Block of postjunctional muscle-type acetylcholine receptors in vivo causes train-of-four fade in mice

Background: Train-of-four (TOF) fade during nerve-mediated muscle contraction is postulated to be attributable to inhibition of prejunctional nicotinic α3β2 acetylcholine receptors (nAChRs), while decrease of twitch tension is attributable to block of postjunctional muscle nAChRs. The validity of these presumptions was tested using specific prejunctional and postjunctional nAChR antagonists, testing the hypothesis that fade is not always a prejunctional phenomenon.

Methods: Pentobarbital anaesthetized mice had TOF fade measured after administration of: either 0.9% saline; the prejunctional α3β2 nAChR antagonist, dihydro-β-erythroidine (DHβE); the postjunctional nAChR antagonists, α-bungarotoxin (α-BTX) or α-conotoxin GI; and a combination of α-BTX and DHβE; or a combination of α-conotoxin GI and DHβE.

Results: Saline caused no neuromuscular changes. Administration of muscle nAChR antagonists, α-BTX or α-conotoxin GI caused significant decrease of twitch tension and TOF fade compared with baseline (P<0.01). DHβE alone caused no change of twitch tension or fade even after 90 min, but its coadministration with α-BTX or α-conotoxin GI significantly accelerated the onset of paralysis and degree of fade compared with α-BTX or α-conotoxin GI alone (P<0.01).

Conclusions: Occupation of postjunctional nAChRs alone by α-BTX or α-conotoxin GI causes fade. As the prejunctional effects of DHβE on fade became manifest only when co-administered with α-BTX or α-conotoxin GI, specific inhibition of prejunctional nAChR alone is not necessary and sufficient to cause fade. Fade observed during repetitive nerve stimulation can be because of block of either postjunctional nAChRs alone, or block of prejunctional and postjunctional nAChRs together.