Polysynaptic neuron

Polysynaptic neuronal pathways involving the basal ganglia and related subcortical nuclei that influence motor behaviour. 

Several classes of drugs modulate the firing rates or patterns of midbrain dopamine neurons by direct, monosynaptic, or indirect, polysynaptic, inputs to the cell bodies within the ventral mesencephalon (i.e., nicotine and opiates). In contrast, amphetamine, cocaine, and methylphenidate act at the level of the dopamine terminal interfering with normal processes of transmitter packaging, release, reuptake, and metabolism. 

The cells comprising lamina V are more diverse than those of lamina IV and their dendrites extend vertically toward the superficial layers. Cell bodies in lamina V contribute to three projection pathways, the SCT, PSDC and STT. However, the STT cells appear to be predominant in this lamina. Lamina V plays an important role in nociception since it receives both A - and C-fibre inputs. Some cells in lamina V also respond to cutaneous low- and high-threshold mechanical stimuli and receive nociceptive inputs from the viscerae. Many of these neurons also project onto mononeurons and so act as interneurons in the polysynaptic withdrawal reflex to noxious stimuli. 

Figure 7.3 Components of a reflex arc. As illustrated by the components of the reflex arc, reflexes may be processed entirely at the level of the spinal cord with no need for input from the brain. A monosynaptic reflex has a single synapse between afferent and efferent neurons a polysynaptic reflex has two or more synapses between these neurons. In this case, intemeurons lie between the sensory and motor neurons. The more intemeurons involved, the more complex the response is.

A reflex is initiated by stimulation of a sensory receptor located at the peripheral ending of an afferent or first-order sensory neuron. This afferent neuron transmits impulses to the spinal cord. Within the gray matter of the spinal cord, the afferent neuron synapses with other neurons. As such, the spinal cord serves as an integrating center for the sensory input. The afferent neuron must ultimately synapse with an efferent or motor neuron. When the afferent neuron synapses directly with the motor neuron, it forms a monosynaptic reflex. An example of this type of reflex is the stretch reflex. When the afferent neuron synapses with an intemeuron that then synapses with the motor neuron, it forms a polysynaptic reflex, e.g., the withdrawal reflex. Most reflexes are polysynaptic. The motor neuron then exits the spinal cord to innervate an effector tissue, which carries out the reflex response. 

Due to its relevance to an understanding of movement disorders, the motor circuit has received the most attention. This circuit is centered on somatosensory, motor and premotor cortices, which send projections to the motor portions of striatum. The connections between the striatum and the basal ganglia output nuclei (GPi/SNr) are organized into direct and indirect pathways [1]. The direct pathway is a monosynaptic projection between striatum and GPi/ SNr, while the indirect pathway is a polysynaptic connection that involves intercalated neurons in GPe and STN. Some striatofugal neurons may also collateralize more extensively, reaching GPe, GPi/SNr and STN. Other motor -related inputs to striatum and STN arise from the intralaminar thalamic nuclei, i.e. the centromedian and parafascicular nuclei (CM/Pf). 

Baclofen appears to affect the neuromuscular axis by acting directly on sensory afferents, y-motor neurons, and collateral neurons in the spinal cord to inhibit both monosynaptic and polysynaptic reflexes. The principal effect is to reduce the release of excitatory neurotransmitters by activation of presynaptic GABAg receptors. This seems to involve a G protein and second-messenger link that either increases K+ conductance or decreases Ca conductance. 

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. 

It is beta-4 (chlorophenyl)-gamma aminobutyric acid. It is a powerful neuronal depressant. It reduces the release of excitatory transmitter and is antinociceptive in animal studies. It inhibits monosynaptic and polysynaptic reflex transmission at spinal level, probably by stimulating the GABAg... 

It is not clear, however, exactly how these drugs inhibit neurons involved in the polysynaptic pathways. There is preliminary evidence that one of these compounds (cyclobenzaprine) might block serotonin receptors on spinal interneurons, thereby decreasing the excitatory influence of serotonin on alpha motor neuron activity.50,55 Although this effect has been attributed to cyclobenzaprine in animals (rats), the effect of this drug and other muscle relaxants in humans remains to be determined. 

Tizanidine (Zanaflex) is classified as an alpha-2 adrenergic agonist, meaning that this drug binds selectively to the alpha-2 receptors in the CNS and stimulates them. Alpha-2 receptors are found at various locations in the brain and spinal cord, including the presynaptic and postsynaptic membranes of spinal interneurons that control alpha motor neuron excitability. Stimulation of these alpha-2 receptors inhibits the firing of interneurons that relay information to the alpha motor neuron that is, interneurons that comprise polysynaptic reflex arcs within the spinal cord.27 Tizanidine appears to bind to receptors on spinal interneurons, decrease the release of excitatory neurotransmitters from their presynaptic terminals (presynaptic inhibition), and decrease the excitability of the postsynaptic neuron (postsynaptic inhibition).40 Inhibition of spinal interneurons results in decreased excitatory input onto the alpha motor neuron, with a subsequent decrease in spasticity of the skeletal muscle supplied by that neuron. 

Moruzzi (9) already clearly dissociated activation from arousal. Stimulation from the sensory terminals leads to monosynaptic and more often polysynaptic reflexes. These polysynaptic reflexes relay in subcortical structures. Depending on the intensity of stimulation, the degree of neuronal recruitment, and so forth, the number of brain structures involved will vary. Stimulation may affect the thalamus, basal forebrain, and a newly recognized loop called the cor-ticothalamocortical loop (10). 

However, activation of the central nervous system (CNS) does not equate with EEG arousals or awakenings. CNS activation implies that integrative neurons were activated and sent information to descending pathways, the nucleus tractus solitarius, and sympathetic controlling cells. An ANS modulation is always associated with an efferent response. CNS activation may lead to an arousal, an awakening, or an important ANS activity change, but activation may be limited to a polysynaptic reflex response with ANS change and no EEG arousal (6). 

Barbiturates are thought to interfere with sodium and potassium transport across cell membranes. This leads to inhibition of the mesencephalic reticular activating system. Polysynaptic transmission is inhibited in all areas of the CNS. Barbiturates also potentiate GABA action on chloride entry into the neuron, although they do not bind at the benzodiazepine receptor. 

Tizanidine is an agonist at alpha-2 adrenergic receptor sites. It is considered to reduce spasticity by increasing the presynaptic inhibition of motor neurones, mainly influencing polysynaptic pathways, thus decreasing the facilitation of spinal motor neurones. It undergoes extensive first-pass metabolism, and the primary isoenzyme involved is CYP1A2. 

Stimulation of the peripheral nerve trunk of intact animals leads to generation of muscle action potentials of three types. According to the duration of latent periods, they fall into the following order M-response (the result of the direct stimulation of a-motor neuron axons), Fl-response (the monosynaptic response), and polysynaptic responses with the variable latent period from 8-12 up to about 40 ms. In test animals of the III group, the changes of temporal parameters refer mainly to the latent period and duration of M-response (Table 7.4). Polysynaptic responses occur at all intensities of excitation and have a more pronounced character than in intact rats. A marked level and more distinct differentiation of the peaks of the complex action potential were noted. 

Diazepam, the most commonly used benzodiazepine in equine medicine, is used as a component of anesthetic protocols (see Ch. 15) and for the treatment of seizures (see Ch. 9). It induces skeletal muscle relaxation by facilitating the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) within the central nervous system. It acts primarily within the spinal cord and exerts inhibitory effects on polysynaptic reflexes and intemuncial neuron transmission. 

Barbiturates act throughout the CNS nonanesthetic doses preferentially suppress polysynaptic responses. Facilitation is diminished, and inhibition usually is enhanced. The site of inhibition is either postsynaptic, as at cortical and cerebellar pyramidal cells and in the cuneate nucleus, substantia nigra, and thalamic relay neurons, or presyruq tic, as in the spinal cord. Enhancement of inhibition occurs primarily at synapses where neurotransmission is mediated by GABA acting at GABA receptors. 

Tizanidine is an a2-adrenergic agonist [581] which is a good and well tolerated muscle relaxant used to treat muscular spasms and spastic conditions [582-587], Its action on adrenoceptors and its antinociceptive effect are well studied it depresses polysynaptic excitation of spinal motor neurones [588-591], Recent clinical trials demonstrated the value of tizanidine in the treatment of tension headaches [592] and lower back pain [593],... 

The basic unit of integrated activity is the reflex arc. This arc consists of a sense organ, an afferent neuron, one or more synapses in a central integrating station (or sympathetic ganghon), an efferent neuron, as well as, an effecdor. The simplest reflex arc is the monosynaptic one, which only has one synapse between the afferent and efferent neuron. With more than one synapses the reflex arc is called polysynaptic. In each of these cases, activity is modified by both spatial and temporal facihtation, occlusion, and other effects (2,3]. 

Fig. 1.4 Diagram of a dorsal view of the brainstem the cerebellum has been removed. The extent of the reticular formation within the brainstem is illustrated. The reticular formation is a polysynaptic network that consists of three regions a series of midUne raphe nuclei (the median reticular formation, which is the site of origin of the major serotonergic pathways in the nervous system) this is flanked bUateraUy by the paramedian reticular formation (an efferent system of magnoceUular neurons with ascending and descending projections) and farthest from the midhne, the lateral reticular formation, consisting of parvoceUular neurons that project transversely See also Color Insert)...

The four main alkaloids are coniine, y-coniceine, iV-methylconiine, and conhydrine. Conhydrine occurs in the smallest proportions and has the weakest pharmacological action [3,4,19,20, 31,67, 85, 87]. The most distinctive action of the three other hemlock alkaloids plus nicotine is their ability, provided the dose is small, to inhibit the crossed extensor reflex and the so-called knee-jerk by an action potential in the spinal cord. Since neurons in the spinal cord may both be inhibited and activated by the action of hemlock, the mechanisms involved are a bit complicated. If the alkaloids initially stimulate inhibitory neurons rather than blocking excitatory ones, the antagonistic relationship of the two substances may be explained. There is evidence that its central synapse is controlled by polysynaptic inhibitory pathways, although the patellar reflex is monosynaptic [3, 19, 67]. It is possible that the C. maculatum piperidine alkaloids may act upon the mechanism that regulates the amniotic liquid, adding to the production of malformations. Finally, lack of fetal movement, whatever its origin, can also cause limb malformations. 

As an alpha-2 agonist, tizanidine decreases presynaptic excitatory neurotransmitter release and postsyn-aptic neurotransmitter effectiveness. Alpha-2 receptor agonists attenuate monosynaptic and polysynaptic reflexes in the spinal cord [25]. Tizanidine decreases excitatory neurotransmitter release and Substance P release from small sensory afferents [28]. Tizanidine decreases locus coeruleus activity, thereby modulating descending motor regulatory pathways [28]. Tizanidine decreases activity of both alpha and gamma motor neurons [28]. 

---