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R J Tallarida

Publications and source records attributed to R J Tallarida.

At least 73 records · Page 4Linked to original sources
PubMed1982

The use of drug-receptor affinity measures in the differentiation of receptors.

The drug-receptor dissociation constant (K), determined by pharmacological procedures, is measured from a dose-effect relation and the modification of that relation by the presence of a second compound (antagonist) that competes for the same receptor. These procedures differ from those that use radiolabeled compounds and do not measure an effect but instead determine the K of the compound by quantitating its displacement of the labeled substance. In several examples the dissociation constants determined from pharmacological procedures are shown to be unique for a particular drug-receptor interaction and can therefore discriminate among receptors. A further demonstration is that K does not equal D50, the potency index. For competitive antagonists the Schild plot is commonly used to measure K. This plot, theoretically linear with a slope of -1, often leads to slopes different from -1 (using conventional linear regression), in which case its x intercept, pA2, and y intercept, -log KB, differ by an amount that depends on the slope. Even when this differences is small, the 95% confidence limits of pA2 and -log KB may be very different and are invariably larger for -log KB, the value that is presumably sought from this analysis. A Schild plot constrained to slope -1 (and, accordingly, different regression equations) should therefore be used in cases of known competitive antagonism such as that between naloxone and morphine. The special problems associated with measuring K for agonists are discussed and illustrated with recent work done in our laboratories in which we employed the new narcotic analgesic buprenorphine to determine by pharmacological methods the dissociation constant for morphine, a value previously undetermined.

Adrenergic alpha-Agonists↗
PubMed1982

The affinity of morphine for its pharmacologic receptor in vivo.

Morphine receptor affinity, an important constant in the classification of opiate receptors, has not yet been determined by a pharmacologic method. In the present study, we used a standard pharmacologic procedure, that of partial receptor occlusion, to make this determination in the rat utilizing the hot water (55 degrees C) tail flick test. The occluding compound was buprenorphine, a new narcotic antagonist analgesic that can bind to opiate receptors in an irreversible manner. When buprenorphine was given to rats in doses of 0.30 and 0.60 mg/kg (s.c.), 30 min before morphine (20-320 mg/kg s.c.) and 60 min before testing, it produced the theoretically predicted alterations in the morphine dose-response relation that are indicative of partial receptor blockade. The morphine receptor apparent dissociation constant (reciprocal of affinity) was calculated to be 1.7 X 10-6 M. This value is greater than those previously obtained in radiolabeled binding studies which have ranged from 3 to 27 X 10-9 M in the absence of sodium chloride to 1 to 5 X 10-7 M in the presence of sodium chloride. Used in this way, buprenorphine may be a valuable tool in the determination of apparent dissociation constants for other narcotic agonists.

Animals↗
PubMed1981

Time course of antagonism of morphine antinociception by intracerebroventricularly administered naloxone in the rat.

The kinetic profile and half-life of naloxone were studied for possible use in determination of pA2 and KB in vivo. Rats were given morphine subcutaneously and after 15 min naloxone or saline, intracerebroventricularly. A further 15 min later, and at 15 min intervals up to 135 min after morphine, the animals were tested for analgesia in the tail flick test. The dose-response curves of the naloxone group were shifted to the right of those for the saline group. The amount of displacement decreased with time, indicative of the disappearance of naloxone. The graph of log (dose ratio-1) vs. time was linear with negative slope, in agreement with the time-dependent form of the equation for competitive antagonism. From this slope, the half-life of naloxone was calculated to be 13.3 min. These results demonstrate that the time-dependent method is useful in obtaining the kinetics of centrally acting opiate antagonists.

Analgesia↗
PubMed1981

Use of programmable protocol timer and data logger in the monitoring of animal behavior.

The quantitative assessment of animal behavior by continuous or intermittent observation often requires much time and intense concentration. We have developed an accurate and convenient system which allows one observer to monitor up to four animals and record two types of behavior simultaneously. The system uses an inexpensive portable microcomputer including keyboard, video monitor, and cassette recorder. A program written in BASIC generates timed visible and audible cues, and tabulated data entered through the keyboard. The total number of occurrences of a particular behavior (e.g., "wet dog" shakes) and the frequency of a second behavior (e.g., grooming) may be measured. Frequency data, bases on intermittent observations, is processed for histogram display. The results may be copied from the video display or recorded on tape for further statistical analysis. The system has provided a convenient way to time experiments and collect data on drug-induced behavior in over 800 rats.

Animals↗
PubMed1981

The effect of preload on the dissociation constant of phentolamine in isolated rabbit thoracic aorta.

The affinity of phentolamine for the alpha-adrenergic receptor of isolated rabbit thoracic aorta was determined under two different preload conditions. In one condition, strips or rings or aorta were preloaded with a 1/4 g weight; in the other condition, with a 10 g weight. To measure affinity, dose-response curves were first obtained for agonist alone and then for agonist in the presence of various concentrations of phentolamine, a reversible alpha-adrenergic antagonist. From these curves, equieffective agonist concentrations were selected and Schild plots constructed to determine the dissociation constant (1/affinity). It was found that values of the dissociation constant, KB, for phentolamine were independent of the agonist used (norepinephrine or phenylephrine) to obtain the dose-response curves. KB was, however, a function of preload conditions. In all cases, IB at 1/4 g was greater than KB at 10 g preload. The magnitude of this difference in affinity with preload though, was less then previously obtained for agonists in the same preparation. The implications of this finding are discussed in terms of the effect of preload on receptor conformation and possible differences between agonist and antagonist binding.

Animals↗
PubMed1980

Effects of ultraviolet radiation and angiotensin on calcium binding in rabbit aortic microsomes.

The microsomal subcellular fraction was isolated from rabbit thoracic aorta by differential centrifugation between 3,000 g and 102,000 g. In one group of experiments, microsomes were incubated in the presence of angiotensin and the calcium binding was determined by liquid scintillation detection. In the other group, the incubation period with angiotensin included exposure to ultraviolet light for part of the time. Microsomes incubated with 10(-6) M angiotensin for 30 min demonstrated a 38% decrease in calcium binding below control level. When incubation with this same concentration of angiotensin was followed by a 20 min exposure to ultraviolet light (3660 A), the calcium binding increased 10% above control level. Irradiation in the absence of angiotensin for 20 min produced a 20% increase in calcium binding above control. Microsomes depleted of their endogenous catecholamine stores and not treated with any stimulating drug exhibited a 32% increase in calcium binding after irradiation with ultraviolet light. The effect of ultraviolet light on calcium binding was found to be positively correlated with the duration of irradiation. The enhanced microsomal binding of calcium due to ultraviolet light corresponds to the decrease in tension which this radiation produces in actively contracted aortic strips.

Angiotensin II↗
PubMed1979

A scale for assessing the severity of diseases and adverse drug reactions. Application to drug benefit and risk.

Physicians were interviewed to assess their willingness to risk adverse drug reactions among patients. These untoward reactions were ranked according to severity and weighted against the primary illness being treated. A specially designed questionnaire in the form of a matrix was used. Severity was divided into seven classes denoted by progressively increasing numerical scores, W1 to W7, whose values could be calculated from analysis of the completed questionnaires. The questionnaires presented several cases, in each of which an illness of specified severity was to be treated with a drug whose untoward reactions differ in severity from that of the primary illness. Each case involved a different permutation of the severities. Analysis of the completed questionnaires yielded the mean values of the scores which were found to range from W1 = 1.00 (the mildest case) to W7 = 817 (the most serious case). It is our opinion that this type of scale is preferable to nonnumerical descriptions of severity such as "mild" or "serious," since, when combined with data on frequency of occurrence, a numerical scale permits a determination of expectation of both benefit and risk.

Attitude of Health Personnel↗
PubMed1979

Determination of the stimulus-response relation for three alpha-adrenergic agonists on rabbit aorta.

A standard rabbit thoracic-aorta strip preparation was used to determine the effect of varying preload on KA(the dissociation constant), A50(the concentration that produces half maximal response) and the ratio KA/A50. Additionally, the stimulus-response relationships were obtained for the drug and preload conditions tested. Values of KA and A50 were calculated from dose-response curves obtained for three alpha-adrenergic agonists (phenylephrine, methoxamine and norepinephrine) in the presence and absence of partial irreversible blockade by phenoxybenzamine. For all three drugs, values of KA and A50 were found to be significantly greater at 1/4 gram preload than at 10 gram preload. However, the ratio KA/A50 was found to be independent of preload conditions. The stimulus-response relationships were all found to be non-linear, in contrast to the predictions of classical receptor theory. The significance of the constancy of KA/A50, rather than either KA or A50, and the non-linear relation between drug stimulus and response is discussed in terms of Stephenson's theory of drug action.

Adrenergic alpha-Agonists↗
PubMed1979

Morphine-induced mydriasis and fluctuation in the rat: time and dose relationships.

The purpose of this investigation was to establish complete dose- and time-response relationships of morphine action on the rat pupil using serial observations. Adult male, albino rats of the Sprague-Dawley strain were used. Pupil size was measured by a series of photographs taken every 60 sec for at least 90 min under dim red illumination. The pupil began to dilate within 20 min after s.c. administration of doses of morphine sulfate as low as 1 mg/kg. The dose-related mydriasis reached a maximum with a dose of 32 mg/kg at 35 to 50 min after injection and lasted for 3 to 4 hr. The mydriasis was characterized by a rapid and marked fluctuation which was also dose-related and reached a peak with 32 mg/kg of morphine sulfate. Naloxone HCl (1 mg/kg) rapidly reversed both the mydriasis and the oscillation, thereby implicating an opiate receptor-mediated mechanism. In addition to providing a convenient measure of narcotic actions, the pupil may offer a particularly useful means for studying opiate receptor mechanisms since it is one of the few cases where, in many species, the anatomical pathways and neurochemical innervations are known.

Animals↗
PubMed1978

The relationship between pharmacokinetics and pharmacodynamic action as applied to in vivo pA2: application to the analgesic effect of morphine.

When the pA2 of an antagonist is determined in vivo, administered doses are used rather than the peak or steady-state tissue concentrations. The present report examines the error which can arise in this method and also presents a method for determining the pA2 from data obtained at times after peak. We applied this time-dependent analysis to time-dose-response data obtained with morphine-naloxone in the rat, using tail compression as the nociceptive stimulus. Good agreement between pA2 values was found: 8.0 with peak effect data, and 8.1 with the time-dependent method. Further, this analysis yielded 20 minutes as the half-life of naloxone. It is concluded that the time-dependent method provides a check on the pA2 in vivo and confirms the utility of this constant in classifying receptors. The appendix contains methodology for application to other agonist-antagonist combinations classified according to their kinetics.

Analgesics↗
PubMed1977

Further studies on the action of ultraviolet light on vascular smooth muscle: effect of partial irreversible receptor blockade.

Isolated rabbit thoracic aorta which is pharmacologically contracted will relax when exposed to ultraviolet light. The relaxation is reversible in that the tension is restored when the light source is removed. The purpose of this investigation was to study further the phenomenon of photorelaxation on vascular smooth muscle. Restoration kinetics were examined for two cases: 1) norepinephrine alone 2) norepinephrine plus phenoxylbenzamine. The photo-induced relaxation in the presence of the irreversible blocker phenoxybenzamine produced a more rapid restoration than the photo-induced relaxation in strips contracted with norepinephrine alone. Angiotensin, which is not blocked by phenoxybenzamine, produced no change in the restoration characteristics of a perturbation on the angiotensin-induced contractions. Strips treated with glycerin, a process which removes storage sites for Ca++, are responsive to exogenous administration of Ca++ but demonstrate no photorelaxation. These results lend supportive evidence to the hypothesis that ultraviolet radiation interferes with the drug-receptor complex.

Angiotensin II↗
PubMed1977

Miosis and fluctuation in the rabbit pupil: effects of morphine and naloxone.

In the unanesthetized rabbit, morphine (12-16 mg/kg i.v.) produced a miosis that was not sustained. The response to the narcotic was a pupillary constriction that became maximal within 2 minutes following i.v. administration, after which time the pupil size fluctuated appreciably. The magnitude of the fluctuation, typically as high as 40% of control diameter, was much larger than can be attributed to "noise." The fluctuations occurred within a frequency of approximately 0.5 to 2/min. The miosis and subsequent fluctuation seen with 12 and 16 mg/kg of morphine was blocked by naloxone (0.5 mg/kg i.v.), but 128 mg/kg of morphine overcame the block. Cumulative dose-response curves for morphine and for morphine after naloxone yielded the value pA2=6.8 which is in agreement with the values obtained using other effects and species. Administration of morphine after exposure to high intensity light produced less miosis than that seen under normal illumination.

Animals↗