Actions of cholinergic drugs in the nematode Ascaris suum. Complex pharmacology of muscle and motorneurons.

Abstract

A B S T R A C T The cholinergic agonists acetylcholine (ACh), nicotine, and pilocarpine produced depolarizations and contractions of muscle of the nematode Ascaris suum. Dose-dependent depolarization and contraction by ACh were suppressed by about two orders of magnitude by 100 ~M d-tubocurarine (dTC), a nicotinic antagonist, but only about fivefold by 100 p-M N-methyl-scopolamine (NMS), a muscarinic antagonist. NMS itself depolarized both normal and synaptically isolated muscle cells. The muscle depolarizing action of pilocarpine was not consistently antagonized by either NMS or dTC. ACh receptors were detected on motorneuron classes DE 1, DE2, DI, and VI as ACh-induced reductions in input resistance. These input resistance changes were reversed by washing in drug-free saline or by application of dTC. NMS applied alone lowered input resistance in DEI, but not in DE2, DI, or VI motorneurons. In contrast to the effect of ACh, the action of NMS in DE1 was not reversed by dTC, suggesting that NMS-sensitive sites may not respond to ACh. Excitatory synaptic responses in muscle evoked by depolarizing current injections into DE1 and DE2 motorneurons were antagonized by dTC; however, NMS antagonized the synaptic output of only the DE1 and DE3 classes of motorneurons, an effect that was more likely to have been produced by motorneuron conduction failure than by pharmacological blockade of receptor. The concentration of NMS required to produce these changes in muscle polarization and contraction, ACh antagonism, input resistance reduction, and synaptic antagonism was 100 p,M, or more than five orders of magnitude higher than the binding affinity for [3H]NMS in larval Ascaris homogenates and adult Caenorhabditis elegans (Segerberg, M. A. 1989. Ph.D. thesis. University of Wisconsin-Madison, Madison, WI). These results describe a nicotinic-like pharmacology, but muscle and motorneurons also have unusual responses to muscarinic agents.

Effects of the muscarinic agonist, 5-methylfurmethiodide, on contraction and electrophysiology of Ascaris suum muscle

“…In an isolated muscle bag preparation of A. suum, Martin and Valkanov (1996) observed evidence of a mecamylamineresistant cholinergic receptor, stimulation of which increased the opening of a non-selective cation channel, an effect that was not blocked by atropine, mecamylamine or tubocurarine. In addition Segerberg and Stretton (1993) reported that pilocarpine, a muscarinic agonist, produced a concentration-dependent depolarization in A. suum muscle that was not antagonized by a muscarinic antagonist (N-methyl-scopolamine) nor the nicotinic antagonist, tubocurarine. The lack of effect of oxtremorine and atropine in previous A. suum studies, together with the modest effect of atropine in our studies, suggests that a GAR-3-like receptor is not involved in mediating the effects of MFI.…”

“…Colquhoun et al (1991) have tested a range of cholinergic agonists on the electrophysiology of A. suum muscle cells and found furtrethonium to be one of the more potent muscarinic agonists. Segerberg and Stretton (1993) have also found evidence of muscarinic-like receptors on A. suum muscle mediating depolarization and contraction; and Martin and Valkanov (1996) have described effects of acetylcholine potentiating the opening of mecamylamineresistant non-selective cation channel currents (I bcat ) in isolated A. suum muscle bags. In Caenorhabditis elegans three G-protein coupled acetylcholine receptors (GAR-1, GAR-2 and GAR-3) have been reported (Hwang et al, 1999;Lee et al, 2000).…”

Evolution of neurotransmitter gamma-aminobutyric acid, glutamate and their receptors

“…Like GABA, glutamate has been proposed to play roles in the nervous system of the most primitive animals. Antagonistic to GABA, glutamate increases the outputs of ectodermal and endodermal impulse generating systems in the phylogenetically basal hydrozoan Hydra vulgaris (Kass-Simon et al, 2003), and acts as an excitatory neurotransmitter in cestode and aplysiidae nervous systems (Davis & Stretton, 1995;Verma et al, 2010;Gerschenfeld, 1973;Kehoe & Marder, 1976;Segerberg & Stretton, 1993). Glutamate is the main excitatory neurotransmitter in the nervous systems of nematodes and fruit fly (Devaud et al, 2008).…”

Ion channels and receptor as targets for the control of parasitic nematodes

“…ACh acts at muscarinic receptors, encoded in nematodes by the gar genes Lee et al, 1999Lee et al, , 2000. These are present in parasitic species, and have atypical muscarinic pharmacology (Segerberg and Stretton, 1993;Kimber et al, 2009), which again suggest that helminth-specific molecules could be developed.…”