[Neuromodulators in otorhinolaryngology].
We comment on basic principles on neuromodulators and some aspects dealing with the new information that these substances may bring to the knowledge of neurobiology in ENT.
Amino Acid Sequence↗
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[Neuromediators and neuromodulators. Evolution of compounds and the evolution of hypotheses].
Probable peculiarities of evolution of neurotransmitters (NM) and neuromodulators (NR) of various types are discussed. The hypothesis of higher evolutionary rate of peptide NM and NR, and of more diverse possibilities of the formation of this type of NM and NR is suggested. Monomolecular MN and NR are presumably more conservative, although they exhibit some advantage with respect to strict differentiation of the systems of synthesis and degradation. Probably, the most ancient NM and NR are presented by such compounds as peptides, some amino acids, and ATP.
Adenosine Triphosphate↗
[Endorphins: neuromodulators and hormones (author's transl)].
The discovery of opiate receptors has resulted in the isolation of endogenous morphinomimetics called endorphins. The enkephalins, which are pentapeptides, are located diffusely within the brain and are thought to act locally as neuromodulators for the release of noradrenaline, dopamine and substance P. beta-endorphin, a peptide with 31 aminoacids, is released from the pituitary with ACTH during stress. The peptide sequency of the common precursor of these hormones, pro-opiocortin, is now established.
Brain↗
The neuromodulation aspects of ischaemic myocardium: the importance of cholinergic system.
The ability of the heart to increase contractility and heart rate is facilitated by postganglionic sympathetic nerve endings that terminate within myocardium. In fact, the heart is often regarded as an "adrenergic" organ because beta-adrenergic agonists are powerful stimulants of cardiac contractility. Muscarinic cholinergic receptors mediate parasympathetic control of heart function. A primary effects of the muscarinic stimulation are opposite to those of beta-adrenergic stimulation. The modulation of an adrenergic receptors stimulation in the heart by cholinergic agonists may be the major means by which the muscarinic agonists alter heart function. When the hypoxic myocytes were exposed to adrenaline, the responsiveness of the cardiac cells to muscarinic stimuli had significantly increased, and a simultaneous potent increase in the expression of muscarinic receptors was observed. These result support the hypothesis that in ischaemic/hypoxic myocardium the role of cholinergic system may be more important than previously assumed. In this review an attempt was made to summarize the physiological and biochemical interactions in an autonomic nervous system in an ischaemic myocardium. The evidences of a relationship between ischaemia and inflammation are discussed. The better knowledge of feasible interactions of neuromodulators of an autonomic nervous system with myocardial and inflammatory cells, should lead to the development of successful pharmacological strategies for the prevention of ischaemic injury.
Animals↗
[Vasopressin as a neurotransmitter and neuromodulator].
Recent data about the antidiuretic hormone arginine vasopressin (AVP) are reviewed which show that except its well known peripheral endocrine functions, it has another not less important function as a neurotransmitter and neuromodulator in the central nervous system. AVP facilitates learning and memory consolidation. Data are also presented about the primary structure of AVP precursor and the sites of its synthesis, as well as about the AVP receptors and the mechanism of its action in different brain areas. Data are given about the ways of inactivation of its second messengers inositol-1,4,5-triphosphate and diacylglycerol. There are also data about AVP antipyretic effect in septum. A hypothesis is presented that the action of some nonsteroid antipyretic substances is mediated through V1-receptors of AVP in septum.
Animals↗
Photomechanical movements of cultured embryonic photoreceptors: regulation by exogenous neuromodulators and by a regulable source of endogenous dopamine.
In the retina of nonmammalian vertebrates, light regulates photoreceptor morphology by causing rod photoreceptor elongation and cone photoreceptor contraction. The opposite photomechanical movements occur in the dark, and proceed with a circadian rhythm in many species in vivo. Using dissociated cultures of embryonic chick retina cells, we have recently demonstrated that photoreceptor cells that differentiate in vitro acquire the capacity of responding to light/dark cycles with photomechanical movements (Stenkamp and Adler, 1993). Here we report that the putative neuromodulators melatonin and dopamine can mimic the effects of darkness and light, respectively, on in vitro photomechanical movement. Pharmacological studies showed that dopamine appears to function by means of a D2-type receptor negatively coupled to adenylate cyclase. The effects of light on the cultured photoreceptors were inhibited by dopamine D2 receptor antagonists, and were attenuated by the dopaminergic neurotoxin 6-hydroxydopamine and by the dopamine synthesis inhibitor alpha-methyl-p-tyrosine. The possible existence of an endogenous source of dopamine in the cultures was also suggested by the presence of tyrosine hydroxylase-like immunoreactivity, and of an Na(+)-dependent mechanism for the accumulation of 3H-dopamine, which was predominantly associated with nonphotoreceptor cells. Additionally, 3H-dopamine release occurred in vitro through a Ca(2+)-dependent mechanism, as well as through reverse function of a nomifensine-sensitive dopamine transporter. Both of these putative release mechanisms appeared to be regulated by light and by melatonin, suggesting a mechanism whereby the putative dopaminergic cells may interact with other cells present in the cultures. These studies suggest that complex paracrine neuromodulatory mechanisms can differentiate in low-density embryonic cell culture, that dopaminergic activities exist in vitro, and that they are important for mediating photomechanical movements.
Animals↗
The possible role of hydrogen sulfide as an endogenous neuromodulator.
Hydrogen sulfide (H2S), which is well known as a toxic gas, is produced endogenously from L-cysteine in mammalian tissues. H2S is present at relatively high levels in the brain, suggesting that it has a physiological function. Two other gases, nitric oxide and carbon monoxide, are also endogenously produced and have been proposed as neuronal messengers in the brain. In this work we show the following: (1) an H2S-producing enzyme, cystathionine beta-synthase (CBS), is highly expressed in the hippocampus; (2) CBS inhibitors hydroxylamine and amino-oxyacetate suppress the production of brain H2S; and (3) a CBS activator, S-adenosyl-L-methionine, enhances H2S production, indicating that CBS contributes to the production of endogenous H2S. We also show that physiological concentrations of H2S selectively enhance NMDA receptor-mediated responses and facilitate the induction of hippocampal long-term potentiation. These observations suggest that endogenous H2S functions as a neuromodulator in the brain.
Aminooxyacetic Acid↗
[Neuromodulation of synaptic transmission with thymopentin].
The effect of thymopentin (TP-5; 1 x 10(-5) and 1 x 10(-4) M), the active center of the thymic hormone thymopoietin was examined upon spontaneous and induced neuromuscular synaptic activity (N-MS) in the isolated diaphragm of Wistar-strain rat. Standard electrophysiological method of intracellular registration was used. Analysis of original experimental microphysiologic results revealed clear depressant neuromodulative effect of TP-5 upon skeletal N-MS in vitro. Effect of TP-5 is expressed in decreased amount of the released median quantal value of neurotransmitter acetylcholine at orthodromic stimulation of the alpha-motor nerve. TP-5 also reduces chemiosensitivity of postsynaptic nicotinic acetylcholine receptors.
Adjuvants, Immunologic↗
Noradrenaline and ATP: cotransmitters and neuromodulators.
Adenosine 5'-triphosphate (ATP) is a cotransmitter with noradrenaline (NA) in sympathetic nerves supplying the vas deferens and a number of blood vessels. ATP is responsible for the excitatory junctional potentials (EJPs) in response to single nerve impulses and the initial twitch responses of the smooth muscle, while NA produces the longer-lasting tonic contractions. The proportions of ATP to NA vary between different sympathetic nerves; they also change during development and in some pathological conditions, including hypertension. Prejunctional neuromodulation of release of the two cotransmitters appears to involve independent mechanisms and is frequency dependent; this raises the question of whether ATP and NA are stored in separate vesicles or whether there are subpopulations of sympathetic nerves with a predominance of ATP or NA. ATP and NA have synergistic postjunctional actions, whether excitatory (as in the vas deferens and most blood vessels) or inhibitory (as in rabbit coronary vessels). It is suggested that use of the term 'adrenergic nerves' as a synonym for sympathetic nerves is no longer appropriate, although 'adrenergic transmission' or 'purinergic transmission' are still useful terms.
Adenosine Triphosphate↗
Modifications by superoxide-generating agent, neurotransmitters and neuromodulators of nitroxidergic nerve function in monkey cerebral arteries.
Isolated monkey cerebral arteries denuded of the endothelium responded to transmural electrical stimulation (5 Hz for 40 sec) with relaxations that are mediated by nitric oxide (NO) synthesized from L-arginine. The relaxant response was slightly inhibited by duroquinone, a superoxide anion-generating agent. The agent markedly inhibited the response after treatment with diethylthiocarbamic acid, an inhibitor of copper/zinc superoxide dismutase. The inhibition was partially reversed by superoxide dismutase. The neurogenic relaxation was reduced by acetylcholine acting on prejunctional muscarinic receptors. Neuropeptide Y, morphine, ATP, clonidine and pituitary adenylate cyclase-activating polypeptide did not change the response to nerve stimulation. Sodium nitroprusside in a dose sufficient to produce relaxation attenuated the neurogenic response. It is concluded that the neurotransmitter liberated from vasodilator nerves in monkey cerebral arteries is free NO rather than a stable analog of NO, like S-nitrosocysteine. Substances other than acetylcholine released as neuromodulators do not seem to regulate the NO-mediated nerve function.
Animals↗
Protirelin (TRH): a potent neuromodulator with therapeutic potential.
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Humans↗
M-channels: neurological diseases, neuromodulation, and drug development.
Efforts in basic neuroscience and studies of rare hereditary neurological diseases are partly motivated by the hope that such work can lead to better understanding of and treatments for the common neurological disorders. An example is the progress that has resulted from identification of the genes that cause benign familial neonatal convulsions (BFNCs). Benign familial neonatal convulsions is a rare idiopathic, generalized epilepsy syndrome. In 1998, geneticists discovered that BFNC is caused by mutations in a novel potassium channel subunit, KCNQ2. Further work quickly revealed the sequences of 3 related brain channel genes KCNQ3, KCNQ4, and KCNQ5. Mutations in 2 of these genes were shown to cause BFNC (KCNQ3) and hereditary deafness (KCNQ4). Physiologists soon discovered that the KCNQ genes encoded subunits of the M-channel, a widely expressed potassium channel that mediates effects of modulatory neurotransmitters and controls repetitive neuronal discharges. Finally, pharmacologists discovered that the biological activities of 3 classes of compounds in development as treatments for Alzheimer disease, epilepsy, and stroke were mediated in part by effects on brain KCNQ channels. Cloned human KCNQ channels can now be used for high-throughput screening of additional drug candidates. Ongoing studies in humans and animal models will refine our understanding of KCNQ channel function and may reveal additional targets for therapeutic manipulation.
Epilepsy, Benign Neonatal↗
Dissociation between sensitization and learning-related neuromodulation in an aplysiid species.
Previous phylogenetic analyses of learning and memory in an opisthobranch lineage uncovered a correlation between two learning-related neuromodulatory traits and their associated behavioral phenotypes. In particular, serotonin-induced increases in sensory neuron spike duration and excitability, which are thought to underlie several facilitatory forms of learning in Aplysia, appear to have been lost over the course of evolution in a distantly related aplysiid, Dolabrifera dolabrifera. This deficit is paralleled by a behavioral deficit: individuals of Dolabrifera do not express generalized sensitization (reflex enhancement of an unhabituated response after a noxious stimulus is applied outside of the reflex receptive field) or dishabituation (reflex enhancement of a habituated reflex). The goal of the present study was to confirm and extend this correlation by testing for the neuromodulatory traits and generalized sensitization in an additional species, Phyllaplysia taylori, which is closely related to Dolabrifera. Instead, our results indicated a lack of correlation between the neuromodulatory and behavioral phenotypes. In particular, sensory neuron homologues in Phyllaplysia showed the ancestral neuromodulatory phenotype typified by Aplysia. Bath-applied 10 microM serotonin significantly increased homologue spike duration and excitability. However, when trained with the identical apparatus and protocols that produced generalized sensitization in Aplysia, individuals of Phyllaplysia showed no evidence of sensitization. Thus, this species expresses the neuromodulatory phenotype of its ancestors while appearing to express the behavioral phenotype of its near relative. These results suggests that generalized sensitization can be lost during the course of evolution in the absence of a deficit in these two neuromodulatory traits, and raises the possibility that the two traits may support some other form of behavioral plasticity in Phyllaplysia. The results also raise the question of the mechanistic basis of the behavioral deficit in Phyllaplysia.
Action Potentials↗
Localization, regulation and functions of neurotransmitters and neuromodulators in cervical sympathetic ganglia.
Cervical sympathetic ganglia represent a suitable model for studying the establishment and plasticity of neurochemical organization in the nervous system since sympathetic postganglionic neurons: (1) express several neuromediators, i.e., short acting transmitters, neuropeptide modulators and radicals, in different combinations; (2) receive synaptic input from a limited number of morphologically and neurochemically well-defined neuron populations in the central and peripheral nervous systems (anterograde influence on phenotype); (3) can be classified morphologically and neurochemically by the target they innervate (retrograde influence on phenotype); (4) regenerate readily, making it possible to study changes in neuromediator content after axonal lesion and their possible influence on peripheral nerve regeneration; (5) can be maintained in vitro in order to investigate effects of soluble factors as well as of membrane bound molecules on neuromediator expression; and (6) are easily accessible. Acetylcholine and noradrenaline, as well as neuropeptides and the recently discovered radical, nitric oxide, are discussed with respect to their localization and possible functions in the mammalian superior cervical and cervicothoracic (stellate) paravertebral ganglia. Furthermore, mechanisms regulating transmitter synthesis in sympathetic neurons in vivo and in vitro, such as soluble factors, cell contact or electrical activity, are summarized, since modulation of transmitter synthesis, release and metabolism plays a key role in the neuronal response to environmental influences.
Acetylcholine↗
Adenosine receptors in brain: neuromodulation and role in epilepsy.
Adenosine is now recognized as an important endogenous modulator of neuronal excitability in the mammalian central nervous system. Adenosine is produced and released in the brain, where it exerts potent depressant effects on neuronal firing and synaptic transmission. Multiple adenosine receptor subtypes have been characterized using biochemical, electrophysiological, and radioligand binding techniques. Adenosine analogues have potent anticonvulsant actions in vitro and antagonize seizures in animals induced by a variety of mechanisms, including kindling. The future development of selective adenosine receptor agonists may provide new and more effective treatment for epilepsy.
Adenosine↗
Localization of the three GnRH types and GnRH receptors in the brain of a cichlid fish: Insights into their neuroendocrine and neuromodulator functions.
The cognate receptor for any of the known gonadotropin-releasing hormones (GnRHs) has not been directly demonstrated. In order to establish this and shed light on the functions of GnRH types, we analyzed the neuroanatomical location and time of initial expression of three distinct GnRH receptors (GnRH-Rs) and the three endogenous GnRHs in the brain of developing and sexually mature tilapia Oreochromis niloticus using immunocytochemistry. In all age groups, including males and females, GnRH-RIA was seen specifically in gonadotropes (Parhar et al. [2002] J Neuroendocrinol 14:657-665) but was undetectable in the brain. On day 8 after fertilization, GnRH-RIB was first seen in the periventricular hypothalamus (lateral recess nucleus, posterior recess nucleus, posterior tuberal nucleus) and GnRH-RIII in the olfactory epithelium, olfactory bulb, telencephalon, preoptic region, mediobasal hypothalamus, thalamus, mesencephalon, and in the hindbrain. Double-label immunocytochemistry showed GnRH1 (Ser(8) GnRH)-immunoreactive neuronal processes projecting mainly to the proximal pars distalis of the pituitary, while GnRH2 (His(5), Trp(7), Tyr(8) GnRH) and GnRH3 (Trp(7), Leu(8) GnRH) fibers were observed in close association with cells containing GnRH-RIB and GnRH-RIII in the brain. These results suggest that GnRH-RIA might be hypophysiotropic in nature, whereas GnRH-RIB and GnRH-RIII could have additional neuromodulatory functions. Further, evidence of close proximity of GnRH-R-containing cells and neuronal processes of multiple GnRH types suggests complex cross-talk between several GnRH ligands and GnRH-Rs.
Animals↗
Neuromodulation of arthropod mechanosensory neurons.
Arthropod mechanosensory afferents have long been known to receive efferent synaptic connections onto their centrally located axon terminals. These connections cause presynaptic inhibition by attenuating the action potentials arriving at the axon terminals, thus reducing the synaptic potentials in the postsynaptic neurons. This type of inhibition can specifically reduce the excitation of selected postsynaptic neurons while leaving others unaffected. However, recent research has demonstrated that sensory signals detected by arthropod mechanosensory neurons can also be synaptically modulated before they ever arrive at the axon terminals. In arachnids and crustaceans, wide and complex networks of synapses on all parts of the afferent neurons, including the somata and dendrites, provide mechanisms to inhibit or enhance the responses to mechanical stimuli as they are being detected. This modulation will affect the signal transmission to all axonal branches and postsynaptic cells of the affected receptor neuron. In addition to the increased complexity of mechanosensory information transmission produced by these synapses, a variety of circulating neuroactive substances also modulate these neurons by acting on their postsynaptic receptors.
Animals↗
Concepts of neuromodulation.
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Electric Stimulation Therapy↗