Reticular formation

Published on 02/03/2015 by admin

Last modified 22/04/2025

Print this page

This article have been viewed 6692 times

24 Reticular formation

1 The reticular formation has very diverse functions. Some of its nuclear groups have direct access to motor neurons in the brainstem and spinal cord. Others have direct access to autonomic effector nuclei including cardiovascular controls. Some may act simultaneously upon somatic and autonomic nuclei.

2 All of the sensory systems contribute afferents to the reticular formation.

3 Ascending projections of the reticular formation to the forebrain, including the ascending reticular activating system (ARAS), are essential for the state of consciousness.

4 Disturbance of function of aminergic projections from the reticular formation have been correlated with psychiatric states including major depression and schizophrenia.

Introduction

The reticular formation is phylogenetically a very old neural network, being a prominent feature of the reptilian brainstem. It originated as a slowly conducting, polysynaptic pathway intimately connected with olfactory and limbic regions. The progressive dominance of vision and hearing over olfaction led to localization of sensory and motor functions within the tectum of the midbrain. Direct spinotectal and tectospinal tracts bypassed the reticular formation, which was largely relegated to automatic functions. In mammals, the tectum in turn has been relegated to minor status with the emergence of very fast pathways linking the cerebral cortex with the peripheral sensory and motor apparatus.

In the human brain, the reticular formation continues to be of importance in automatic and reflex activities, and it has retained its linkages to the limbic system.

Organization

The term reticular formation refers only to the polysynaptic network in the brainstem, although the network continues rostrally into the thalamus and hypothalamus, and caudally into the propriospinal network of the spinal cord.

The ground plan is shown in Figure 24.1A. In the midline, the median reticular formation comprises a series of raphe nuclei (pron. ‘raffay’ and derived from the Greek word for seam). The raphe nuclei are the major source of serotonergic projections throughout the neuraxis (see next section).

Figure 24.1 Reticular formation (RF). (A) Subdivisions. (B) Aminergic and cholinergic cell groups.

Next to this is the paramedian reticular formation. This part of the network contains magnocellular neurons throughout; in the lower pons and upper medulla, some gigantocellular neurons also appear, before the network blends with the central reticular nucleus of the medulla oblongata.

Outermost is the lateral, parvocellular (small-celled) reticular formation. Parvocellular dendrites are long and they branch at regular intervals. They have a predominantly transverse orientation, and their interstices are penetrated by long pathways running to the thalamus. The lateral network is mainly afferent in nature. It receives fibers from all of the sensory pathways, including the special senses:

• Olfactory fibers are received through the medial forebrain bundle, which passes alongside the hypothalamus.

• Visual pathway fibers are received from the superior colliculus.

• Auditory pathway fibers are received from the superior olivary nucleus.

• Vestibular fibers are received from the medial vestibular nucleus.

• Somatic sensory fibers are received from the spinoreticular tracts and from the spinal and principal (pontine) nuclei of the trigeminal nerve.

Most parvocellular axons ramify extensively among the dendrites of the paramedian reticular formation. However, some synapse within the nuclei of cranial nerves and act as pattern generators (see later).

The paramedian reticular formation is a predominantly efferent system. The axons are relatively long. Some ascend to synapse in the midbrain reticular formation or in the thalamus. Others have both ascending and descending branches contributing to the polysynaptic network. The magnocellular component receives corticoreticular fibers from the premotor cortex and gives rise to the pontine and medullary reticulospinal tracts.

Aminergic neurons of the brainstem

Embedded in the reticular formation are sets of aminergic neurons (Figure 24.1B). They include one set producing serotonin (5-hydroxytryptamine) and three sets producing catecholamines, as listed in Table 24.1.

• The serotonergic neurons have the largest territorial distribution of any set of CNS neurons. In general terms, those of the midbrain project rostrally into the cerebral hemispheres; those of the pons ramify in the brainstem and cerebellum; and those of the medulla supply the spinal cord (Figure 24.2). All parts of the CNS gray matter are permeated by serotonin-secreting axonal varicosities. Clinically, enhancement of serotonin activity is part of the treatment for a prevalent condition known as major depression (Ch. 26).

• The dopaminergic neurons of the midbrain fall into two groups. At the junction of tegmentum and crus are those of the substantia nigra, which will be considered in Chapter 33. Medial to these, dopaminergic neurons in the ventral tegmental nuclei (Figure 24.3) project mesocortical fibers to the frontal lobe and mesolimbic fibers to the nucleus accumbens in particular (Ch. 34).

• The noradrenergic neurons are only marginally less prodigious than the serotonergic ones. About 90% of the somas are pooled in the cerulean nucleus (locus ceruleus), a ‘violet spot’ in the floor of the fourth ventricle at the upper end of the pons (Figure 24.4). Neurons of the cerulean nucleus project in all directions, as indicated in Figure 24.5.

• Epinephrine-secreting neurons are relatively scarce and are confined to the medulla oblongata. Some project rostrally to the hypothalamus, others project caudally to synapse upon preganglionic sympathetic neurons in the spinal cord.

Table 24.1 Aminergic neurons of the reticular formation

Transmitter	Location
Serotonin	Raphe nuclei of midbrain, pons, medulla
Dopamine	Tegmentum of midbrain
Norepinephrine	Midbrain, pons, medulla
Epinephrine	Medulla

Figure 24.2 Serotonergic projections from the brainstem midline (raphe).

Figure 24.3 Dopaminergic projections from the midbrain.

Figure 24.5 Noradrenergic projections from the pons and medulla oblongata.

Figure 24.4 Part of a transverse section through the upper part of the pons, showing elements of the reticular formation.

In the cerebral cortex, the ionic and electrical effects of aminergic neuronal activity are quite variable. First, more than one kind of postsynaptic receptor exists for each of the amines. Second, some aminergic neurons liberate a peptide substance also, capable of modulating the transmitter action – usually by prolonging it. Third, the larger cortical neurons receive many thousands of excitatory and inhibitory synapses from local circuit neurons, and they have numerous different receptors. Activation of a single kind of aminergic receptor may have a large or small effect depending on the existing excitatory state.

Although our understanding of the physiology and pharmacology of the monoamines is far from complete, no-one disputes their relevance to a wide range of behavioral functions.

Functional Anatomy

The range of functions served by different parts of the reticular formation is indicated in Table 24.2.

Table 24.2 Elements of the reticular formation and their perceived functions

Element	Function
Premotor cranial nerve nuclei	Patterned cranial nerve activities
Pontine locomotor center	Pattern generation
Magnocellular nuclei	Posture, locomotion
Salivatory nuclei	Salivary secretion, lacrimation
Pontine micturition center	Bladder control
Medial parabrachial nucleus	Respiratory rhythm
Central reticular nucleus of medulla oblongata	Vital centers (circulation, respiration)
Lateral medullary nucleus	Conveys somatic and visceral information to the cerebellum
Ascending reticular activating system (ARAS)	Arousal
Aminergic neurons	Sleeping and waking, attention and mood, sensory modulation, blood pressure control

Pattern generators

Patterned activities involving cranial nerves include:

• Conjugate (in parallel) movements of the eyes locally controlled by premotor nodal points (gaze centers) in the midbrain and pons linked to the nuclei of the ocular motor nerves (Ch. 23).

• Rhythmical chewing movements controlled by the supratrigeminal premotor nucleus in the pons (Ch. 21).

• Swallowing, vomiting, coughing, and sneezing, controlled by separate premotor nodal points in the medulla linked to the appropriate cranial nerves and to the respiratory centers.

Locomotor pattern generators are described in Box 24.1. An overview of gait controls is provided in Box 24.2. Higher-level bladder controls are described in Box 24.3.

Box 24.1 Locomotor pattern generators

From animal experiments, it has long been agreed that lower vertebrates and lower mammals possess locomotor pattern generators in the spinal cord, within the gray matter neurologically connected to each of the four limbs. These spinal generators comprise electrically oscillating circuits delivering rhythmically entrained signals to flexor and extensor muscle groups. Spinal generator activity is subject to supraspinal commands from a mesencephalic locomotor region (MLR), which in turn obeys commands from motor areas of the cerebral cortex and corpus striatum.

The MLR contains the pedunculopontine nucleus, close to the superior cerebellar peduncle where this passes along the upper corner of the fourth ventricle to enter the midbrain (Figure 17.16). These nuclei send fibers down the central tegmental tract to the oral and caudal pontine nuclei serving extensor motor neurons and to medullary magnocellular neurons serving flexor motor neurons.

A major focus of spinal rehabilitation is on activation of spinal locomotor reflexes in patients who have experienced injury resulting in partial or complete spinal cord transection. It is now well established that even after complete transection at cervical or thoracic level, a lumbosacral locomotor pattern can be activated by continuous electrical stimulation of the dura mater at lumbar segmental level. The stimulation strongly activates posterior root fibers feeding into the generator in the base of the anterior gray horn. Surface EMG recordings taken from flexor and extensor muscle groups reveal an oscillating pattern of flexor and extensor motor neuron activation, although the pattern is not identical to the normal one. A normal pattern requires the lesion to be incomplete, with preservation of some supraspinal projection from the pedunculopontine nucleus.

Generation of actual stepping movements is possible in complete lesions if the individual is supported over a moving treadmill belt while the dura is being stimulated, presumably because of the additional cutaneous and proprioceptive inputs to the generator. Muscle strength and stepping speed improve over a period of weeks but not enough to enable unassisted locomotion within a walking frame.

Current research aims at improving the opportunity for supraspinal motor fibers to ‘bridge the gap’ by clearing tissue debris from the gap and replacing that tissue with a medium having a matrix that will support regenerating axons both physically and chemically.

References

Blessing WW. Lower brainstem regulation of visceral, cardiovascular and respiratory function. In: Paxinos G, Mai JK, editors. The human nervous system. ed 2. Amsterdam: Elsevier; 2004:465-479.

Fouad K, Pearson K. Restoring walking after spinal cord injury. Progr Neurobiol. 2004;73:107-126.

Grasso R, Ivanenko YP, Zago M, et al. Distributed plasticity of locomotor pattern generators in spinal cord injured patients. Brain. 2004;127:1029-1034.

Jahn K, Deutschlander A, Stephan T, et al. Supraspinal locomotor control in quadriceps and humans. Prog Brain Res. 2008;171:353-372.

McCrea DA, Ryback IA. Organization of mammalian locomotor system and pattern generation. Brain Res Rev. 2008;57:134-146.

Box 24.2 Overview of gait controls. (Assistance of Professor Tim O’Brien, Director, Gait Laboratory, Central Remedial Clinic, Dublin is gratefully acknowledged.)

Figure Box 24.2.1 Overview of gait controls.

Box 24.3

The assistance of Professor Mary Pat FitzGerald, Department of Urogynecology, Stritch School of Medicine, Loyola University, Chicago, is gratefully acknowledged.

Higher-level bladder controls

The micturition control center is in the paramedian pontine reticular formation on each side, with interconnections across the midline. Magnocellular neurons project from here all the way to micturition-related parasympathetic neurons in segments S2–4 of the spinal cord (Figure Box 24.3.1).

Activation of the micturition control center produces not only a rise in intravesical pressure but also relaxation of the external urethral striated sphincter, brought about by simultaneous excitation of GABAergic internuncials synapsing in the nucleus of Onuf in sacral segments of the spinal cord (Ch. 13).

More laterally in the pons is the L (lateral) center projecting to Onuf’s nucleus. In this context, the micturition control center is referred to as the M (medial) center.

At higher levels, cells in the lateral part of the right periaqueductal gray matter (PAG) receive fibers ascending from the sacral posterior gray horn and project excitatory fibers to the insula which generates conscious sensation of normal bladder filling and relays its activity to the medial prefrontal cortex. The lateral PAG also receives an excitatory input from the right hypothalamus.

Some spinoreticular projections from the sacral cord excite the L center. Others relay via the thalamus to cells in a part of the right anterior cingulate cortex (ACCx) known to be active during tasks requiring attention.

This right-sided bias is thought to be related to emotional aspects of micturition.

The micturition cycle

1 When the bladder is half-full, vesical afferents from stretch receptors in the detrusor and in the mucous membrane of the trigone relay this information along spinoreticular fibers reaching pons, midbrain, and insula via thalamus (Figure Box 24.3.2).

2 The insular cortex projects to the decision center in the medial prefrontal cortex, keeping it informed about the level of bladder filling.

3 As indicated in Chapter 13, activity in the sympathetic system is stepped up so that bladder compliance can be increased (via β₂ receptors). Parasympathetic neurons are silenced by α₂ neuronal interaction.

4 Spinoreticular fibers synapsing in the L nucleus of the pons activate Onuf’s nucleus in the sacral cord, thereby raising the tone of the external urinary sphincter.

5 With completion of filling, there is perception of urgency. If time or place is not suitable, part of the medial prefrontal gyrus comes alive. This area puts the ACCx on hold by reducing its level of activity via association-fiber projections to inhibitory internuncials there. Likewise, projections to hypothalamus and midbrain inhibit preoptic area and PAG by activating appropriate internuncials.

6 A final measure, one that cannot be long sustained, is voluntary contraction of the entire pelvic floor. The command for this contraction is sent from the prefrontal cortex to the perineal representation on the medial side of the motor cortex in the paracentral lobule.

7 When time and place permit, the medial prefrontal cortex releases its three prisoners. The pelvic floor is allowed to sag in the manner described in Chapter 13, and the hypothalamus joins PAG in activating the M nucleus while inactivating L via inhibitory internuncials.

The right-sided bias of micturition control is consistent with the clinical observation that, among stroke patients of either sex, urinary incontinence is more commonly associated with right-sided lesions of the brain.

Role of monoamines

The motor and sensory spinal cord nuclei serving the bladder are abundantly supplied with serotonergic neurons descending from the magnus raphe nucleus (MRN) in the medulla oblongata. Animal experiments have shown that local applications of 5 HT are excitatory to pelvic sympathetic and sacral anterior horn neurons, inhibitory to pelvic parasympathetic and sacral posterior horn neurons. Distension of the bladder is known to stimulate the MRN (via spinoreticular activation of the periaqueductal gray matter). A quick review of the lower-level bladder controls (Box 13.3) suggests that the MRN sets the general tone in favor of bladder filling.

Noradrenergic fibers descending to the anterior gray horn from the cerulean nucleus potentiate the effect of local glutamate release onto the cells of Onuf’s nucleus, thereby enhancing external sphincter tone during the filling phase.

(In real life not all glow simultaneously!)

Reference

Fowler CJ, Griffiths DJ. A decade of functional brain imaging applied to bladder control. Neurourol Urodynam. 2009.

Figure Box 24.3.1 Higher-level bladder controls.

Figure Box 24.3.2 Depiction of areas showing increased fMRI activity at some time during the storage phase of the micturition cycle. PAG, periaqueductal gray matter; PMC, pontine micturition center.

The salivatory nuclei belong to the parvocellular reticular formation of pons and medulla. They contribute preganglionic parasympathetic fibers to the facial and glossopharyngeal nerves.

Respiratory control

The respiratory cycle is largely regulated by dorsal and ventral respiratory nuclei located at the upper end of the medulla oblongata on each side. The dorsal respiratory nucleus occupies the midlateral part of the solitary nucleus. The ventral nucleus is dorsal to the nucleus ambiguus (hence the term retroambiguus nucleus in Figure 17.11). A third, medial parabrachial nucleus, adjacent to the cerulean nucleus, seems to have a pacemaker function governing respiratory rate (cycles per minute). As will be seen in Chapter 34, stimulation of this nucleus by the amygdala, in anxiety states, results in characteristic hyperventilation.

The dorsal respiratory nucleus has an inspiratory function. It projects to motor neurons on the opposite side of the spinal cord supplying diaphragm, intercostals, and accessory muscles of inspiration. It receives excitatory projections from chemoreceptors in the medullary chemosensitive area and in the carotid body.

Medullary chemosensitive area

Close to the site of attachment of the glossopharyngeal nerve to the medulla oblongata, the choroid plexus of the fourth ventricle pouts through the lateral aperture of the fourth ventricle (Figure 24.6). At this location, cells of the lateral reticular formation at the medullary surface are exquisitely sensitive to the H⁺ ion concentration in the neighboring cerebrospinal fluid. In effect, this chemosensitive area samples the Pco₂ level in the blood supplying the brain. Any increase in H⁺ ions stimulates the dorsal respiratory nucleus through a direct synaptic linkage. (Several other nuclei within the medulla are also chemosensitive.)

Figure 24.6 Respiratory control systems. All sections are viewed from below and behind. (A) is an enlargement taken from (B).

(A) Inhibitory interaction between dorsal and ventral respiratory nuclei (DRN, VRN). Chorodial capillaries discharge cerebrospinal fluid (CSF) close to the medullary chemosensitive area (CSA), whence neurons project to DRN.

(B) The glossopharyngeal nerve (IX) contains chemoreceptive neurons reaching from carotid body to DRN.

(C) Phrenic motor neurons are activated by the contralateral DRN.

(D) Muscles of the abdominal wall are activated by the contralateral VRN to produce forced expiration.

Carotid chemoreceptors

The pinhead carotid body, close to the stem of the internal carotid artery (Figure 24.6), receives from this artery a twig which ramifies within it. Blood flow through the carotid body is so intense that the arteriovenous Po₂ changes by less than 1% during passage. The chemoreceptors are glomus cells to which branches of the sinus nerve (branch of IX) are applied. The carotid chemoreceptors respond to either a fall in Po₂ or a rise in Pco₂ and cause reflex adjustment of blood gas levels.

Chemoreceptors in the aortic bodies (beneath the aortic arch) are relatively insignificant in humans.

The ventral respiratory nucleus is expiratory (in the main). During quiet breathing, it functions as an oscillator, engaged in reciprocal inhibition (via GABAergic internuncials) with the inspiratory center. During forced breathing, it activates anterior horn cells supplying the abdominal muscles required to empty the lungs.

Cardiovascular control

Cardiac output and peripheral arterial resistance are controlled by the neural and endocrine systems. Because of the prevalence of essential hypertension in late middle age, major research efforts are under way to understand the mechanisms of cardiovascular control.

Afferents signaling increased arterial pressure arise in stretch receptors (a multitude of free nerve endings) in the wall of the carotid sinus and aortic arch (Figure 24.7). Known as baroreceptors, these afferents project to medially placed cells of the solitary nucleus constituting the baroreceptor center. Afferents from the carotid sinus travel in the glossopharyngeal nerve; those from the aortic arch travel in the vagus nerve. The baroreceptor nerves are known as ‘buffer nerves’ because they act to correct any deviation of the arterial blood pressure from the norm.

Figure 24.7 Baroreceptor reflexes. (A) Upper medulla oblongata. (B) Spinal cord segments T1–L3. (C) Posterior wall of heart.

Baroreceptor reflex ((left).

1 Stretch receptors in the carotid sinus excite fibers in the sinus branch of the glossopharyngeal nerve. ICA, internal carotid artery.

2 Baroreceptor neurons of the solitary nucleus respond by stimulating cardioinhibitory neurons in the dorsal (motor) nucleus of the vagus (DMX).

3 Preganglionic, cholinergic parasympathetic vagal fibers synapse upon mural ganglion cells on the posterior wall of the heart.

4 Postganglionic, cholinergic parasympathetic fibers reduce pacemaker activity, thus reducing the heart rate.

Barosympathetic reflex (right).

1 Carotid sinus stretch receptor afferents excite baroreceptor medial neurons of the solitary nucleus.

2 Baroreceptor neurons respond by exciting the inhibitory neurons of the vasomotor depressor center in the central reticular nucleus of the medulla.

3 Adrenergic and noradrenergic neurons of the pressor center in the lateral reticular nucleus (rostral ventrolateral medulla) are inhibited.

4 Tonic excitation of the lateral gray horn is reduced.

5 and 6 Preganglionic and postganglionic sympathetic tone to peripheral arterioles is reduced, thus lowering the peripheral arterial resistance.

Cardiac output and peripheral arterial resistance depend on a balance in the activity of sympathetic and parasympathetic efferents. Two major reflexes, barovagal and barosympathetic, help to lower a raised blood pressure as detailed in the caption to Figure 24.7.

Sleeping and wakefulness

Electroencephalography (EEG) reveals characteristic patterns in the electrical activity of cerebral cortical neurons that accompany various states of consciousness. The normal waking state is characterized by rapid, low-amplitude waves. The onset of sleep is accompanied by slow, high-amplitude waves, the higher amplitude being due to the synchronized activity of larger numbers of neurons. This type of sleep is called S (synchronized) sleep. It lasts for about 90 minutes before being replaced by D (desynchronized) sleep in which the EEG pattern resembles the waking state. Dreams occur during D sleep and there are rapid eye movements (hence the more usual term, REM sleep). Several S and D phases occur during a normal night’s sleep, as described in Chapter 30.

Details of brainstem involvement in sleep phenomena are available in psychology texts. Some salient experimental evidence is summarized:

• In animal experiments, destruction of the midbrain raphe neurons, or pharmacological prevention of serotonin synthesis, results in insomnia lasting for several days.

• Serotonin and norepinephrine neuronal activities fluctuate in parallel. Both are most active during attentive wakefulness, sluggish during S sleep, and virtually silent during REM sleep.

• Brainstem serotonin neurons form numerous surface varicosities on the walls of the third ventricle. Serotonin liberated into the cerebrospinal fluid seems to be metabolized by hypothalamic neurons to form a sleep-inducing substance.

• Cholinergic neurons close to the cerulean nucleus are active during REM sleep and they appear to cause the rapid eye movements by playing upon the ocular motor nuclei.

Ascending reticular activating system

This term refers to the participation of reticular formation neurons in activation of the cerebral cortex, as shown by a change in EEG records from high-amplitude, slow waves to low-amplitude, fast waves during spontaneous arousal from sleep. The strongest candidates for such a role are sets of cholinergic neurons close to the cerulean nucleus (Figure 24.4). In addition to supplying the above-mentioned fibers to the ocular motor nuclei, these neurons project to almost all thalamic nuclei, and they have an excitatory effect upon thalamic neurons projecting to the cerebral cortex.

The hypothalamus is an important control center for various body rhythms, including sleep and wakefulness. A second candidate for cortical activation has been found in the hypothalamus, namely the tuberomammillary nucleus. This nucleus contains histaminergic neurons having widespread projections to the cerebral cortex (Ch. 26).

Following arousal, the waking-state EEG pattern seems to be sustained by the continuing discharge of the brainstem and hypothalamic neurons mentioned; also by a third set of neurons, embedded in the basal forebrain immediately above the optic chiasm. The third set occupies the basal nucleus of Meynert (Ch. 34) projecting cholinergic axons to most parts of the cerebral cortex.

Sensory modulation: gate control

Sensory transmission from primary to secondary afferent neurons (at the levels of the posterior gray horn and posterior column nuclei) and from secondary to tertiary (at the level of the thalamus) is subject to gating. The term gating refers to the degree of freedom of synaptic transmission from one set of neurons to the next.

Tactile sensory transmission is gated at the level of the posterior column nuclei. Corticospinal neurons projecting from the postcentral gyrus may facilitate or inhibit sensory transmission at this level, as mentioned in Chapter 16.

Nociceptive transmission from the trunk and limbs is gated in the posterior gray horn of the spinal cord. From the head and upper part of the neck, it is gated in the spinal trigeminal nucleus. A key structure in both areas of gray matter is the substantia gelatinosa, which is packed with small excitatory and inhibitory internuncial neurons. The excitatory transmitter is glutamate; the inhibitory one is GABA for some internuncials, enkephalin (an opiate pentapeptide) for others.

Finely myelinated (Aδ) polymodal nociceptive fibers synapse directly upon dendrites of relay neurons of the lateral spinothalamic tract and of its trigeminal equivalent. The Aδ fibers signal sharp, well-localized pain. Unmyelinated, C-fiber nociceptive afferents have mainly indirect access to relay cells, via excitatory gelatinosa internuncials. The C fibers signal dull, poorly localized pain. Most of them contain substance P, which may be liberated as a cotransmitter with glutamate.

Segmental antinociception

Large (A category) mechanoreceptive afferents from hair follicles synapse upon anterior spinothalamic relay cells (and their trigeminal equivalents). They also give off collaterals to inhibitory (mainly GABA) gelatinosa cells which synapse in turn upon lateral spinothalamic relay cells (Figure 24.8). Some of the internuncials also exert presynaptic inhibition upon C-fiber terminals, either by axo-axonic contacts (which are very difficult to find in experimental material), or by dendro-axonic contacts. Gating of the spinothalamic response to C-fiber activity can be induced by stimulating the mechanoreceptive afferents, thereby recruiting inhibitory gelatinosa cells. This simple circuit accounts for the relief afforded by ‘rubbing the sore spot’. It also provides a rationale for the use of transcutaneous electrical nerve stimulation (TENS) by physical therapists for pain relief in arthritis and other chronically painful conditions. The standard procedure in TENS is to apply a stimulating electrode to the skin at the same segmental level as the source of noxious C-fiber activity, and to deliver a current sufficient to produce a pronounced buzzing sensation.

Figure 24.8 Antinociceptive pathways. (A) Posterior view of brainstem. (B) Right posterior gray horn of spinal cord, viewed from above. The periaqueductal gray matter (PAG) contains an excitatory projection to the magnus raphe nucleus (MRN), and enkephalinergic internuncials (Enk) which exert tonic inhibition upon the projection cells. Inhibitory fibers from the hypothalamus release (disinhibit) the excitatory neurons, and MRN responds in turn.

The effects within the spinal nucleus of trigeminal (V) and posterior gray horn are the same: serotonin liberated by MRN neurons excites enkephalinergic internuncials which inhibit nociceptive projection cells.

The nociceptive pathway at cord level is represented by the C-fiber input to an excitatory internuncial (EI), which in turn excites the lateral spinothalamic or spinoreticular projection cell (LST/SRT) unless this is being inhibited by the enkephalinergic internuncial. Rubbing the sore spot sends impulse trains along A fibers inducing the Enk cell to exert presynaptic inhibition on the EI terminal, and postsynaptic inhibition on the LST/SRT projection cell. Passage of purely tactile information into the anterior spinothalamic tract (AST) is not impeded.

Supraspinal antinociception

Magnus raphe nucleus (Figure 24.8)

From the magnus raphe nucleus (MRN) in the medulla oblongata, raphespinal fibers descend bilaterally within Lissauer’s tract and terminate in the substantia gelatinosa at all levels of the spinal cord. In animals, electrical stimulation of the MRN may produce total analgesia throughout the body, with little effect on tactile sensation. Many fibers of the raphespinal tract liberate serotonin, which excites inhibitory internuncials in the posterior gray horn and spinal trigeminal nucleus. The internuncials induce both pre- and postsynaptic inhibition on the relevant relay cells.

There is evidence that noradrenergic projections to the posterior horn from pons and medulla are also involved in supraspinal antinociception, by a direct inhibitory effect on spinothalamic neurons.

• Diffuse noxious inhibitory controls. The MRN is not somatotopically arranged, but it does receive inputs from spinoreticular and trigeminoreticular neurons responding to peripheral noxious stimulation. This anatomical connection accounts for what are called diffuse noxious inhibitory controls. Painful stimulation of one part of the body may produce pain relief in all other parts. The arrangement accounts well for the heterotopic relief of pain in acupuncture (Ch. 31), where needles are used to excite nociceptive afferents in the most superficial musculature rather than in the skin.

• Stimulus-induced analgesia. MRN is intensely responsive to stimulation of the PAG of the midbrain. This connection has been used to advantage for patients suffering intractable pain: a fine stimulating electrode can be inserted into PAG and wired so that the patient can control the level of self-stimulation.

• Stress-induced analgesia. At rest, the PAG projection to the MRN is under tonic inhibition by inhibitory internuncials present within PAG. The internuncials are themselves inhibited by opioid peptides, notably by β-endorphin released from a small set of hypothalamic neurons projecting to PAG. In life-threatening situations, where injury may be the price to be paid for escape, PAG may be released (disinhibited) by the hypothalamus. This seems to be the mechanism whereby a bullet wound may be scarcely noticed in the heat of battle. (As will be seen in Ch. 34, excitatory neurons in the PAG may also be stimulated directly by the amygdala, located in the anterior temporal lobe, in fearful situations.)

In addition to the segmental and supraspinal controls of nociceptive transmission from primary to secondary afferents, gating occurs within the thalamus (see Ch. 27).

Furthermore, perception of the aversive (unpleasant) quality of pain seems to require participation of the anterior cingulate cortex (Ch. 34), which is rich in opiate receptors.

Clinical Panel 24.1 Urge incontinence

Urge incontinence is defined as an inability of adult women to control voiding when the storage phase of the micturition cycle is still incomplete. It is characterized by an acute sense of urgency quickly followed by uncontrollable voiding regardless of the circumstances. Hence the term ‘overactive bladder’ or ‘detrusor overactivity’. Many cases have a history of childhood bladder irritability in the form of daytime micturition frequency and/or nocturnal eneuresis (bed wetting).

fMRI studies in adult cases reveal increased activity of the right insular cortex, which is considered responsible for the heightened state of bladder awareness, and of the anterior, emotion-related area of the cingulate cortex, consistent with the sense of urgency and fear of imminent voiding.

As mentioned in Chapter 8, G-protein-gated muscarinic receptors, activated by postganglionic fibers from pelvic ganglia, are abundant on the detrusor muscle of the bladder. Accordingly, the drugs of choice are muscarinic receptor antagonists. However, antimuscarinic side-effects such as dry mouth and constipation may require this therapy to be withdrawn.

Botulinum toxin has been increasingly used to treat detrusor overactivity in recent years. It is known to disrupt the interface between cholinergic synaptic vesicles and target muscle fibers (whether striated or smooth), thereby rendering the synapse ineffective. A flexible cystoscope is passed through the urethra and numerous small Botox injections are inserted into the bladder wall. Twice yearly sessions are standard for the longer term.

References

FitzGerald MP, Thom DH, Wassel-Fyr C, et al. Childhood urinary symptoms predict adult overactive bladder symptoms. J Urol. 2006;175:989-993.

Griffiths D, Tadic SD. Bladder control, urgency and urge incontinence: evidence from functional brain imaging. Neurourol Urodynam. 2008;27:466-474.

Nitti VW. Botulinum toxin for the treatment of idiopathic and neurogenic overactive bladder: state of the art. Rev Urol. 2006;8:198-208.

Core Information

Recent Posts

Meta

Categories

Search Engine

Reticular formation

Introduction

Organization

Aminergic neurons of the brainstem

Functional Anatomy

Pattern generators

The micturition cycle

Role of monoamines

Respiratory control

Medullary chemosensitive area

Carotid chemoreceptors

Cardiovascular control

Sleeping and wakefulness

Ascending reticular activating system

Sensory modulation: gate control

Segmental antinociception

Supraspinal antinociception

Magnus raphe nucleus (Figure 24.8)

Ground plan

Aminergic neurons

Pattern generators

Antinociception

Related

Recent Posts

Meta

Categories

Search Engine

Reticular formation

Magnus raphe nucleus (Figure 24.8)

Share this:

Related

Related posts: