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Biomedical subjects

R C Frederickson

Publications and source records attributed to R C Frederickson.

At least 37 records · Page 2Linked to original sources
PubMed1981

Metkephamid, a systemically active analog of methionine enkephalin with potent opioid alpha-receptor activity.

Metkephamid is an analog of methionine enkephalin that retains high affinity for the delta receptor and is a systemically active analgesic. Since it is at least 100 times more potent than morphine as an analgesic when placed directly into the lateral ventricles, and is 30 to 100 times more potent on the delta receptor and yet is roughly equipotent on the mu receptor in vitro, it is concluded that it probably produces analgesia by action on delta receptors as well as, or rather than, on mu receptors. It has less tendency to produce respiratory depression, tolerance, and physical dependence than standard analgesics, and it is presently undergoing clinical trial.

Analgesics↗
PubMed1981

Excitatory effect of L-aspartate and L-glutamate on Purkinje cells in rat cerebellum.

L-aspartate and L-glutamate were microiontophoretically applied onto Purkinje cells and unidentified cerebellar neurons of urethane-anesthetized rats. Both amino acids produced a dose-dependent increase in the spontaneous firing rate of all cells tested. Fifty-three percent (8 of 15 cells) of the dose-response relationships for L-aspartate as compared to those for L-glutamate on Purkinje cells were not parallel, implying different mechanisms of action (suggesting different receptors). On these 8 Purkinje cells, L-glutamate was three times more potent than L-aspartate. Only thirty-three percent of the dose-response relationships (8 of 24 cells) for the two agents on the unidentified cerebellar cells were not parallel. There was no statistical difference in the potency of L-aspartate as compared to L-glutamate on these particular cells. Tests for antagonism on Purkinje cells revealed L-glutamic acid diethyl ester (GDEE) to be a more effective blocker of L-aspartate than of L-glutamate while DL-alpha-aminoadipic acid (DL alpha AA)) was not selective in antagonizing the action of either amino acid. These data are discussed in terms for L-aspartate functioning as a neurotransmitter in the cerebellum of rat and possessing receptor sites distinct from those for L-glutamate.

Action Potentials↗
PubMed1979

K-stimulated release of leu- and met-enkephalin from rat striatal slices: lack of effect of morphine and naloxone.

The release of leu- and met-enkephalin from rat striatal slices was determined by superfusing the slices in vitro and running the superfusates directly over columns of Amberlite XAD-2 from which the peptides were eluted with methanol and measured by radioimmunoassay. Depolarization by high K concentrations increased the release of both pentapeptides many fold; the degree of increase, however, depended in part on the length of time chosen for the stimulation period, suggesting that the stimulation effect was very short lived. The stimulated release of both peptides (but not the resting release) was at least partially dependent on Ca in the medium and was totally inhibited by high Mg concentrations. Selected concentrations of naloxone and morphine in the superfusing medium had no effect on the resting or stimulated release of the peptides. The results support the hypothesis that these peptides serve as neurotransmitters in the striatum, but autoregulation of their release by morphine and naloxone could not be demonstrated.

Animals↗
PubMed1978

A comparison of the inhibitory effects of taurine and GABA on identified Purkinje cells and other neurons in the cerebellar cortex of the rat.

The microiontophoretic application of taurine and GABA was studied in the cerebellar cortex of the rat. Both taurine and GABA produced a dose-dependent depression of spike frequency of cerebellar neurons. GABA (2-42 nA, mean 27 nA) induced an inhibition of spike discharge on all 138 cells tested, including 29 Purkinje cells. Taurine (60-200 nA, mean 108 nA) induced an inhibition of spike discharge on 93 of the 106 cerebellar neurons tested, including inhibition on 22 of 25 Purkinje cells. Iontophoretic application of bicuculline and picrotoxin antagonized the inhibitory effects of both GABA and taurine on Purkinje cells as well as on cerebellar neurons in general. Strychnine did not antagonize the inhibition of either GABA or taurine. Simultaneous application of taurine and GABA produced a synergistic inhibitory effect on the firing rate of Purkinje cells. Taurine, in contrast to GABA, appeared to be more depressant when applied in the Purkinje cell dendritic zone than when applied near the soma. The data are discussed in terms of taurine functioning as a neurotransmitter in the cerebellum of the rat and having receptor sites distinct from those for GABA.

Aminobutyrates↗
PubMed1978

Dual actions of substance P on nociception: possible role of endogenous opioids.

Substance P produces analgesia when administered to mice in very small doses by the intraventricular route (1.25 to 5 nanograms per mouse). The analgesic effect can be blocked by naloxone. At higher doses (greater than 50 nanograms per mouse), this activity is lost. At these higher doses, however, substance P produced hyperalgesia when combined with naloxone and analgesia when combined with baclofen [beta-(4-chlorophenyl)-gamma-aminobutyric acid]. Substance P may have dual actions in brain, releasing endorphins at very low doses and directly exciting neuronal activity in nociceptive pathways at higher doses.

Animals↗
PubMed1977

A comparison of thalidomide and pentobarbital - new methods for identifying novel hypnotic drugs.

We have compared the sleep-producing effects of thalidomide and pentobarbital. In a dose range that did not produce ataxia, thalidomide increased slow wave sleep and rapid eye movement sleep in cats (2-8 mg/kg p.o.) and rats (16 mg/kg p.o.). Pentobarbital had hypnotic activity in the same dose range but produced ataxia also at these doses. Thalidomide reduced spontaneous activity of both mice and rats. This occurred over a dose range of 8 to 1000 mg/kg p.o., but plateaued at a level of activity well above the complete inactivity of anesthesia that occurred with pentobarbital at well above the complete inactivity of anesthesia that occurred with pentobarbital at doses (greater than or equal to 32 mg/kg p.o.) above the hypnotic range. Several simple screens for thalidomide-like activity have been described which, together, could facilitate the search for thalidomide-like hypnotics. Pentobarbital, at doses 3 to 10 times the hypnotic range, prevented audiogenic seizures in physically dependent rats withdrawn from sodium barbital but thalidomide did not substitute for barbiturates even at doses 30 times those that increased sleep. Thalidomide, but not pentobarbital, enhanced the sleep-producing effect of electrical stimulation of basal forebrain in cats. The latter two findings suggest that thalidomide probably has a mechanism of action different from that of pentobarbital and that this may involve the activation of a sleep center in the forebrain.

Animals↗
PubMed1976

Enkephalin-induced depression of single neurons in brain areas with opiate receptors--antagonism by naloxone.

Enkephalin, applied microiontophoretically, depressed spontaneous and glutamate-induced firing of single neurons in frontal cortex, caudate nucleus, and periaqueductal gray matter, where enkephalin and high concentrations of opiate receptors are found. Many of the depressions were blocked by the specific narcotic antagonist naloxone. The data are compatible with a neurotransmitter or neuromodulator role for this new brain pentapeptide.

Action Potentials↗
PubMed1976

Correlation between the in vivo and an in vitro expression of opiate withdrawal precipitated by naloxone: their antagonism by l-(-)-delta9-tetrahydrocannabinol.

Guinea pigs treated with a single s.c. injection of a slowly released morphine suspension (300 mg/kg) exhibited a quantifiable withdrawal syndrome after naloxone injection (0.01-10 mg/kg s.c.). Ileum removed from such animals responded to naloxone (1-300 ng/ml) by contracting. These contractions could be blocked by scopolamine or tetrodotoxin. Both the in vivo and in vitro responses were specific for the opiate-dependent state and were dependent on naloxone dose. Time courses of the development and decline of the two responses were similar. Weaker opioids, pentazocine and codeine, were less effective than morphine in producing a dependent state and sensitizing ileum to naloxone. 1-(-)-delta9-Tetrahydrocann abinol [1-(-)-delta9-THC] antagonized the effect of naloxone on ileum without affecting responses to acetylcholine. 1-(-)-delta9-THC produced a stereospecific, dose-dependent (1-10 mg/kg p.o.) inhibition of naloxone-precipitated withdrawal in guinea pigs and rats that was more complete than and different from that produced by sedatives. Pentobarbital inhibited withdrawal only at doses that produced ataxia. 1-(-)-delta9-THC had a biphasic effect on locomotor activity of guinea pig in the dose range that inhibited withdrawal, stimulation at 1 mg/kg and depression at 3 to 10 mg/kg. Our results suggest that cannabinoids may be useful in opiate detoxification. The inhibition by 1-(-)-delta9-THC of the action of naloxone in "dependent" ileum seems to be via reduction in acetylcholine release. Whereas the end result of 1-(-)-delta9-THC action in brain may not necessarily be a reduction in acetylcholine release as in ileum, the mechanism by which it produces this effect in the ileum model may explain its ability to antagonize withdrawal.

Acetylcholine↗