saturation studies of the binding of [3H]spiroxatrine revealed a single population of sites with a Kd = 2.21 nM. Further pharmacologic characterization with the 5-HT1A ligands 8-hydroxy-2-(di-n-propylamino)tetralin, ipsapirone, and WB4101 and the butyrophenone compounds spiperone and haloperidol gave results that were consistent with [3H]spiroxatrine labeling 5-HT1A sites. This ligand produced stable, reproducible binding with a good ratio of specific to nonspecific binding. The binding of [3H]spiroxatrine was sensitive to GTP, suggesting that this ligand may act as an agonist. This was supported by the finding that spiroxatrine inhibits forskolin-stimulated adenylate cyclase activity (a proposed 5-HT1A receptor model) in the rat hippocampus. Since [3H]spiroxatrine is structurally distinct from other currently available radioligands for the 5-HT1A site, it should provide new information about the properties of this putative serotonergic receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Properties of the interaction between ketamine and opiate binding sites in vivo and in vitro.

Analgesia induced by ketamine appears to be partially mediated by opiate mechanisms. Not only is its action attenuated by the narcotic antagonist naloxone, but the drug has a weak affinity for, and interacts stereoselectively at, opiate receptors. It also produces a classical narcotic action on the guinea-pig ileum. The present study showed that analgesic doses of the drug in rats yielded concentrations sufficient to interact effectively at opiate binding sites in vivo. A dose-dependent (80-120 mg/kg i.p.) inhibition of the binding of [3H]naloxone was observed in both brain and spinal cord. All regions of the brain (except the cerebellum) were affected, but the reduction was significant in the cortex, hippocampus, thalamus and striatum. Thus, a component of ketamine-induced analgesia could be related to a functional interaction with opiate receptors. Additionally, ketamine may be similar to morphine in its preference for the mu, rather than the delta sub-type of opiate receptors, and thus may promote mu-mediated pharmacological effects. For example, in vitro studies of radioligand binding showed that ketamine and morphine were four times more effective in inhibiting the binding of [3H]dihydromorphine than that of [3H] [D-Ala2, D-Leu5] enkephalin. On the other hand, ketamine also effectively interacted at a component of the sigma opiate/phencyclidine binding sites that appears to be relatively insensitive to morphine. This component may be involved in dysphoria induced by ketamine.

Animals↗
PubMed1986

Evaluation of the direct actions of drugs with a serotonergic link in spinal analgesia on the release of [3H]serotonin from spinal cord synaptosomes.

Morphine, ketamine, ethylketocyclazocine and quipazine, drugs with an apparent local spinal serotonergic action, which contributes to their analgesic effects, were tested for their ability to alter the release of [3H]serotonin ([3H]5-HT) from a synaptosomal preparation from the spinal cord of the rat. Related compounds including [D-Ala2, D-Leu5]enkephalin (DADLE), n-allylnormetazocine and phencyclidine were also examined. None of the drugs was found to be capable of inducing a direct release of [3H]5-HT or of facilitating potassium-induced release of 5-HT. However, quipazine inhibited the depressant action of exogenous 5-HT on overflow of 3H (mediated through the 5-HT autoreceptor), an action that should facilitate serotonergic neurotransmission. In contrast to the other drugs, DADLE was found to depress K+ stimulated release of 5-HT. The results suggests that the serotonergic mechanism involved in the antinociceptive action of some of these drugs (i.e. ketamine, morphine and ethyl-ketocyclazocine) is not related to direct presynaptic interactions to promote release of 5-HT. On the other hand, a small population of serotonergic nerves critical for analgesia may be involved and are not detected using tissue from the whole spinal cord, However, it seems equally plausible that these drugs may produce their antinociceptive action through interactions with other neurotransmitter systems that in turn interface with the serotonergic nerves, perhaps through interneurons or collateral connections.

Analgesia↗
PubMed1985

Demonstration of an autoreceptor modulating the release of [3H]5-hydroxytryptamine from a synaptosomal-rich spinal cord tissue preparation.

A superfusion system employed to measure the K+-stimulated release of [3H]5-hydroxytryptamine [(3H]5-HT, [3H]serotonin) from a synaptosomal-rich spinal cord tissue preparation was carefully characterized, then used to examine the regulation of spinal 5-HT release. Spinal 5-HT release is apparently modulated by an autoreceptor. Exogenous 5-HT depressed, in a concentration-dependent manner, the K+-stimulated release of [3H]5-HT. Similarly, lysergic acid diethylamide (LSD) produced a concentration-dependent decrease in [3H]5-HT release. Methiothepin and quipazine blocked the inhibition of release induced by exogenous 5-HT. The 5-HT2 receptor antagonists spiperone and ketanserin failed to alter the action of 5-HT at the spinal 5-HT autoreceptor. Spiperone and ketanserin were shown, however, to alter the storage of [3H]5-HT. When used in concentrations greater than 10 nM, the drugs evoked increases in basal [3H]5-HT and [3H]5-hydroxyindoleacetic acid ( [3H]5-HIAA) effluxes which were independent of the presence of calcium ions. A good agreement existed between the potencies of drugs for modifying autoreceptor function and their abilities to compete for high-affinity [3H]5-HT binding in the spinal cord (designated 5-HT1). Furthermore quipazine, in concentrations that preferentially interact with the 5-HT1B subtype, antagonized the actions of exogenous 5-HT on K+-stimulated release. Spiperone, in a concentration that approximated the affinity constant of 5-HT1A sites for the drug, was ineffective in altering the ability of exogenous 5-HT to modulate K+-stimulated [3H]5-HT release. These results suggest that 5-HT1B sites are associated with serotonergic autoreceptor function in the spinal cord.

Animals↗