Presynaptic inhibition of segmental interneurons

In experiments on spinal cats changes in the second negative postsynaptic component (N₂) of the dorsal surface potential (DSP) of the spinal cord recorded in the region of segment L7 was used as the index of inhibition of segmental dorsal horn interneurons. Conditioning and testing stimuli were applied at increasing time intervals to the popliteal and superficial peroneal nerves respectively. Changes in the N₂ component were compared with changes in the N₁ component of the DSP, reflecting mainly activity of nonsegmental ascending dorsal horn interneurons. After an initial short facilitation a conditioning volley of pulses evokes prolonged (over 500 msec) inhibition of the N₂ component, characterized by the presence of two maxima (on the average at the 16th and 80th milliseconds) which indicate that two systems with different latent periods play a role in this inhibition. In its shape and temporal characteristics the curve of inhibition of the N₂ component corresponds to the two-component dorsal root potential (DRP) recorded in spinal animals in response to stimulation of flexor afferents (FRA) [8, 19]. Together with other features, this similarity is evidence of the presynaptic nature of this inhibition. Intravenous injection of hexobarbital has a stronger action on inhibition of the N₂ component, leading to a marked increase in its depth and duration. Suggestions are made regarding the functional organization of systems responsible for presynaptic inhibition of segmental dorsal horn interneurons.Deceased.Dnepropetrovsk State University. Translated from Neirofiziolgiya, Vol. 4, No. 1, pp. 75–82, January–February, 1972.     

Beating irregularity of single pacemaker cells isolated from the rabbit sinoatrial node.

Single pacemaker heart cells discharge irregularly. Data on fluctuations in interbeat interval of single pacemaker cells isolated from the rabbit sinoatrial node are presented. The coefficient of variation of the interbeat interval is quite small, approximately 2%, even though the coefficient of variation of diastolic depolarization rate is approximately 15%. It has been hypothesized that random fluctuations in interbeat interval arise from the stochastic behavior of the membrane ionic channels. To test this hypothesis, we constructed a single channel model of a single pacemaker cell isolated from the rabbit sinoatrial node, i.e., a model into which the stochastic open-close kinetics of the individual membrane ionic channels are incorporated. Single channel conductances as well as single channel open and closed lifetimes are based on experimental data from whole cell and single channel experiments that have been published in the past decade. Fluctuations in action potential parameters of the model cell are compared with those observed experimentally. It is concluded that fluctuations in interbeat interval of single sinoatrial node pacemaker cells indeed are due to the stochastic open-close kinetics of the membrane ionic channels.     

Presynaptic inhibition and antidromic discharges in crayfish primary afferents.

The mechanisms of presynaptic inhibition have been studied in sensory afferents of a stretch receptor in an in vitro preparation of the crayfish. Axon terminals of these sensory afferents display primary afferent depolarisations (PADs) mediated by the activation of GABA receptors that open chloride channels. Intracellular labeling of sensory axons by Lucifer yellow combined with GABA immunohistochemistry revealed the presence of close appositions between GABA-immunoreactive boutons and sensory axons close to their first branching point within the ganglion. Electrophysiological studies showed that GABA inputs mediating PADs appear to occur around the first axonal branching point, which corresponds to the area of transition between active and passive propagation of spikes. Moreover, this study demonstrated that whilst shunting appeared to be the sole mechanism involved during small amplitude PADs, sodium channel inactivation occurred with larger amplitude PADs. However, when the largest PADs (>25 mV) are produced, the threshold for spike generation is reached and antidromic action potentials are elicited. The mechanisms involved in the initiation of antidromic discharges were analyzed by combining electrophysiological and simulation studies. Three mechanisms act together to ensure that PAD-mediated spikes are not conveyed distally: 1) the lack of active propagation in distal regions of the sensory axons; 2) the inactivation of the sodium channels around the site where PADs are produced; and 3) a massive shunting through the opening of chloride channels associated with the activation of GABA receptors. The centrally generated spikes are, however, conveyed antidromically in the sensory nerve up to the proprioceptive organ, where they inhibit the activity of the sensory neurons for several hundreds of milliseconds.     

Presynaptic inhibition of nociceptive neurotransmission by somatosensory neuron-secreted suppressors

Noxious stimuli cause pain by activating cutaneous nociceptors.The Aδ-and C-fibers of dorsal root ganglion(DRG) neurons convey the nociceptive signals to the laminae Ⅰ—Ⅱ of spinal cord.In the dorsal horn of spinal cord,the excitatory afferent synaptic transmission is regulated by the inhibitory neurotransmitter γ-aminobutyric acid and modulators such as opioid peptides released from the spinal interneurons,and by serotonin,norepinepherine and dopamine from the descending inhibitory system.In contrast to the accumulated evidence for these central inhibitors and their neural circuits in the dorsal spinal cord,the knowledge about the endogenous suppressive mechanisms in nociceptive DRG neurons remains very limited.In this review,we summarize our recent findings of the presynaptic suppressive mechanisms in nociceptive neurons,the BNP/NPR-A/PKG/BK_(Ca) channel pathway,the FSTL1/α1Na~+-K~+ ATPase pathway and the activin C/ERK pathway.These endogenous suppressive systems in the mechanoheat nociceptors may also contribute differentially to the mechanisms of nerve injury-induced neuropathic pain or inflammation-induced pain.     

Presynaptic actions of endocannabinoids mediate alpha-MSH-induced inhibition of oxytocin cells

We recently showed that central injections of alpha-melanocyte-stimulating hormone (alpha-MSH) inhibits oxytocin cells and reduces peripheral release of oxytocin, but induces oxytocin release from dendrites. Dendritic oxytocin release can be triggered by agents that mobilize intracellular calcium. Oxytocin, like alpha-MSH, mobilizes intracellular calcium stores in oxytocin cells and triggers presynaptic inhibition of afferent inputs that is mediated by cannabinoids. We hypothesized that this mechanism might underlie the inhibitory effects of alpha-MSH. To test this, we recorded extracellularly from identified oxytocin and vasopressin cells in the anesthetized rat supraoptic nucleus (SON). Retrodialysis of a CB1 cannabinoid receptor antagonist to the SON blocked the inhibitory effects of intracerebroventricular injections of alpha-MSH on the spontaneous activity of oxytocin cells. We then monitored synaptically mediated responses of SON cells to stimulation of the organum vasculosum of the lamina terminalis (OVLT); this evoked a mixed response comprising an inhibitory component mediated by GABA and an excitatory component mediated by glutamate, as identified by the effects of bicuculline and 6-cyano-7-nitroquinoxaline-2,3-dione applied to the SON by retrodialysis. Application of CB1 receptor agonists to the SON attenuated the excitatory effects of OVLT stimulation in both oxytocin and vasopressin cells, whereas alpha-MSH attenuated the responses of oxytocin cells only. Thus alpha-MSH can act as a "switch"; it triggers oxytocin release centrally, but at the same time through initiating endocannabinoid production in oxytocin cells inhibits their electrical activity and hence, peripheral secretion.     

Presynaptic inhibition of transmitter release from rat sympathetic neurons by bradykinin

Bradykinin is known to stimulate neurons in rat sympathetic ganglia and to enhance transmitter release from their axons by interfering with the autoinhibitory feedback, actions that involve protein kinase C. Here, bradykinin caused a transient increase in the release of previously incorporated [3H] noradrenaline from primary cultures of dissociated rat sympathetic neurons. When this effect was abolished by tetrodotoxin, bradykinin caused an inhibition of tritium overflow triggered by depolarizing K+ concentrations. This inhibition was additive to that caused by the alpha2-adrenergic agonist UK 14304, desensitized within 12 min, was insensitive to pertussis toxin, and was enhanced when protein kinase C was inactivated. The effect was half maximal at 4 nm and antagonized competitively by the B2 receptor antagonist Hoe 140. The cyclooxygenase inhibitor indomethacin and the angiotensin converting enzyme inhibitor captopril did not alter the inhibition by bradykinin. The M-type K+ channel opener retigabine attenuated the secretagogue action of bradykinin, but left its inhibitory action unaltered. In whole-cell patch-clamp recordings, bradykinin reduced voltage-activated Ca2+ currents in a pertussis toxin-insensitive manner, and this action was additive to the inhibition by UK 14304. These results demonstrate that bradykinin inhibits noradrenaline release from rat sympathetic neurons via presynaptic B2 receptors. This effect does not involve cyclooxygenase products, M-type K+ channels, or protein kinase C, but rather an inhibition of voltage-gated Ca2+ channels.     

Presynaptic inhibition in humans: a comparison between normal and spastic patients.

During the last 40 years, several studies in man have been devoted to the pathophysiological mechanisms underlying spasticity. Spasticity is characterised by a velocity dependent increase in muscle tone. Many spinal pathways control stretch reflex excitability and a malfunction in any one of them could theoretically produce the exaggeration of the stretch reflex. Delwaide showed that the vibration-induced inhibition of Ia fibres is reduced in spastic patients. However, the relation between a decrease in presynaptic Ia inhibition and the pathophysiology of spasticity has been recently questioned since it was argued that homosynaptic depression (or post-activation depression) also contributes to the vibratory-induced depression of monosynaptic reflexes. This paper is thus devoted to a review of the methods recently developed to study selectively presynaptic Ia inhibition in man and to a reevaluation of the relations between modifications in presynaptic Ia inhibition and spasticity in hemiplegic and spinal spastic patients.     

Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors

We report a type of synaptic modulation that involves retrograde signaling from postsynaptic metabotropic glutamate receptors (mGluRs) to presynaptic cannabinoid receptors. Activation of mGluR subtype 1 (mGluR1) expressed in cerebellar Purkinje cells (PCs) reduced neurotransmitter release from excitatory climbing fibers. This required activation of G proteins but not Ca2+ elevation in postsynaptic PCs. This effect was occluded by a cannabinoid agonist and totally abolished by cannabinoid antagonists. Depolarization-induced Ca2+ transients in PCs also caused cannabinoid receptor-mediated presynaptic inhibition. Thus, endocannabinoid production in PCs can be initiated by two distinct stimuli. Activation of mGluR1 by repetitive stimulation of parallel fibers, the other excitatory input to PCs, caused transient cannabinoid receptor-mediated depression of climbing fiber input. Our data highlight a signaling mechanism whereby activation of postsynaptic mGluR retrogradely influences presynaptic functions via endocannabinoid system.     

Peculiarities of orthodromic inhibition in pacemaker neurons in Helix pomatia

We used the intracellular recording method to study the effect of a group of nerves in the visceral complex on the activity of a pacemaking giantneuron located in the peripheral part of the visceral ganglion in a mollusk. Single excitations of the left and right pallial, the intestinal, and the anal nerves with electrical stimuli evoked similar responses, consisting of phases of rapid depolarization (duration 100 msec, amplitude 3–5 mV) and slower hyperpolarization (duration 400 msec, amplitude 5–8 mV). The excitation also had an aftereffect, which was expressed in inhibition of the background activity of the pacemaker for several seconds. The most interesting of the functional characteristics of that response was the effects of summation. With rhythmic excitation by stimuli of low frequency (0.5–1 c/sec) the result of summation was general hyperpolarization of the neuron and the appearance of giant inhibitory postsynaptic potentials (IPSP's) with an amplitude of 12–16 mV. With higher frequency of excitation (2–3 c/sec and upward) we observed depolarization replacing the hyperpolarization of the neuron, but IPSP's of large amplitude were absent. At the end of rhythmic excitation prolonged inhibition of the pacemaker's activity, lasting some minutes, occurred in all cases. This article discusses the possible mechanisms of that type of prolonged inhibition of the pacemaker's activity, the origin of the phases in biphasic responses, and the reasons for differences in the course of summation of biphasic postsynaptic potentials.M. V. Lomonosov Moscow State University. Translated from Neirofiziologiya, Vol. 3, No. 4, pp. 426–433, July–August, 1971.