Role Of Presynaptic Receptors Research Articles

Role of Presynaptic Glutamate Receptors in Pain Transmission at the Spinal Cord Level

Nociceptive primary afferents release glutamate, activating postsynaptic glutamate receptors on spinal cord dorsal horn neurons. Glutamate receptors, both ionotropic and metabotropic, are also expressed on presynaptic terminals, where they regulate neurotransmitter release. During the last two decades, a wide number of studies have characterized the properties of presynaptic glutamatergic receptors, particularly those expressed on primary afferent fibers. This review describes the subunit composition, distribution and function of presynaptic glutamate ionotropic (AMPA, NMDA, kainate) and metabotropic receptors expressed in rodent spinal cord dorsal horn. The role of presynaptic receptors in modulating nociceptive information in experimental models of acute and chronic pain will be also discussed.

Role of Presynaptic Glutamate Receptors in Pain Transmission at the Spinal Cord Level

Nociceptive primary afferents release glutamate, activating postsynaptic glutamate receptors on spinal cord dorsal horn neurons. Glutamate receptors, both ionotropic and metabotropic, are also expressed on presynaptic terminals, where they regulate neurotransmitter release. During the last two decades, a wide number of studies have characterized the properties of presynaptic glutamatergic receptors, particularly those expressed on primary afferent fibers. This review describes the subunit composition, distribution and function of presynaptic glutamate ionotropic (AMPA, NMDA, kainate) and metabotropic receptors expressed in rodent spinal cord dorsal horn. The role of presynaptic receptors in modulating nociceptive information in experimental models of acute and chronic pain will be also discussed.

Presynaptic receptors regulating the time course of neurotransmitter release from vertebrate nerve endings

A number of different types of presynaptic receptors was revealed in central and peripheral chemical synapses activated both by main mediator and co-mediators released simultaneously. Physiological significance and mechanisms of functioning of these receptors are not clear yet. They are assumed to provide negative or positive feedback decreasing or increasing the number of neurotransmitter quanta released in response to nerve impulse and thus regulating synaptic transmission. At the same time, there is one more way of secretion process modulation associated with the changes of timing of transmitter release. This mechanism was shown to contribute to the efficiency of synaptic transmission. The role of presynaptic receptors in regulation of the kinetics of quanta release is one of the interesting questions of modern neurophysiology. This paper overviews the results obtained by the authors that demonstrate the contribution of presynaptic receptors of different types into the regulation of temporal parameters of quantal secretion at the vertebrates neuromuscular junction. It was shown that activation of the cholinergic nicotinic receptors leads to a decrease of the amplitude of postsynaptic response not only due to reduction of the quantity of released quanta but also due to increased the level of asynchronous release. On the contrary, the facilitating effect of catecholamines on the neuromuscular synapse is the result of activation of presynaptic β1-adrenoreceptors which leads to greater synchronization of release process and, consequently, to the increase of the amplitude of the postsynaptic response. Presynaptic purine receptors, involved in the modulation the intensity of secretion, are also capable of alteration of the time course of secretion. Activation of ryanodine receptors results in the increase of the number of quanta released with prolonged latencies leading to appearance of the phase of delayed asynchronous neurotransmitter release.

Regulation of vesicle traffic and neurotransmitter release in isolated nerve terminals.

In this overview current insights in the regulation of presynaptic transmitter release, mainly acquired in studies using isolated CNS nerve terminals are highlighted. The following aspects are described. (i) The usefulness of pinched-off nerve terminals, so-called synaptosomes, for biochemical and ultrastructural studies of presynaptic stimulus-secretion coupling. (ii) The regulation of neurotransmitter release by multiple Ca2+ channels, with special emphasis on the specificity of different classes of these channels with respect to the release of distinct types of neurotransmitters, that are often co-localized, such as amino acids and neuropeptides. (iii) Possible molecular mechanisms involved in targeting synaptic vesicle (SV) traffic toward the active zone. (iv) The role of presynaptic receptors in regulating transmitter release, with special emphasis on different glutamate subtype receptors. Isolated nerve terminals are of great value as model system in order to obtain a better understanding of the regulation of the release of distinct classes of neurotransmitters in tiny CNS nerve endings.

Adrenergic mechanisms of regulation of the various stages of chemical carcinogenesis: Role of presynaptic receptors

Adrenergic mechanisms of regulation of the various stages of chemical carcinogenesis: Role of presynaptic receptors

Selected Aspects of Presynaptic Modulation of Noradrenaline Release from the Heart

This article presents selected aspects of the presynaptic modulation of noradrenaline release from the heart. Several presynaptic effector systems that mediate either inhibition or facilitation of noradrenaline release are discussed. In particular, the potencies of muscarinic agonists and antimuscarinic drugs in muscarine receptor-mediated inhibition are reviewed. Evidence is presented that presynaptic inhibitory muscarine receptors can apparently not be differentiated from postsynaptic muscarine receptors in the heart. Presynaptic inhibitory alpha-adrenoceptors belong to the alpha 2 subtype. The physiological role of autoinhibition by the endogenous transmitter in the heart is discussed in relation to the influence that important clearance mechanisms have to reduce the concentration of noradrenaline in the synaptic cleft under physiological conditions. Inhibitory presynaptic dopamine receptors differ from postsynaptic receptors, but evidence of a physiological role for presynaptic receptors is lacking. The significance of transsynaptic modulation of noradrenaline release from the heart by prostaglandins and adenosine is briefly discussed. Opioid receptors appear to inhibit noradrenaline release in the heart to some extent. Finally, several other receptor systems, possibly involved in the regulation of transmitter release from sympathetic nerves in the heart, are mentioned.

Presynaptic dopamine receptors and α-adrenoceptors as mediators of the bradycardic action of N-n-propyl-N-n-butyl dopamine

The role of presynaptic receptors in then bradycardic action of N-n-propyl-N-n-butyl dopamine (PBDA) was investigated. A biphasic effect on blood pressure and a decrease in heart rate were seen upon intravenous administration of PBDA to pentobarbital-anesthetized dogs. The bradycardia produced by PBDA was unaffected by bilateral vagotomy; however, it was abolished by cardic sympathetic denervation. When PBDA was readministered following restoration of the cardiac sympathetic nerve activity by electrical stimulation, at frequency of 1 Hz, decrease in heart rate was again observed. The cardioinhibitory action of PBDA was completely abolished by sulpiride, whereas phentolamine and yohimbine caused only partial attenuation, suggesting the involvement of both presynaptic α-adrenoceptors as well as dopamine receptors in the bradycardiac action of PBDA. Additional experiments were performed tol study the influence of stimulus frequency on the cardioinhibition produced by PBDA. Administration of PBDA to animals with different levels of cardiac sympathetic nerve activity (0.25–2 Hz) resulted in decreases in heart rate. However, yohimbine antagonized this action of PBDA only at the two higher frequencies of cardiac nerve stimulation. Sulpiride completely abolished the bradycardia observed at all the different frequencies of cardiac nerve stimulation. These results demonstrate that activation of presynaptic receptors on cardiac sympathetic nerves can result in a decrease in heart rate. PBDA causes by bradycardia via an action on presynaptic dopamine receptors when the cardiac sympathetic nerve activity is low, while presynaptic dopamine receptors as well as α-adrenoceptors are involved in the decrease in heart rate produced by this compound at higher levels of sympathetic nerve activity.

The role of presynaptic receptors in the cardiovascular actions of N,N-di-n-propyldopamine in the cat and dog.

Intravenous administration of N,N-di-n-propyldopamine (DPDA: 50 and 200 micrograms/kg/min, i.v.) produces hypotensive and bradycardic effects in anaesthetized cats and dogs. These effects were abolished by ganglionic blockade and antagonized by haloperidol or (SR)-sulpiride suggesting a neurogenic mechanism of action, mediated by specific dopamine receptors. The renal blood flow increases to DPDA in dogs were resistant to ganglionic blockade indicating some activity at postsynaptic vascular dopamine receptors. Studies with DPDA in vivo administered via the intravertebral and intravenous routes suggested a peripheral site of action for the hypotensive effects of this compound. In vitro, in isolated perfused cat spleens prelabeled with 3H-noradrenaline, DPDA (0.01--1 microM) produced a concentration-dependent inhibition of tritium release elicited by nerve stimulation at 1 Hz which was selectively antagonized by 1 microM (SR)-sulpiride implicating presynaptic inhibitory dopamine receptors in the mediation of this effect. In isolated rabbit splenic arteries, contracted by prostaglandin-F2 alpha, dopamine,ADTN (2-amino-6,7-dihydroxytetrahydronaphthalene) and apomorphine produced concentration-dependent relaxations while DPDA exhibited only weak postsynaptic dopamine-like effects. In vivo DPDA reduced, in a frequency dependent manner, the end organ responses to sympathetic nerve stimulation in the cat nictitating membrane and in the dog renal vascular bed. Both effects were mediated through activation of presynaptic inhibitory dopamine receptors by DPDA. In conclusion these results suggest a predominantly presynaptic agonist effect for DPDA in vitro and a similarly important action in vivo, mediated mainly via dopamine receptors. Furthermore evidence is presented which suggests that pre- and postsynaptic dopamine receptors may differ in their pharmacological properties and that presynaptic dopamine receptors could be important target receptors in the development of novel antihypertensive drugs.

The role of presynaptic receptors in the release and synthesis of 3H-dopamine by slices of rat striatum

Striatal slices were continuously superfused with L-3,5-(3)H-tyrosine (50 muCi/ml) and 4H-H2O [index of 3H-dopamine (3H-DA) synthesis] and 3H-DA estimated in 0.5 ml (2.5 min) superfusate fractions. Depolarization with 50 mM K+ for 7.5 min induced a marked increase in 3H-DA release and a biphasic effect on synthesis (slight increase in the first fraction followed by a significant decrease in the third and fourth fractions). The decrease in the rate of 4H-H2O formation induced by K+ was not related to modifications of the specific activity of tyrosine in tissues. The possibility that the inhibition of synthesis was due to alterations in DA concentration in the synaptic cleft was examined. Benztropine in a concentration which produced inhibition of DA uptake (10(-6) M) increased the K+ induced overflow of 3H-DA but failed to alter the inhibition of synthesis. On the other hand, when the powerful neuroleptic fluphenazine was added to the superfusion medium in a concentration which only weakly blocked 3H-DA uptake (10(-6) M) it potentiated 3H-DA release and prevented the inhibition of synthesis both in the absence or presence of benztropine. A similar effect was seen following the in vivo treatment of rats with fluphenazine (2 mg/kg; 1 1/2 h before sacrifice). The addition of exogenous DA (0.6 X 10(-6) M) or NA (10(-6) M) to the superfusion medium increased 3H-DA outflow and reduced DA synthesis while isoproterenol (10(-6) M) was without effect. The DA inhibitory effect on synthesis was still observed in the presence of benztropine (10(-6) M) while the NA effect was prevented. This concentration of benztropine blocked both DA and NA uptake. The administration of fluphenazine (10(-6) M) significantly prevented the decrease in 3H-DA synthesis induced by exogenous DA and partially prevented the effect of NA. In addition, the effect of exogenous DA on the inhibition of synthesis was still seen in the presence of 2-amino-4-hydroxy-6,7-dimethyl-5,6,-7,8-tetrahydropteridine hydrochloride (DMPH4) (to protect against end-product inhibition). The present results provide direct support for the concept that activation of presynaptic DA receptors located on DA terminals in the striatum of the rat results in an inhibition of synthesis and release of the transmitter.