CHAPTER VI 



Skeletal neuromuscular transmission 



PAULFATT I Biophysics Department, University College, London, England 



CHAPTER CONTENTS 



Morphology 



Local Electrical Response 



Activity of the Nerve Terminals 



Properties of the Junctional Receptor 



Conclusion : Mechanism of Transmission 



THE EXISTENCE OF A REGION between motor nerve and 

 voluntary muscle which has special properties 

 emerged from experiments on the action of the South 

 American Indian arrow poison, curare, performed lay 

 Claude Bernard about 1850 (2). Bernard's aim in the 

 first place was to show that muscle was excitable inde- 

 pendently of its nerve supply. Having; pre\iously 

 paralyzed a frog with curare, he isolated a nerve- 

 muscle preparation and showed that, while an elec- 

 trical stimulus applied to the nerve was ineffective, 

 a contraction resulted if it were applied directly to 

 the muscle. Inferring that curare interfered with the 

 functioning of the nerve but not of the muscle, he 

 carried the investigation a step further by preparing a 

 frog with a ligature which interrupted the blood 

 supply to the hind legs but not the nervous connec- 

 tions. When curare was introduced above the liga- 

 ture, a paralysis developed which affected only the 

 anterior part of the body. Most significant was the 

 observation that pinching the skin above the ligature 

 did not elicit movement in that region but caused the 

 normal reflex thrust of the hind legs. It was concluded 

 from this that curare did not cause a loss of sensation, 

 and its effect was therefore ascribed to a poisoning of 

 the motor nerve, for, as was already seen, in the 

 presence of curare the muscle could still be excited 

 directly. But since curare apparently did not affect 

 the motor nerve in its more central course from the 



spinal cord to the level of the ligature either, it wa 

 maintained that the poison acted on the motor nerve 

 only in its most peripheral part, where contact was 

 made with the muscle. 



Following this penetrating study, investigations 

 were carried out over a number of years by other 

 workers into the method of action of substances that 

 affect nerve-muscle transmission more or less specif- 

 ically. Besides curare, one of the chief of these was 

 nicotine. When a small amount of this drug was 

 injected into an animal or added to the solution 

 bathing an isolated muscle, a contraction occurred 

 which was abolished by curare at the same time as 

 was the contraction produced by nerve stimulation. 

 It was further found that chronic denervation did not 

 eliminate the capacity of the muscle for responding 

 to nicotine, which was still antagonized by curare, 

 although the nerve terminals underwent severe 

 deterioration (34, 46, 57, 59). From this it was con- 

 cluded that the site of action of curare, as well as 

 nicotine, was not in the nerve endings, as had pre- 

 viously been supposed, but in the muscle fiber. 



A quantitative investigation of the effects of these 

 substances was made by Langley about 1910 (58, 

 60, 61). By the application of small droplets of nicotine 

 solution along a mu.scle fiber, he found that nicotine 

 in low concentration initiated a contraction only when 

 applied in the region of the nerve endings. A concen- 

 tration one thousand times greater than the minimum 

 effective dose was required to produce a contraction 

 elsewhere along the muscle fiber. Furthermore, 

 curare interfered with the action of nicotine in low 

 concentration but had no effect on the contraction 

 produced by the high concentration that did not act 

 exclusively in the innervated region. The manner in 

 which curare and nicotine acted was inferred from the 

 observation that increasing concentrations of curare 



'99 



