Synaptic modelling

Bliss, T. V. and Collingridge, G. L. A synaptic model of memory long-term potentiation in the hippocampus. Nature 361 31-39,1993. 

Now, to be sure, McCulloch-Pitts neurons are unrealistically rendered versions of the real thing. For example, the assumption that neuronal firing occurs synchronously throughout the net at well defined discrete points in time is simply wrong. The tacit assumption that the structure of a neural net (i.e. its connectivity, as defined by the set of synaptic weights) remains constant over time is known be false as well. Moreover, while the input-output relationship for real neurons is nonlinear, real neurons are not the simple threshold devices the McCulloch-Pitts model assumes them to be. In fact, the output of a real neuron depends on its weighted input in a nonlinear but continuous manner. Despite their conceptual drawbacks, however, McCulloch-Pitts neurons are nontrivial devices. McCulloch-Pitts were able to show that for a suitably chosen set of synaptic weights wij, a synchronous net of their model neurons is capable of universal computation. This means that, in principle, McCulloch-Pitts nets possess the same raw computational power as a conventional computer (see section 6.4). 

They act as analgesics by inhibiting release of nociceptive neurotransmitters from primary afferent terminals as well as by depressing post-synaptic potentials on second order neurons. Opioid receptors are also present on some nociceptors and their expression and peripheral transport is increased upon peripheral inflammation. Peripheral opioid analgesia has been established in animal models. Although clinical studies have yielded mixed results so far, this field holds great promise. Despite side effects, such as euphoria, dysphoria, sedation, respiratory depression and obstipation and tolerance and dependence phenomena which arise upon... 

Fig. 4.1 Hypothetical model of pathogenesis of pain in DSP. (1) Injury of peripheral nerve fibers due to multifocal inflammation and secreted macrophage activation products results in abnormal spontaneous activity of neighboring uninjured nociceptive fibers ( peripheral sensitization ). (2) Furthermore, the aberrant inflammatory response in DRG leads to alterations in neuronal sodium and calcium channel expression and ectopic impulse generation. (3) This results in central remodeling within the dorsal horn due to A-fiber sprouting and synaptic formation with pain fibers in lamina 11, and maintenance of neuropathic pain ( central sensitization ). Reproduced with permission from (Keswani et al. 2002)...

In parallel with the identification of distinct transporters for GABA there has been continued interest in the development of selective blockers of these transporters and the therapeutic potential that could result from prolonging the action of synaptically released GABA. It has been known for a long time that certain pro-drugs of nipecotic add (e.g. nipecotic acid ethyl ester) are able to cross the blood-brain barrier and are effective anticonvulsants in experimental models of epilepsy. More recently, several different systemically active lipophillic compounds have been described that act selectively on GAT-1, GAT-2 or GAT-3 (Fig. 11.4). Of these, tiagabine (gabitiil), a derivative of nipecotic acid that acts preferentially on GAT -1, has proved clinically useful in cases of refractory epilepsy. 

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