Neuromuscular junction stimulation

Studies Creatine kinase (CK) was slightly elevated (380 lU/L upper normal for men is 370 lU/L). Liver-function tests and other blood chemistries were normal. The serum anti-neuronal/anti-Hu antibody test was positive. Immunofixation showed a monoclonal IgG-kappa band. Sensory and motor nerve conduction velocities were slightly slowed (dysschwannian) in the lower limbs, and BMG was normal. Cerebrospinal fluid (CSF) protein was slightly elevated (48mg/dL upper normal is 45mg/dL), without detectable lymphocytes or tumor cells. Repetitive neuromuscular junction stimulation at low and high frequency was normal. 

Nerve conductions were normal. Also normal was low-frequency repetitive neuromuscular-junction stimulation (distinct from MG, which typically shows a decrementalresponse). BMGshowedBSAPs [1] on voluntary contraction in the upper and lower limbs, and also slight signs of recent denervation. 

The concept of chemical neurotransmission originated in the 1920s with the classic experiments of Otto Loewi (which were themselves inspired by a dream), who demonstrated that by transferring the ventricular fluid of a stimulated frog heart onto an unstimulated frog heart he could reproduce the effects of a (parasympathetic) nerve stimulus on the unstimulated heart (Loewi Navratil, 1926). Subsequently, it was found that acetylcholine was the neurotransmitter released from these parasympathetic nerve fibers. As well as playing a critical role in synaptic transmission in the autonomic nervous system and at vertebrate neuromuscular junctions (Dale, 1935), acetylcholine plays a central role in the control of wakefulness and REM sleep. Some have even gone as far as to call acetylcholine a neurotransmitter correlate of consciousness (Perry et al., 1999). 

Holtzman, E., Freeman, A. R. and Kashner, A. Stimulation-dependent alterations in peroxidase uptake at lobster neuromuscular junctions. Science 173 733-736,1971. 

FIGURE18-4 Neuropeptides and conventional neurotransmitters are released from different parts of the nerve terminal. A neuromuscular junction containing both large dense-core vesicles (containing the neuropeptide SCP) and also small synaptic vesicles (containing acetylcholine) was stimulated for 30 min at 12 Hz (3.5 s every 7 s). Depletion of the small clear vesicles at the muscle face and of the peptide granules at the nonmuscle face of the nerve terminal was observed. After stimulation, there was an increase in the number of large dense-core vesicles within one vesicle diameter of the membrane. (Adapted from reference [37].)... 

Measuring muscle-evoked responses to repetitive motor nerve electrical stimulation permits detection of presyn-aptic neuromuscular junction dysfunction. In botulism and the Lambert-Eaton syndrome, repetitive stimulation elicits a smaller than normal skeletal muscle response at the beginning of the stimulus train, due to impaired initial release of acetylcholine-containing vesicles from presyn-aptic terminals of motor neurons followed by a normal or accentuated incremental muscle response during repeated stimulation. This incremental response to repetitive stimulation in presynaptic neuromuscular disorders can be distinguished from the decremental response that characterizes autoimmune myasthenia gravis, which affects the postsynaptic component of neuromuscular junctions. 

Botulinum exotoxin impedes release of neurotransmitter vesicles from cholinergic terminals at neuromuscular junctions. Botulinum exotoxin is ingested with food or, in infants, synthesized in situ by anaerobic bacteria that colonize the gut. A characteristic feature of botulinum paralysis is that the maximal force of muscle contraction increases when motor nerve electrical stimulation is repeated at low frequency, a phenomenon attributable to the recruitment of additional cholinergic vesicles with repetitive depolarization of neuromuscular presynaptic terminals. Local administration of Clostridium botulinum exotoxin is now in vogue for its cosmetic effects and is used for relief of spasticity in dystonia and cerebral palsy [21]. 

Neuromuscular Nicotinic receptors are responsible for transmission at the neuromuscular junction. While briefly causing stimulation, this phase is rapidly obscured by desensitization and neuromuscular blockade. Thus, nicotine has muscle-relaxant effects. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

At the neuromuscular junction, the terminus of the axon is separated from the sarcolemma by a cleft about 4 nm wide. When an action potential arrives at the terminus, it activates a voltage-sensitive Ca " ion channel. This results in Ca + ions diffusing into the terminus increasing the intracellular Ca + ion concentration, which stimulates exo-cytosis of acetylcholine from the terminus into the cleft. The acetylcholine diffuses across the cleft and binds to receptors on the motor end-plate (Figure 13.12) on the muscle side of the cleft. The binding of acetylcholine to... 

Stimulation of the parasympathetic system releases acetylcholine at the neuromuscular junction in the sinoatrial node. The binding of acetylcholine to its receptor inhibits adenylate cyclase activity and hence decreases the cyclic AMP level. This reduces the heart rate and hence reduces cardiac output. This explains why jumping into very cold water can sometimes stop the heart for a short period of time intense stimulation of the vagus nerve (a parasympathetic nerve) markedly increases the level of... 

Like in the neuromuscular junction the neurotransmission can be inhibited either by receptor blockade (non-depolarizing) or by overstimulation (depolarizing) of the receptors. The alkaloid nicotine, in low doses, stimulates ganglia and the adrenaline release from the adrenal medulla. High doses lead to a continuous depolarization of the postsynaptic membrane and thereby to an inactivation of the neurotransmission. All ganglion blockers in clinical use were synthetic amines of the nondepolarizing type trimethaphan, hexamethonium and mecamylamide. 

In addition to autonomic ganglia, nicotinic receptors are found in a variety of organs, and their stimulation will produce quite different results in these different tissues. Activation of nicotinic receptors on the plasma membrane of the cells of the adrenal medulla leads to the exo-cytotic release of epinephrine and norepinephrine stimulation of nicotinic receptors at the neuromuscular junction results in the contraction of skeletal muscle (see... 

Low doses of nicotine stimulate respiration through activation of chemoreceptors in the aortic arch and carotid bodies, while high doses directly stimulate the respiratory centers. In toxic doses, nicotine depresses respiration by inhibiting the respiratory centers in the brainstem and by a complex action at the receptors at the neuromuscular junction of the respiratory muscles. At these neuromuscular receptors, nicotine appears to occupy the receptors, and the end plate is depolarized. After this, the muscle accommodates and relaxes. These central and peripheral effects paralyze the respiratory muscles. 

Succinylcholine acts primarily at the skeletal neuromuscular junction and has little effect at autonomic ganglia or at postganglionic cholinergic (muscarinic) junctions. Actions at these sites attributed to succinylcholine may arise from the effects of choline. Succinylcholine has no direct action on the uterus or other smooth muscle structures. It does not enter the CNS and does not cross the placental barrier. It may, however, release histamine from mast cells. Because succinylcholine works by stimulating rather than blocking end plate receptors, anti-AChEs will not reverse muscle paralysis and may actually prolong the block. 

A 45-year-old man in otherwise good health complains of muscle weakness early in the morning but says it is less of a problem as the day goes on. The neurologist performs electromyography and notes no alteration in nerve conduction velocity but does observe facilitation in the compound action potential with repetitive 50-Hz stimulation. This indicates a defect at the prejunctional side of the neuromuscular junction. Which of the following is a possible cause ... 

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