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R J Tallarida

Publications and source records attributed to R J Tallarida.

89 records · Page 5Linked to original sources
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Chaos and control in mass-action binding of endogenous compounds.

Endogenous compounds, such as hormones and neurotransmitters, interact with cellular receptors in controlled reactions governed by the mass-action law. Autoreceptors, a subset of the receptor pool, when activated by the endogenous ligand, result in a negative feedback that reduces the further release of ligand. This paper discusses and illustrates this control system when the concentrations (free and bound) are near or slightly beyond the limits of effective feedback control. Specifically, a forced periodic input function, simulating periodic release of the ligand, is used in the simulation of this controlled binding reaction in which a parameter representing the upper limit of control is varied. The solution of the system differential equations, representing free and bound ligand, is shown to pass from periodic to chaotic as the parameter is varied.

Computer Simulation↗
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Extraction and measurement of morphine: correlation of brain level and s.c. dose in drug-naive and morphine-tolerant rats.

A method was recently developed by Raffa et al (1) for rapid analysis of brain levels of morphine in rats given the drug subcutaneously. The technique combines the extraction procedure of Sprague and Takemori (2) and the HPLC methodology of Peterson et al (3). The purpose of the present work was verification of the accuracy of this technique and its application to an accompanying study in which the dissociation constants of morphine determined in drug-naive and morphine-tolerant rats were compared. Male, Sprague-Dawley rats (180-220 g) were given morphine sulfate s.c. 60 min prior to testing. Each rat in the "tolerant" group received two 75 mg morphine pellets subcutaneously which were removed 96 h later. Brain levels of morphine were measured a further 24 h later. Morphine levels in rat brain ranged from 52 to 1800 ng, corresponding to subcutaneous doses of 2.5 to 320 mg/kg. This range of brain levels agrees well with those obtained using different methods (4,5). We found no significant difference in brain levels of morphine in naive and tolerant rats given the same doses of morphine (10, 20, 40, and 80 mg/kg, s.c.). Thus, in the determination of dissociation constants for morphine, the same relation can be used for both naive and morphine-tolerant rats when converting administered dose to brain level.

Animals↗
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Estimation in vivo of the receptor constants of morphine in naive and morphine-tolerant rats.

The efficacy and dissociation constant of morphine in naive and morphine-tolerant rats were estimated by the method of partial irreversible blockade of a fraction of the receptor population with buprenorphine. The dissociation constant (KA) of morphine increased from 3.3 x 10(-5) M in naive to 1.4 x 10(-4) M in morphine-tolerant animals, indicating a decrease in the affinity of morphine for its receptor in the tolerant state. The efficacy of morphine (KA/A50 + 1) was constant in naive and tolerant animals (4.23 and 4.46, respectively). When the data were recalculated following conversion of administered dose to brain morphine concentration, the value of KA was 1.7 x 10(-7) M in naive and 7.7 x 10(-7) M in morphine-tolerant rats, while the efficacy was 2.5 and 3.4, respectively. In addition, the stimulus-effect relationship varied in the two states, with the curve in the tolerant animal being of different shape and broader range than in the naive rat. The present results suggest that (a) tolerance to opiate agonists may involve affinity changes and (b) post-receptor events leading to the measured effect may also be affected.

Analgesia↗
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Estimation of the dissociation constant of naloxone in the naive and morphine-tolerant guinea-pig isolated ileum: analysis by the constrained Schild plot.

The pA2 values for naloxone-morphine were determined using ilea taken from naive and morphine-tolerant guinea-pigs. This constant decreased from 8.56 (+/- 0.22) in the naive to 7.95 (+/- 0.12) in tolerant tissues. The values of the pA2's were based on Schild plots using conventional regression techniques; this regression resulted in values of -log KB of 8.79 (+/- 1.5) and 8.18 (+/- 1.2) in naive and morphine-tolerant ilea, respectively. While pA2 differed, the difference in -log KB was not statistically significant. Since these two values are theoretically equivalent, the above finding appears paradoxical. Constraining the slope of the Schild plot to the theoretically required -1 resolved this discrepancy by reducing the error inherent in the calculation of -log KB determined by conventional regression.

Animals↗
PubMedDate not supplied

Effects of chronic treatment with verapamil on adrenoceptor-mediated contraction of rabbit aorta.

Rabbits received twice-a-day doses of verapamil for 8 days and, on day 9 they were sacrificed in order to test contractile responses of the aorta in vitro. Isolated rings of aorta received graded doses of KCl, norepinephrine and norepinephrine along with either phentolamine, phenoxybenzamine or additional (acute) verapamil. Treated rings (those from animals that received verapamil chronically) developed significantly less tension (E) in response to depolarizing doses of KCl, but the degree of developed tension was restored and, in fact, enhanced when the aortic tissue was tested after cold storage 24 hr later (day 10). Responses (E) to norepinephrine in verapamil-pretreated rings were less than in controls by amounts that correlated with the daily verapamil dose and these too were enhanced after cold storage for 24 hr. The equilibrium dissociation constant (KA) of norepinephrine for the alpha 1-adrenoceptor, determined by the method of partial receptor blockade, was increased (reduction in affinity) by amounts that also depended on the daily verapamil dose. In contrast to agonist affinity, phentolamine affinity, determined from Schild-plot analysis, was not different from controls, even for the highest daily dosage of verapamil. Stimulus-effect curves were also the same in control and verapamil-pretreated groups, thus suggesting that the chronic treatment did not affect the basic contractile process distal to the receptor. Further, aortae from pretreated rabbits showed more depression to acute verapamil than was seen in controls and this depression in Emax could not be overcome with even high doses of norepinephrine. In addition to the known alpha-blocking and calcium channel blocking actions of verapamil, these data show that chronic verapamil affects norepinephrine, but not phentolamine-receptor affinity, thus suggesting that the chronic action of this calcium entry blocker may preferentially alter a site on the receptor to which norepinephrine binds.

Animals↗