Local stimulus

Action events involve a multiphase biochemical-bioelectric process. A localized stimulus to an excitable cell can launch a series of cascading molecular events affecting the membrane s ionic permeability. The accompanying changes in TMP feed back on the membrane by way of voltagegated channels and magnify the effect of the stimulus. If the stimulus amplitude reaches a threshold value, this causes further and more dramatic changes in the membrane s ionic permeability. 

Ideally, such prodrugs should remain intact during their transit through the organism and, like HO-1, deliver small amounts of CO in the site of disease in response to some local stimulus. This process avoids the use of large amounts of CO in circulation and minimizes the dose of prodrug to be used. 

The foUowing examples are provided to iUustrate some of the considerations, not to exhaustively explore this compHcated issue. A model of the whole body is typically needed even for a relatively local stimulus, especiaUy when the heat input represents a significant fraction of the whole body heat load. The reader is referred to extensive handbook entries on environmental response for more information [43,44]. Whole body models of the thermoregulatory system are discussed in Wissler [45]. 

Ultrasound is an important local stimulus for triggering drug release at the target tissue. Ultrasound-responsive drug delivery systems have become an important research focus in targeted therapy. 

Grb-2 facilitates the transduction of an extracellular stimulus to an intracellular signaling pathway, (b) The adaptor protein PSD-95 associates through one of its three PDZ domains with the N-methyl-D-aspartic acid (NMDA) receptor. Another PDZ domain associates with a PDZ domain from neuronal nitric oxide synthase (nNOS). Through its interaction with PSD-95, nNOS is localized to the NMDA receptor. Stimulation by glutamate induces an influx of calcium, which activates nNOS, resulting in the production of nitric oxide. 

Autacoids are literally self-medicating agents that are liberated from or produced by cells in response to a stimulus. They differ from hormones in that they usually act locally after release, rather than reaching their target organ via the bloodstream. 

Stimulus molecules approach the receptor area in a random distribution. Therefore, there cannot be a homogeneous distribution of chemical or enzymic processing capabilities over the area, as this would produce a chaotic mass of information. The capabilities of such precise chemoreceptory discrimination that we observe can only arise from an ordered system in such a way that specific reaction-types would be localized, or at least be concentrated in specific areas of the epithelium. ... 

By external stimulus at the plate electrode, migration of the ions in the solvent is induced, which changes the spatial concentration and so the local course of reactions [68]. By this means, weak electrical fields change the propagation velocity of the reaction zone through the capillary strong electrical fields ( supercritical ) further affect the global feature of the reaction in the capillary. 

The key factor in the development of sepsis is inflammation. Inflammation is intended to be a local and contained response to infection or injury. Infection or injury is controlled through pro- and anti-inflammatory mediators. Pro-inflammatory mediators facilitate clearance of the injuring stimulus, promote resolution of injury, and are involved in processing of damaged tissue.1,13-16 In order to control the intensity and duration of the inflammatory response, antiinflammatory mediators are released that act to regulate pro-inflammatory mediators.15-16 The balance between pro- and anti-inflammatory mediators localizes infection/injury of host tissue.13-16 However, systemic responses ensue when equilibrium in the inflammatory process is lost. 

The cell bodies of third-order sensory neurons are located in the thalamus. These neurons transmit the pain signal to the somatosensory cortex. The function of this region of the brain is to localize and perceive the intensity of the painful stimulus. Further transmission of the signal to the association areas of the cerebral cortex is important for the perception and meaningfulness of the painful stimulus. 

Consistent with their role as immune receptors, each human TLR is expressed by at least one subset of myeloid cells (MCs) or lymphocytes [7,8]. TLRs are also present on stromal elements like endothelium particularly after local inflammatory stimulus [9-11]. These distribution patterns can determine the physiological consequences of stimulation or antagonism, and affect the balance of toxicity versus therapeutic effect. Another consideration for medicinal chemistry is subcellular localization of TLRs. While most are expressed on the cell surface, some (TLRs 3,7,8, and 9) can localize to endosomes where they survey ingested material for ligands, so drug access to this compartment can be crucial when targeting these TLRs [12]. 

FIGURE 6-1 Path of excitation in a simplified spinal reflex that mediates withdrawal of the leg from a painful stimulus. In each of the three neurons and in the muscle cell, excitation starts with a localized slow potential and is propagated via an action potential (a.p.). Slow potentials are generator potential (g.p.) at the skin receptor the excitatory postsynaptic potentials (e.p.s.p.) in the interneuron and the motoneuron and end-plate potential (e.p.p.) at the neuromuscular junction. Each neuron makes additional connections to other pathways that are not shown. 

Pain is thought to originate from myofascial factors and peripheral sensitization of nociceptors. Central mechanisms are also involved. Mental stress, nonphysiologic motor stress, a local myofascial release of irritants, or a combination of these may be the initiating stimulus. In predisposed individuals, chronic, tension-type headache can evolve. 

---