A Nerve Stimulant

As a nerve stimulant, coca leaves have been used immemorially by the Peruvian and Bolivian natives. In 1853, it was stated (Wood and Bache, 1894)  

In one case, where 900 grains of coca leaf were used by a physician named Mantegazza, the following symptoms appeared  

The ingestion of coca leaf caused great increase in the number of heart-beats, and a condition of intoxication resembling that produced by hasheesh. He was possessed by a feeling of intense joyousness, while a succession of visions and phantasmagoria, most brilliant in form and color, trooped rapidly before his eyes. He then passed into a condition of delirious excitement, which was succeeded by a deep sleep lasting three hours. (Culbreth, 1927) 

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Benefits A bitter aromatic herb with a fig/date-like flavour that is claimed to be a nerve stimulant and was used to treat nervous exhaustion and anxiety of a sexual nature. It is claimed to be a mild irritant of the genito-urinary tract. 

Tropomyosin is an elongated protein that lies along the thin filament and prevents the association of myosin with actin in the resting state. Troponin is a complex of three polypeptide chains TnC, Tnl and TnT. Ca2+ ions released into the sarcoplasm from the sarcoplasmic reticulum in response to a nerve stimulation bind to TnC and cause a conformational change in the protein. This movement is transmitted by an allosteric mechanism through Tnl and TnT to tropomyosin, causing the latter to move out of the way and allowing the actin and myosin to associate. 

The pharmacological effects of the R- and 5-enantiomers of ketamine have been compared in 11 subjects who received //-ketamine 0.5 mg and then 5-ketamine 0.15 mg, separated by 1 week (432). Before and after each drug administration they were subjected to a painful stimulus using a nerve stimulator applied to the right central incisor tooth. Pain suppression was equal with the two drugs. The subjects reported more unpleasant psychotomimetic effects with 5-ketamine and more pleasant effects with //-ketamine. Seven of eleven subjects preferred //-ketamine, while none preferred 5-ketamine. These results suggest that the neuropsychiatric effect of ketamine may be predominantly due to the 5-enantiomer, and that //-ketamine may be a better alternative. This study is in direct distinction to earlier work suggesting that //-ketamine is responsible for most of the undesirable neuropsychiatric side effects of ketamine. 

A 60-year-old 70 kg woman with a fractured radius had an axillary brachial plexus block for postoperative analgesia after uneventful general anesthesia (5). A 50 mm insulated regional block needle attached to a nerve stimulator was used to locate the brachial plexus, and after negative aspiration, levobupivacaine 125 mg was injected with intermittent aspiration. Within 30 seconds the patient had a generalized tonic-clonic seizure which lasted about 30 seconds and self-terminated. She remained car-diovascularly stable and made an uneventful recovery. 

A 56-year-old 70 kg woman with a Colles fracture received a brachial plexus block at the humeral canal with 0.75% ropivacaine 40 ml using a nerve stimulator (11). The local anesthetic was administered slowly with negative intermittent aspiration. However, 15 minutes later she had two generalized convulsions, which were treated with diazepam. The total venous ropivacaine concentration measured 2 hours after the block was 2.3 gg/ml. 

Cocaine hydrochloride should melt at 180°-186°(B.E), 183°(P.G.), 186° (Fr Codex). It should be perfectly colour-less, and should afford a bright, neutral solution in water. This salt of cocaine is the one most generally employed in medicine. It is largely used for producing local anesthesia in minor operations and in dental practice. Given internally, or in small hypodermic doses, it acts as a nerve stimulant, restorative, and tonic. The mental exhilaration it produces often conduces to the formation of the cocaine habit, which is even more unfortunate than the morphia habit in its results. Source Barrowcliff 1920... 

Cocaine, extracted from Erythroxylon coca and used as a nerve stimulant and anaesthetic. 

Nervous system In a retrospective study to analyse the incidence of peripheral neuropathy in 157 patients with continuous sciatic nerve block in the popliteal fossa, three patients with an associated common superficial peroneal and sural nerve injury were identified via clinical and electromyographical studies [21 ]. In 44% percent of the patients US guidance was combined with a nerve stimulator technique. The authors conclude that methodological bias or technical problems (lateral vs posterior approach, US guidance) may account for the higher (1.9%) than average (0-0.5%) rate of peripheral neuropathy. It is of note that anatomically the common superficial peroneal and sural nerves were more affected than the tibial nerve, possibly due to their superficial location. 

Traditional Medicine. Used in Iranian folk medicine to treat abdominal cramps and diarrhea in Nepalese folk medicine as an aphrodisiac, diuretic, antispasmodic, emmen-agogue, expectorant, anthelmintic, and sedative in India to treat nervous disorders of children and women, cough, bronchitis, and pneumonia in children, and asthma, bronchitis, or flatulence in adults used in Chinese medicine (since the 7th century) as a nerve stimulant in treating neurasthenia in chronic bronchitis and as an expectorant, antiflatn-lent, and laxative. 

The dB/d/is limited to 6 T/s out of concern that larger values could cause nerve stimulation. The r-f exposure is limited to a specific absorption rate (SAR) of 0.4 W/kg for the whole body, 0.32 W/kg averaged over the head, and less than 8.0 W/kg spatial peakia any one gram of tissue. These numbers are designed to limit the temperature rise to less than 1°C and localized temperature of no greater than 38°C head, 39°C tmnk, and 40°C ia the extremities. 

Contraction of muscle follows an increase of Ca " in the muscle cell as a result of nerve stimulation. This initiates processes which cause the proteins myosin and actin to be drawn together making the cell shorter and thicker. The return of the Ca " to its storage site, the sarcoplasmic reticulum, by an active pump mechanism allows the contracted muscle to relax (27). Calcium ion, also a factor in the release of acetylcholine on stimulation of nerve cells, influences the permeabiUty of cell membranes activates enzymes, such as adenosine triphosphatase (ATPase), Hpase, and some proteolytic enzymes and facihtates intestinal absorption of vitamin B 2 [68-19-9] (28). 

Local anesthetics produce anesthesia by blocking nerve impulse conduction in sensory, as well as motor nerve, fibers. Nerve impulses are initiated by membrane depolarization, effected by the opening of a sodium ion channel and an influx of sodium ions. Local anesthetics act by inhibiting the channel s opening they bind to a receptor located in the channel s interior. The degree of blockage on an isolated nerve depends not only on the amount of dmg, but also on the rate of nerve stimulation (153—156). 

NPY is primarily (but not exclusively) synthesised and released by neurons, which in the peripheral nervous system are predominantly sympathetic neurons [1]. In most cases, NPY acts as a co-transmitter that is preferentially released upon high frequency nerve stimulation. NPY can be metabolised by the enzyme dipeptidylpeptidase IV (also known as CD26) to generate the biologically active fragment NPY3 36. 

Nonadrenergic noncholinergic inhibitory responses to autonomic nerve stimulation are mainly mediated through NO synthesized by nNOS NO plays a crucial role as a neurotransmitter from the peripheral efferent nerves, thus being called nitrergic. This provides a... 

A stimulus must reach the threshold to cause a response in a nerve fiber. Note that stimuli a, b, and d do not reach the threshold therefore, they do not cause a response in a nerve fiber. Stimuli c, e, f, and g do reach and surpass the threshold, resulting in stimulation of nerve fiber. 

Peptides in the a-conotoxin family are inhibitors of nicotinic acetylcholine receptors. They were first isolated from C. geographus venom as components which cause paralysis in mice and fish when injected intraperitoneally (27). Early physiological experiments (28) indicated that a-conotoxins GI, GII, and GIA (see Table III) all act at the muscle end plate region. Mini end-plate potentials and end plate potentials evoked in response to nerve stimulation are inhibited in the presence of a-conotoxins in the nM to pM range. a-Conotoxin GI was subsequently shown to compete with rf-tubocurarine and a-bungarotoxin for the acetylcholine receptor (29). 

When a nerve-muscle preparation is stimulated in the presence of a sea snake neurotoxin, there is no twitch. However, when the muscle itself is stimulated directly in the presence of a neurotoxin, the muscle contracts. This means that neurotoxin does not inhibit the muscle itself. Moreover, postsynaptic neurotoxin does not inhibit the release of acetylcholine from the nerve ending. Therefore, the site of snake toxin inhibition must be in the postsynaptic site 20). Later it was shown that a neurotoxin strongly binds to the acetylcholine receptor (AChR). 

Figure 1.9 Comparison of the effects of an endogenously released and exogenously applied neurotransmitter on neuronal activity (identity of action). Recordings are made either of neuronal firing (extracellularly, A) or of membrane potential (intracellularly, B). The proposed transmitter is applied by iontophoresis, although in a brain slice preparation it can be added to the bathing medium. In this instance the applied neurotransmitter produces an inhibition, like that of nerve stimulation, as monitored by both recordings and both are affected similarly by the antagonist. The applied neurotransmitter thus behaves like and is probably identical to that released from the nerve...

Many early studies of transmitter release depended on measuring its concentration in the effluent of a stimulated, perfused nerve/end-organ preparation. This technique is still widely used to study drug-induced changes in noradrenaline release from sympathetic neurons and the adrenal medulla. However, it is important to realise that the concentration of transmitter will represent only that proportion of transmitter which escapes into the perfusate ( overflow ) (Fig. 4.2). Monoamines, for instance, are rapidly sequestered by uptake into neuronal and non-neuronal tissue whereas other transmitters, such as acetylcholine, are metabolised extensively within the synapse. Because of these local clearance mechanisms, the amount of transmitter which overflows into the perfusate will depend not only on the frequency of nerve stimulation (i.e. release rate) but also on the dimensions of the synaptic cleft and the density of innervation. 

One approach, and the first to be adopted, is to study transmitter release from slices which have been preloaded with radiolabelled transmitter. In these experiments, drug-induced changes in the release of transmitter is usually monitored using the doublepulse technique. This involves comparing the effects of a test drug on the amount of transmitter released in response to a reference pulse and a second identical test pulse. If all the radiolabelled transmitter that overflows in the effluent is collected, and the amount which remains in the slice at the end of the experiment is also measured, it is possible to calculate not only how much radiolabelled transmitter was originally contained in the slice but also the effects of drugs on fractional release , i.e. the proportion of the store of radiolabelled transmitter which is released by nerve stimulation. As with... 

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