Resistance to d-Tubocurarine in Lower Motor Neuron Injury Is Related to Increased Acetylcholine Receptors at the Neuromuscular Junction

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Abstract
The hypothesis that lower motor neuron injury with its associated proliferation of acetylcholine receptors (AChR), induces resistance to the neuromuscular effects of d-tubocurarine (dTC) was tested in the rat. The left gastrocnemius was denervated by a 75-80% lesion of the sciatic nerve. The effective dose for 95% twitch depression (ED95) was studied in the denervated gastrocnemius and compared to the contralateral denervated and sham-injured (control) gastrocnemius muscles approximately 2 weeks after injury. The AChR number was quantitated by the specific ligand 125I-.alpha.-bungarotoxin (125I-.alpha.-BT). Plasma dTC concentrations, measured by high-performance liquid chromatography (HPLC), were correlated to twitch tension during spontaneous recovery from neuromuscular blockade in the denervated animal. The ED95 (mean .+-. SE) of dTC for the denervated leg was significantly (P < 0.05) higher (0.26 .+-. 0.06 mg.cntdot.kg-1) than contralateral (0.16 .+-. 0.03) and sham-operated left (0.13 .+-. 0.03) legs. The twitch tension recovered to 50% of control twitch height at significantly (P < 0.05) higher plasma dTC concentrations in the denervated (0.78 .mu.g.cntdot.ml-1) compared to contralateral (0.24 .mu.g.cntdot.ml-1) limb. The AChR number was significantly increased in the denervated limb (1041 .+-. 96 fmol.cntdot.mg protein-1) compared to contralateral right (109 .+-. 4) and control left limb (113 .+-. 11). There was a significant (P < 0.05) positive correlation (R2 = 0.73) between ED95 and AChR number; that is, 73% of the variability in ED95 could be explained by changes in AChR. This study, therefore, confirms the hypothesis that proliferation of AChR after nerve denervation results in resistance to the neuromuscular effects of dTC. Since a partial lower motor neuron lesion of one side does not affect contralateral neuromuscular responses, the contralateral normal side can be used to assess neuromuscular function, and therefore contrasts with reports on upper motor neuron denervation in which altered sensitivity to neuromuscular relaxants may occur on the affected as well as "unaffected" skeletal muscles.