Stimulus-response effect

FIGURE 2.16 Effects of successive rectangular hyperbolae on receptor stimulus, (a) Stimulus to three agonists, (b) Three rectangular hyperbolic stimulus-response functions in series. Function 1 ((3 = 0.1) feeds function 2 ((3 = 0.03), which in turn feeds function 3 ((3 = 0.1). (c) Output from function 1. (d) Output from function 2 (functions 1 and 2 in series), (e) Final response output from function 3 (all three functions in series). Note how all three are full agonists when observed as final response. 

FIGURE 3.6 Classical model of agonism. Ordinates response as a fraction of the system maximal response. Abscissae logarithms of molar concentrations of agonist, (a) Effect of changing efficacy as defined by Stephenson [24], Stimulus-response coupling defined by hyperbolic function Response = stimulus/(stimulus-F 0.1). (b) Dose-response curves for agonist of e = 1 and various values for Ka. 

FIGURE 3.10 Constitutive activity due to receptor overexpression visualization through binding and function, (a) Constitutive activity observed as receptor species ([RaG]/[RL0J) and cellular function ([RaG]/ ([RaG] + 3), where P = 0.03. Stimulus-response function ([RaG]/([RaG] + p)) shown in inset. The output of the [RaG] function becomes the input for the response function. Dotted line shows relative amounts of elevated receptor species and functional response at [R]/KG= 1. (b) Effects of an inverse agonist in a system with [R]/ Kq= 1 (see panel a) as observed through receptor binding and cellular function. 

The operational model allows simulation of cellular response from receptor activation. In some cases, there may be cooperative effects in the stimulus-response cascades translating activation of receptor to tissue response. This can cause the resulting concentration-response curve to have a Hill coefficient different from unity. In general, there is a standard method for doing this namely, reexpressing the receptor occupancy and/or activation expression (defined by the particular molecular model of receptor function) in terms of the operational model with Hill coefficient not equal to unity. The operational model utilizes the concentration of response-producing receptor as the substrate for a Michaelis-Menten type of reaction, given as... 

The first idea to consider is the effect of receptor density on sensitivity of a functional system to agonists. Clearly, if quanta of stimulus are delivered to the stimulus-response mechanism of a cell per activated receptor the amount of the total stimulus will be directly proportional to the number of receptors activated. Figure 5.8 shows Gi-protein-mediated responses of melanophores transiently transfected with cDNA for human neuropeptide Y-l receptors. As can be seen from this figure, increasing receptor expression (transfection with increasing concentrations of receptor cDNA) causes an increased potency and maximal response to the neuropeptide Y agonist PYY. 

By utilizing complete dose-response curves, the method devised by Barlow, Scott, and Stephenson [9] can be used to measure the affinity of a partial agonist. Using null procedures, the effects of stimulus-response mechanisms are neutralized and receptor-specific effects of agonists are isolated. This method, based on classical or operational receptor theory, depends on the concept of equiactive concentrations of drug. Under these circumstances, receptor stimuli can be equated since it is assumed that equal responses emanate from equal stimuli in any given system. An example of this procedure is given in Section 12.2.1. 

The combined results demonstrate the complexity of the system. Cross-linking must include kinetic contributions to the lateral resistance that are similar to those observed in the networks, but a combination of structural and dynamic factors is likely responsible for the signihcant but opposite effects from kinetically dissimilar cross-links. Stimulus-responsive polymer brush layers hold great potential (Minko et al. 2000 Motornov et al. 2003 Granville et al. 2004 Kaholek et al. 2004a,... 

On the other hand, Tamada et al.44 have investigated stimulus-responsive gels utilizing the photochemical reaction of a polymeric azobenzene unit doped with IL (Fig. 23.5). Photoisomerization of the azobenzene group resulted in shrinkage of the irradiated site. It was also reported that ionic conductivity of the gel could be controlled by photoirradiation. The ionic conductivity of the gel decreased after UV light irradiation this effect was coupled with an increase in viscosity, in turn suppressing diffusion of the component ions within the gel. 

As noted above, Passmore et al. (2003) were the first to demonstrate that Kv7.2, 7.3 and 7.5 are expressed at the protein level in sensory neurons and also that functional M-currents can be measured under voltage-clamp. They were further able to demonstrate that pharmacological activation of Kv7 channels by direct application of retigabine to the spinal cord inhibited both C fiber and AS fiber-mediated signaling. This was true when the afferent fibers were excited by either electrical or tactile stimuli. Moreover, wind-up , an increased sensitivity of the stimulus/response relationship to repetitive stimuli, is also inhibited. These results demonstrate a clear role of Kv7 channels in sensory neuron processing. Gerlach et al. (2006, 2007) have also reported direct effects of ICA-27243 on both M-currents and membrane potential in isolated DRG neurons. Activation of the M-current by ICA-27243... 

Hirose K, Ishibashi K, Shiba Y, Doi Y, Tobe Y (2008) Highly effective and reversible control of the rocking rates of rotaxanes by changes to the size of stimulus-responsive ring components. Chem Eur J 14 5803-5811... 

Unlike other manufacturing industries, where the produet ean be accurately specified in terms of its performance, food is measured by individuals, and its qualities of appearance, texture and flavour are measured subjeetively against a set of criteria established by experience. We know what we hke, and it is very dependent on our own cultural background and lifestyle. As eonsumers, we detect some qualities instantly with our eyes, nose and mouth, aU of whieh have multiple sensors with stimulus/ response behaviour that is not completely understood. We have to recognise that these qualities are defined subjectively, and are described in words that have, as yet, no clear numerical definition. There are other quaUties such as the efifeet of food on our longer-term health and well-being that as individuals we are not weU equipped to measure. We cannot easily detect the effect of salt on our blood pressure or antioxidants on our cancer resistance. The development of biomarkers for health is outside the scope of this volume. 

Stimulus-response specificity is a concept describing conditions where a very specific response can be predicted with tremendous regularity when a stimulus is applied. One example would be that an electrical shock to muscle tissue evokes a contraction. This model is appropriate for some types of medical interventions. For example, for acute cardiac and respiratory arrest, the techniques of cardiopulmonary resuscitation (CPR) can be used with most victims, regardless of their age, socioeconomic status, sex, or religious beliefs. When there is an obstructed airway, performing an emergency tracheotomy is appropriate for victims regardless of their emotional status, personality style, or level of psychosocial maturity. Likewise, some medications have fairly universal effects on all people for instance, sodium pentothal produces unconsciousness (Deckert 1985). 

Systemic administration of classical antipsychotics or clozapine block amphetamine-induced discriminative stimulus responses in the rat (205,206). The amphetamine response can also be blocked by direct injection of the drug into the nucleus accumbens (207). While classical antipsychotics completely inhibit the response, clozapine and olanzapine are somewhat less active, risperidone and remoxipride are weakly active, and sertindole and quetiapine were inactive (208, 209). Based on these findings, it has been proposed that the antagonism of the amphetamine discriminative stimulus response may be an indication of neuroleptic-induced deficit properties (209). Antipsychotic drugs also seem to inhibit the discriminative stimulus effects of hallucinogenic 5-HT agonists like DOI, DOM, and LSD in proportion to their 5-HT antagonist potencies (209-211). 

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