<p>Denervation of skeletal muscle fibres is known to lead to a marked alteration of their normal characteristics. The mechanism for this is not clear, but there is great interest in the possibility that the changes are the result of the cutting off of neurotrophic factors which normally continuously act on the muscle fibres. To study this question, colchicine, a drug known to interfere with neurorial transport, was injected through the epineurium of one sciatic nerve in rats, in an attempt to prevent the postulated neurotrophic factors from reaching the extensor digitorum longus (EDL) muscle, without interfering with impulse activity in the nerve, or the consequent activity of the muscle. Following this procedure, ipsilateral EDl muscle fibres were found to exhibit extrajunctional sensitivity to acetylcholine ( ACh ), tetrodotoxin ( TTX ) resistant action potentials, and lowered membrane potentials ( RMP ); all characteristic changes observed in denervated skeletal muscle fibres. These fibres however, were shown not to be denervated, since they displayed miniature end-plate potentials (m.e.p.p.s) and neuromuscular transmission was normal.</p> <p>Unexpectedly, the contralateral EDL muscle fibres which were examined as a routine control, also displayed the features of "denervation" following an injection of colchicine into the ipsilateral sciatic nerve, and were virtually indistinguishable from the ipsilateral EDL fibres. It thus appeared possible that nerve injections of colchicine were acting systemically, and indeed this was shown to be the case when similar denervation-like changes were caused bilaterally after intraperitoneal (I.P.) injections of the same dose of colchicine.</p> <p>Although thesis results showed that colchicine was acting systemically, it was still possible that it, was effective by blocking neuronal transport in the muscle nerves. Axoplasmic transport was therefore measured in the sciatic nerve of rats, following colchicine injections both systemically and into the contralateral nerve. At no time was there any evidence of an impairment of transport, even though both EDL muscles contained fibres which displayed extrajunctional sensitivity to ACh. lt was concluded that extrajunctional sensitivity to ACh following colchicine injections was not due to an interference with axoplasmic transport.</p> <p>In the injected sciatic nerve, an impairment of transport was consistently observed and this generally was associated with a detectable paresis and a small percentage (5-7%) of apparently denervated EDL muscle fibres. In addition, the indirectly evoked tetanic tensions produced by the ipsilateral EDL muscles decreased in comparison to the contralateral EDL muscles, commencing about 2 days following the sub-epineural injection of colchicine. From these observations, it was suggested that the demonstrable impairment of axoplasmic transport in the ipsilateral sciatic nerve caused the impairment of neuromuscular transmission on that side.</p> <p>Colchicine was also chronically applied to rat sciatic nerves by the use of drug-impregnated silicone rubber nerve-cuffs. This procedure prevented the systemic effect of colchicine, but the mechanical presence of the cuff resulted in a usually transitory and variable block of impulse conduction in the nerve. Since muscle inactivity per se also leads to changes previously believed to be due to denervation, the changes that were observed with colchicine-cuffs did not constitute unequivocal evidence supporting neurotrophic effects on the ipsilateral EDL muscle fibres.</p> <p>It was concluded from the results presented in this thesis that the results of experiments involving colchicine injections or drug-impregnated nerve-cuffs do not unequivocably support the existence of a neurotrophic control of skeletal muscle fibre properties.</p> <p>Finally, preliminary experiments in which colchicine was used in association with denervation indicated that the most likely mechanism of action of colchicine was a direct one on the muscle fibre membrane itself.</p> / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/7865 |
| Date | January 1977 |
| Creators | Fried, Andreas Joseph |
| Contributors | Diamond, J., Medical Sciences |
| Source Sets | McMaster University |
| Detected Language | English |
| Type | thesis |
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