Presynaptic inhibition

Partial depolarisation of (ii) by presynaptic inhibition reduces potential change induced by action potential and the release of NT... 

Figure 1.6 Presynaptic inhibition of the form seen in the dorsal horn of the spinal cord, (a) The axon terminal (i) of a local neuron is shown making an axo-axonal contact with a primary afferent excitatory input (ii). (b) A schematic enlargement of the synapse, (c) Depolarisation of the afferent terminal (ii) at its normal resting potential by an arriving action potential leads to the optimal release of neurotransmitter, (d) When the afferent terminal (ii) is already partially depolarised by the neurotransmitter released onto it by (i) the arriving acting potential releases less transmitter and so the input is less effective...

Anatomical evidence can also be presented to support the concept of presynaptic inhibition and examples of one axon terminal in contact with another are well documented. These do not show the characteristics of either type I or II synapses but... 

GABAergic presynaptic inhibition of excitatory transmission of primary afferent neurones of the spinal cord resulting in epileptiform convulsions, myosis, and dyspnea with more or less prolonged apnea. 

The dopaminergic potential of the Dendrobium species is, to date, open for exploration. An interesting feature of the Dendrobium species is their ability to elaborate sesquiterpene alkaloids, the chemical structure of which resembles the one of strychnine. One such alkaloid is dendrobine, which is widespread in the genus. Kudo et al. noted that dendrobine, isolated from Dendrobium nobile, exhibits a strychnine-like presynaptic inhibition in frog spinal cord (64). 

Kudo Y, Tanaka A, Yamada K. Dendrobine, an antagonist of beta-alanine, taurine and of presynaptic inhibition in the frog spinal cord. Br J Pharmacol 1983 78 709-715. 

Figure 8.2 The endogenous analgesic system. The three major components of the endogenous analgesic system include the periaqueductal gray matter in the midbrain nucleus raphe magnus in the medulla and pain inhibitory complex in the dorsal horns of the spinal cord. This system causes presynaptic inhibition of pain fibers entering the spinal cord. The binding of enkephalin to opioid receptors on the pain fibers prevents release of the neurotransmitter, substance P. As a result, the pain signal is terminated in the spinal cord and does not ascend to higher centers in the CNS.

Compared to a,-receptors, a2-receptors have only moderate distribution on the effector tissues however, they have important presynaptic effects. Alpha-one receptors are found on effector tissue cells at the neuroeffector junction the a2-receptors are found on the varicosities of the postganglionic neuron. Norepinephrine released from this neuron not only binds to the a.j-receptors on the effector tissue to cause some physiological effect but also binds to the a2-receptors on the neuron. Alpha-two receptor stimulation results in presynaptic inhibition" or in a decrease in the release of norepinephrine. In this way, norepinephrine inhibits its own release from the sympathetic postganglionic neuron and controls its own activity. Both ar and a2-receptors have equal affinity for norepinephrine released directly from sympathetic neurons as well as circulating epinephrine released from the adrenal medulla. 

Adenosine has no direct effect on TMN neurons (Haas Panula, 2003) however, indirectly, adenosine, acting via adenosine A1 receptors, presynaptically inhibits the GABAergic input to TMN neurons. 

Stevens, D. R., Kuramasu, A., Eriksson, K. S., Selbach, O. Haas, H. L. (2004). Alpha 2-adrenergic receptor-mediated presynaptic inhibition of GABAergic IPSPs in rat histaminergic neurons. Neuropharmacology 46, 1018-22. 

Ennis M., Zhou F., Ciombor K. et al. (2001). Dopamine D2 receptor-mediated presynaptic inhibition of olfactory nerve terminals. J. Neurophysiol. 86,... 

Oliet, S. H. Poulain, D. A. (1999). Adenosine-induced presynaptic inhibition of IPSCs and EPSCs in rat hypothalamic supraoptic nucleus neurones. J. Physiol 520 (3), 815-25. 

Ultrastructural studies showed S receptor immunoreactivity was presynaptically localized to sensory inputs to the spinal cord [48]. Dorsal rhizotomy caused a dramatic decrease in <5 receptor immunoreactivity in spinal cord and <5 receptors were also expressed in the peripheral ganglia which send inputs to the spinal cord. These findings support the notion that <5 receptors are presynaptic to sensory inputs and are involved in the presynaptic inhibition of the release of transmitters involved in mediating nociceptive transmission. 

Presynaptic mGluR activation can lead to presynaptic inhibition 283... 

Kamiya, H. and Ozawa, S. (2000) Kainate receptor-mediated presynaptic inhibition at the mouse hippocampal mossy fibre synapse../. Physiol. 523, 653-665. 

Nonpeptide receptors Adenosine Aj Human cDNA Cardiac arrhythmia, asthma, myocardial ischemia, obesity, pain, renal disease, sleep apnea, stroke, cancer, inflammation, glaucoma, cystic fibrosis, Alzheimer s disease, Parkinson s disease Bradycardia, lipolysis inhibition, reduction of glomerular filtration and natriuresis, tubero-glomerular feedback, antinociception, renal vasodilatation-constriction, reduction of central cholinergic and noradrenergic nerve activity, presynaptic inhibition of excitatory neuro transmission... 

Another important mechanism whereby the release of a neurotransmitter may be altered is by presynaptic inhibition. Initially this mechanism was thought to be restricted to noradrenergic s)mapses, but it is now known to occur at GABA-ergic, dopaminergic and serotonergic terminals also. 

In addition to the physiological process of autoinhibition, another mechanism of presynaptic inhibition has been identified in the peripheral nervous system, although its precise relevance to the brain is unclear. In the dorsal horn of the spinal cord, for example, the axon terminal of a local neuron makes axo-axonal contact with a primary afferent excitatory input, which leads to a reduction in the neurotransmitter released. This is due to the local neuron partly depolarizing the nerve terminal, so that when the axon potential arrives, the change induced is diminished, thereby leading to a smaller quantity of transmitter being released. In the brain, it is possible that GABA can cause presynaptic inhibition in this way. 

Pharmacology Major muscle relaxant actions occur in the following 2 proposed sites At the spinal level resulting in enhancement of GABA-mediated presynaptic inhibition, and at supraspinal sites, probably in the brain stem reticular formation. 

Benzodiazepines also possess muscle relaxant activity. Their pharmacology is discussed in Chapter 30. Diazepam Valium) has been used for control of flexor and extensor spasms, spinal spasticity, and multiple sclerosis. The muscle relaxant effect of the benzodiazepines may be mediated by an action on the primary afferents in the spinal cord, resulting in an increased level of presynaptic inhibition of muscle tone. Polysynaptic reflexes are inhibited. The most troublesome side effect is drowsiness, which is dose dependent. Tolerance to both the therapeutic effects and the side effects develops. 

Blackmer T, Larsen EC, Takahashi M, Martin TF, Alford S, Hamm HE (2001) G protein betagamma subunit-mediated presynaptic inhibition regulation of exocytohc fusion downstream of Ca2+ entry. Science 292 293-297... 

Mecfianism of Action Askeletal muscle relaxant that increases presynaptic inhibition of spinal motor neurons mediated by alphaj-adrenergic agonists, reducing facilitation to postsynaptic motor neurons. Therapeutic Effect Reduces muscle spasticity. Pharmacokinetics ... 

Tizanidine is an a -adrenergic receptor agonist at supraspinal and spinal levels. This effect results in inhibition of spinal polysynaptic reflex activity. It presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. Tizanidine has no direct effect on skeletal muscle, the neuromuscular junction or on monosynaptic reflex activity. 

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