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R C Frederickson

Publications and source records attributed to R C Frederickson.

At least 55 records · Page 3Linked to original sources
PubMed1975

Effects of cholinergic and anticholinergic drugs and a partial cholinergic agonist on the development and expression of physical dependence on morphine in rat.

Cholinergic and anticholinergic agents were tested against the induction and expression of morphine dependence in rats. Mecamylamine hydrochloride, administered during abstinence, exacerbated the syndrome at the time of peak severity (20-40 hours after with-holding morphine) but accelerated the subsequent decline in severity of withdrawal. Atropine sulfate acted similarly but none of its effects proved statistically significant. When administered together, these drugs were not additive but were antagonistic in their central actions at the time of peak withdrawal. Atropine methylnitrate reduced withdrawal severity throughout the observation period mainly by antagonism of the peripheral expression of many of the parasympathetic signs. Eserine sulfate administered during the period of habituation or of abstinence had little effect on the severity of the total withdrawal syndrome but decreased weight loss. Choline chloride effectively reduced overall withdrawal severity and weight loss throughout the entire course of withdrawal monitored for up to 100 hours after withholding morphine. This occurred whether choline was administered during morphine habituation or after withholding the morphine. These results support the view that a derangement of cholinergic function is a factor in the morphine abstinence syndrome; evidence is yet lacking to decide whether this is the primary derangement of neurotransmitter function. The effectiveness of choline may be explained by its action as a partial agonist to normalize cholinergic function at all stages of derangement. The reduction in withdrawal severity by treatment with choline during the habituation to morphine indicates an inhibition of the development of dependence rather than mere suppression of the signs during withdrawal.

Animals↗
PubMedDate not supplied

Cross-tolerance studies distinguish morphine- and metkephamid-induced analgesia.

In vitro data demonstrate that metkephamid (LY127623), an analog of methionine enkephalin, has a high affinity for the delta opioid receptor, as well as the mu-receptor. Data generated utilizing two in vivo measures of receptor selectivity, furthermore, indicate that metkephamid's analgesic activity is in part mediated by delta opioid receptors. The analgesic activity of metkephamid was investigated in the mouse writhing assay following chronic treatment with morphine, the prototypic mu agonist. Mice were treated chronically with increasing doses of morphine or saline and the inhibition of writhing measured in response to an acute injection of morphine or metkephamid. The dose response curve for morphine was shifted to the right 3- to 4-fold following chronic administration of morphine. In contrast, no such shift in the dose response curve for metkephamid was observed in these morphine-tolerant mice. In a further series of tests, a 50 mg/kg dose of naloxazone 20 hr prior to the assessment of morphine or metkephamid analgesia in the mouse hot plate test substantially shifted the dose-response curve for morphine to the right, while leaving the dose-response curve for metkephamid unchanged. These results suggest that delta-receptor activation contributes to the analgesia produced by metkephamid.

Analgesia↗
PubMedDate not supplied

A fragment of substance P with specific central activity: SP(1-7).

Amino-terminal fragments of substance P (SP), SP(1-7) and SP(1-8), were found to produce naloxone-reversible antinociception in the mouse similar to that produced by SP. Similar to SP, these peptides produce antinociception only within a narrow dose range. They have no activity on smooth muscle or blood pressure. These results suggest that contrary to peripheral effects of SP, which are mediated by receptors which recognize the carboxy-terminal part of the SP molecule, certain central actions of SP are mediated by receptors which recognize the amino-terminal part of the SP molecule. SP may be metabolized to this active fragment prior to its action at these receptors.

Analgesia↗
PubMedDate not supplied

Metkephamid (Tyr-D-ala-Gly-Phe-N(Me)Met-NH2), a potent opioid peptide: receptor binding and analgesic properties.

The interaction of metkephamid (Tyr-D-Ala-Gly-Phe-N(Me)Met-NH2) with 3H-dihydromorphine and 3H-D-Ala2-D-Leu5-enkephalin binding has been examined in rat brain homogenates. Displacements of both 3H-ligands by metkephamid indicate that metkephamid interacts competitively with greatest potency to the high affinity binding component for both ligands (mu1 site). Unlike most enkephalins and opiates, metkephamid binds equipotently to both morphine-selective (mu2) and enkephalin-selective (delta) binding sites. Metkephamid is differentiated from morphine by its better than 12-fold higher affinity for the delta receptor. Blockade of the high affinity (mu1) binding in vivo with high doses of naloxazone dramatically reduces metkephamid's analgesic potency.

Animals↗
PubMedDate not supplied

Astroglia in Alzheimer's disease.

Amyloid deposits are characteristic of Alzheimer's Disease (AD) and there is growing evidence that amyloid may play an important role in the genesis of this neurodegenerative disease. This review discusses data which suggests that reactive astrocytes and microglia may be a necessary concomitant with amyloid to produce the neuropathology which manifests as AD. Several hypotheses and supporting data for mechanisms by which reactive astrocytes may mediate this neuropathology are presented. These include the possibility that amyloid induces excitotoxicity by interferring with astrocytic glutamate uptake, the possibility that amyloid has this effect via an action on a tachykinin-related receptor and the possibility that proteoglycans released by astrocytes may facilitate the deposition of amyloid plaques. Both symptomatic treatment to enhance cognitive function and treatment to stop the progression of AD are needed. It is hoped that answers to some of the unique questions raised here may provide new insight into the etiology and treatment of AD.

Alzheimer Disease↗
PubMedDate not supplied

Amyloid beta protein (A beta) removal by neuroglial cells in culture.

Because the mechanisms of A beta degradation in normal and Alzheimer's disease brain are poorly understood, we have examined whether various cortical cells are capable of processing this peptide. Rat microglia and astrocytes, as well as the human THP-1 monocyte cell line, degraded A beta 1-42 added to culture medium. In contrast, neither rat cortical neurons or meningeal fibroblasts effectively catabolized this peptide. When A beta fibrils were immobilized as plaque-like deposits on culture dishes, both microglia and THP-1 cells removed the peptide. Astrocytes were incapable of processing the A beta deposits, but these cells released glycosaminoglycase-sensitive molecules that inhibited the subsequent removal of A beta by microglia. This implied that astrocyte-derived proteoglycans associated with the amyloid peptide and slowed its degradation. The addition of purified proteoglycan to A beta that was in medium or focally deposited also resulted in significant inhibition of peptide removal by microglia. These data suggest that A beta can be catabolized by microglia and proteoglycans which co-localize with senile plaques may slow the degradation of A beta within these pathologic bodies.

Amyloid beta-Peptides↗
PubMedDate not supplied

Deposits of A beta fibrils are not toxic to cortical and hippocampal neurons in vitro.

Amyloid beta peptide (A beta), which is deposited as insoluble fibrils in senile plaques, is thought to play a role in the neuropathology of Alzheimer's disease. We have developed a model in which rat embryonic cerebral cortical or hippocampal neurons are seeded onto culture dishes containing deposits of substrate-bound, fibrillar A beta. The neurons attached rapidly to A beta 1-40 and A beta 1-42 substrates and extended long, branching neurites. Quantitative assessment demonstrated that survival of neurons on the A beta matrices was equivalent to or better than on control substrates of poly L-lysine or poly L-ornithine. In contrast, preparations of A beta fibrils added directly to the culture medium caused neuronal death as previously reported in the literature. These results reveal that the response of neurons to deposited A beta 1-40 and A beta 1-42 is substantially different from that observed with suspensions of the amyloid peptides, with the former serving as growth-promoting substrates for cortical and hippocampal neurons. This may thus imply that fibrillar A beta of senile plaques is not sufficient by itself to cause the plaque-associated neuronal degeneration characteristic of AD.

Alzheimer Disease↗