All the classical transmitter ligand molecules evolved at least 1000 million years ago. With the possible exception of the Porifera and coelenterates (Cnidaria), they occur in all the remaining phyla. All transmitters have evolved the ability to activate a range of ion channels, resulting in excitation, inhibition and biphasic or multiphasic responses. All transmitters can be synthesised in all three basic types of neurones, i.e. sensory, interneurone and motoneurone. However their relative importance as sensory, interneurone or motor transmitters varies widely between the phyla. It is likely that all neurons contain more than one type of releasable molecule, often a combination of a classical transmitter and a neuroactive peptide. Second messengers, i.e. G proteins and phospholipase C systems, appeared early in evolution and occur in all phyla that have been investigated. Although the evidence is incomplete, it is likely that all the classical transmitter receptor subtypes identified in mammals, also occur throughout the phyla. The invertebrate receptors so far cloned show some interesting homologies both between those from different invertebrate phyla and with mammalian receptors. This indicates that many of the basic receptor subtypes, including benzodiazepine subunits, evolved at an early period, probably at least 800 million years ago. Overall, the evidence stresses the similarity between the major phyla rather than their differences, supporting a common origin from primitive helminth stock.

Neuropeptides are ubiquitous signalling molecules in all metazoans possessing nervous systems, from the simple nerve nets of the cnidarians to the immensely complex systems of mammals. While the discipline of peptide neuroendocrinology was born through the study of higher vertebrates, there now exists a plethora of information regarding neuropeptides and peptidic regulatory factors in invertebrates. Such phylogenetic studies have revealed that peptidic neurotransmission is of early evolutionary origin and that, while invertebrates have nervous systems which are simpler in terms of nerve cell number and organisation when compared with vertebrates, the complexity of the peptidic ‘vocabulary’ of invertebrate neurones is of a similar order of magnitude. Most research on invertebrate neuropeptides has been directed towards representative members of groups such as the insects and molluscs and it is only in recent years that efforts have been focused on the helminths (platyhelminths and nematodes). Here, the putative origins of peptidic transmitters is discussed and the current state of knowledge on helminth neuropeptides is reviewed. In order to place the study of helminth neuropeptides in an historical and conceptual perspective, methodological development and conceptual modifications in the disciplines of vertebrate and higher invertebrate peptide neuroendocrinology have been summarised.

As the most primitive metazoan phylum, the Platyhelminthes occupies a unique position in nervous system evolution. Centrally, their nervous system consists of an archaic brain from which emanate one or more pairs of longitudinal nerve cords connected by commissures; peripherally, a diverse arrangement of nerve plexuses of varying complexity innervate the subsurface epithelial and muscle layers, and in the parasitic taxa they are most prominent in the musculature of the attachment organs and egg-forming apparatus. There is a range of neuronal-cell types, the majority being multi- and bipolar. The flatworm neuron is highly secretory and contains a heterogeneity of vesicular inclusions, dominated by densecored vesicles, whose contents may be released synaptically or by paracrine secretion for presumed delivery to target cells via the extracellular matrix. A wide range of sense organ types is present in flatworms, irrespective of life-styles. The repertoire of neuronal substances identified cytochemically includes all of the major candidate transmitters known in vertebrates. Two groups of native flatworm neuropeptides have been sequenced, neuropeptide F and FMRFamide-related peptides (FaRPs), and immunoreactivities for these have been localised in dense-cored neuronal vesicles in representatives of all major fiatworm groups. There is evidence of co-localisation of peptidergic and cholinergic elements; serotoninergic components generally occupy a separate set of neurons. The actions of neuronal substances in flatworms are largely undetermined, but FaRPs and 5-HT are known to be myoactive in all of the major groups, and there is immuno-cytochemical evidence that they have a role in the mechanism of egg assembly.

Our understanding of the neurobiology of the Platyhelminthes has come in large part from free-living turbellarians. In addition to providing considerable information about the capabilities of the rudimentary nervous system present in all members of the phylum, turbellarians have provided the most definitive information about the variety of ion channels present in the membranes of neurones and muscle cells, and about the physiology and pharmacology of those channels. Furthermore, preparations of single, viable muscle cells have provided some of the most conclusive evidence about the variety of transmitters present, and the types of response they evoke. Here, we review what is known about the physiology and pharmacology of the turbellarian neuromuscular system. Particular attention is given to the triclad flatworm Bdelloura Candida, the best studied species in this respect, but other species are included where relevant.

The trematode and cestode flatworms include numerous parasitic forms of major medical and economic importance. A better knowledge of the neuromuscular physiology of these animals could lead to development of new control measures against these parasites. Since these animals are near the stem from which all other animals have evolved, better knowledge of these animals could also yield valuable information about the early evolution of nerve and muscle systems in the animal kingdom. This review focuses on what is known about the characteristics of the somatic muscle in these animals. The anatomy of the muscles is described along with a review of current information about their electrophysiology, including descriptions of the ion channels present. Also included is a summary of recently acquired data concerning the nature of serotonin, peptide, acetylcholine and glutamate receptors on the membranes of the muscles.

Analysis of the electrical properties of neurons in the motornervous system of Ascaris suum suggests that it is largely an analogue system. The motorneurons do not conduct action potentials and they release transmitter tonically at their normal resting potential; transmitter release is increased or decreased as a continuous function of membrane potential. Despite extensive physiological descriptions of the electrical properties of the neurons and their synapses, as well as morphological descriptions of the synaptic circuitry of the system, the predicted activities of the neurons in the circuit differ from those observed by direct recording in semi-intact behaving animals. We conclude that the description of the circuit is incomplete. There are several possibilities for the missing elements, including chemical, proprioceptive, and additional neuronal components. Recently, attention has been focussed most heavily on the intercellular chemical signalling systems; in addition to those mediated by classical neurotransmitters, a surprisingly complex array of neuropeptides has been identified. One family of these peptides, the AF peptides, has been analyzed in detail. It comprises at least 20 peptides, and they fall into sequence-related subfamilies. One of these subfamilies, containing 6 peptides, is encoded by a single transcript, suggesting that the AF peptides are under multiple genetic control. All AF peptides tested have potent activity on the motornervous system and or on muscle. There are multiple physiological activities, and cellular localization studies show multiple patterns of cellular expression. Studies on Panagrellus and Caenorhabditis emphasize the diversity of this family and its genetic control.

The occurrence of classical neurotransmitter molecules and numerous peptidic messenger molecules in nematode nervous systems indicate that although structurally simple, nematode nervous systems are chemically complex. Thus far, studies on one nematode neuropeptide family, namely the FMRFamide-related peptides (FaRPs), have revealed an unexpected variety of neuropeptide structures in both free-living and parasitic species. To date 23 nematode FaRPs have been structurally characterized including 12 from Ascaris suum, 8 from Caenorhabditis elegans, 5 from Panagrellus redivivus and 1 from Haemonchus contortus. Ten FaRP-encoding genes have been identified in Caenorhabditis elegans. However, the full complement of nematode neuronal messengers has yet to be described and unidentified nematode FaRPs await detection. Preliminary characterization of the actions of nematode neuropeptides on the somatic musculature and neurones of A. suum has revealed that these peptidic messengers have potent and complex effects. Identified complexities include the biphasic effects of KNEFIRFamide/KHEYLRFamide (AF1/2; relaxation of tone followed by oscillatory contractile activity) and KPNFIRFamide (PF4; rapid relaxation of tone followed by an increase in tone), the diverse actions of KSAYMRFamide (AF8 or PF3; relaxes dorsal muscles and contracts ventral muscles) and the apparent coupling of the relaxatory effects of SDPNFLRFamide/SADPNFLRFamide (PF1/PF2) to nitric oxide release. Indeed, all of the nematode FaRPs which have been tested on somatic muscle strips of A. suum have actions which are clearly physiologically distinguishable. Although we are a very long way from understanding how the actions of these peptides are co-ordinated, not only with those of each other but also with those of the classical transmitter molecules, to control nematode behaviour, their abundance coupled with their diversity of structure and function indicates a hitherto unidentified sophistication to nematode neuromuscular intergration.

Three groups of anthelmintic drugs act directly and selectively on muscle membrane receptors of parasitic nematodes. These groups of anthelmintics are: (1) The Nicotinic Agonists(levamisole, pyrantel, morantel and oxantel) that act on acetylcholine receptors of nematode somatic muscle; (2) The GAB A Agonist, piperazine, that acts on nematode muscle GABA receptors; and (3) The Avermectins that open glutamate gated Cl- channels on nematode pharyngeal muscle. The electrophysiology and pharmacology of muscle and neuromuscular transmission the nematode parasite, Ascaris suum, is outlined and effects of anthelmintics that interfere with transmission described. Resistance to anthelmintics has appeared in some parasitic nematodes but the mechanisms of this resistance remain to be determined

The nematode nervous system employs many of the same neurotransmitters as are found in higher animals. The inactivation of neurotransmitters is absolutely essential for the correct functioning of the nervous system, In this article we discuss the various mechanisms used generally in animal nervous systems for synaptic inactivation of neurotransmitters and review the evidence for similar mechanisms operating in parasitic and free-living nematodes. The sequencing of the entire Caenorhabditis elegans genome means that the sequence of nematode genes can be accessed from the C. elegans database (ACeDB) and this wealth of information together with the increasing knowledge of the genetics of this free-living nematode will have great impact on all aspects of nematode neurobiology. The review will provide an insight into how this information may be exploited to identify and characterize target proteins for the development of novel anti-nematode drugs.

The free living nematode, C. elegans is understood at a level of detail equalled by few other organisms, and much of the cell biology and sequence information is proving of considerable utility in the study of parasitic nematodes. Already, C. elegans provides a convenient vehicle for investigating anthelmintic drug action and resistance mechanisms. Among the ionotropic receptors, with their important roles in the behaviour and development of the organism, are targets for anthelmintics. The subunits of nicotinic acetylcholine receptors of C. elegans form a large and diverse multigene family. Members of this family are among the 11 genes associated with resistance to the anthelmintic drug levamisole.

In this chapter we summarize the available data on a novel class of ligand-gated anion channels that are gated by the neurotransmitter glutamate. Glutamate is classically thought to be a stimulatory neurotransmitter, however, studies in invertebrates have proven that glutamate also functions as an inhibitory ligand. The bulk of studies conducted in vivo have been on insects and crustaceans, where glutamate was first postulated to act on H-receptors resulting in a hyperpolarizing response to glutamate. Recently, glutamate-gated chloride channels have been cloned from several nematodes and Drosophila. The pharmacology and electrophysiological properties of these channels have been studied by expression in Xenopus oocytes. Studies on the cloned channels demonstrate that the invertebrate glutamate-gated chloride channels are the H-receptors and represent important targets for the antiparasitic avermectins.

Anthelmintic resistance has compromised the control of nematode parasites in several animal-based industries. Studies of resistance have not only improved our understanding of this phenomenon but also shed light on physiological systems of parasitic helminths. In addition, research on molecular aspects of anthelmintic resistance may provide selectable markers for use in future transfection studies with helminths. Several anthelmintics act on helminth neuromuscular systems. Drugs such as levamisole are cholinergic agonists and, based on pharmacological studies, levamisole-resistant nematodes appear to have altered acetylcholine receptors. It is likely that anticholinesterase anthelmintics share cross resistance with levamisole. Ivermectin appears to be a glutamate agonist. In vitro studies of ivermectin-resistant nematodes suggest that IVM receptors are located on pharyngeal and somatic muscle. The free-living nematode Caenorhabditis elegans may provide a model for anthelmintic resistance. It has been useful in cloning drug receptors from parasites but differences between its life history and habitat compared with parasitic nematodes may limit its usefulness for studying resistance in these parasites.

Rational approaches to anthelmintic discovery include the design of screens for compounds directed at specific proteins in helminths that are pharmacologically distinguishable from their vertebrate homologues. The existence of several anthelmintics that selectively target the neuromusculature of helminths (e.g. levamisole, ivermectin, praziquantel, metrifonate), together with recent basic research in helminth physiology, have contributed to the recognition that neurobiology distinguishes these organisms from their vertebrate hosts. In this survey, we focus on mechanism-based screening and its application to anthelmintic discovery, with particular emphasis on targets in the neuromusculature of helminths. Few of these proteins have been exploited in chemotherapy. However, recent studies in comparative pharmacology and molecular biology, including the C. elegans genome project, have provided insights on potential new targets and, in some cases, molecular probes useful for their incorporation in mechanism-based screens.