Nucleus Reticularis Magnocellularis Research Articles

Effects of midbrain and medullary stimulation on spinomesencephalic tract cells in the cat

1. The effects of electrical stimulation at different rostrocaudal levels of the midbrain, and at sites in the rostral medulla ipsilateral and contralateral to spinal recording sites, were evaluated against the responses of 46 cells belonging to the cat spinomesencephalic tract (SMT). 2. Inhibitory and/or excitatory effects of brain stem stimulation were observed on SMT cells that responded best (26 cells) or exclusively (12 cells) to noxious mechanical or thermal stimuli, as well as on 7 cells responding only to tap and/or stimulation of deep tissues. Recording sites for 32 cells were located in laminae V-VIII (27 cells) and laminae I-III (5 cells). 3. Midbrain stimulation sites were located in the superior colliculus, central gray (CG), red nucleus, and the midbrain reticular formation. Both inhibitory-only and excitatory-only effects were observed, although the most common effect of midbrain stimulation was excitation followed by inhibition (mixed effects). The effects of stimulation at different midbrain levels were determined for each cell. Stimulation in the caudal, middle, or rostral midbrain was often found to exert different effects on the same SMT cell. 4. Stimulation in the rostral medulla at sites located in nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis, and nucleus reticularis magnocellularis produced the same complement of effects observed with midbrain stimulation. Excitation followed by inhibition was the most common effect observed. 5. Stimulus intensities required to produce excitatory or inhibitory effects from midbrain were 114 +/- 85 (SD) microA and 210 +/- 91 microA, respectively. Stimulus currents required to produce excitatory or inhibitory effects from medullary stimulation sites were 124 +/- 56 microA and 70 +/- 60 microA, respectively. The mean currents required to produce mixed effects were 221 +/- 120 microA (midbrain) and 127 +/- 71 microA (medulla). Increasing the stimulus intensity used to evaluate brain stem effects increased the magnitude and duration of effects for 33 cells. Mixed effects were observed on 11 cells at stimulus intensities greater than those required to produce inhibitory-only effects. 6. Significant differences were found between the latencies of excitation and inhibition produced from different brain stem levels. These differences suggest that midbrain and medullary stimulation activate descending pathways with a wide range of conduction velocities and/or supraspinal and spinal connectivities. 7. The spinal trajectory of pathways contributing to the varied effects of brain stem stimulation as well as the complex receptive fields (RFs) of SMT cells were evaluated by the placement of lesions in the cervical spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for co-existence of thyrotropin-releasing hormone, substance P and serotonin in ventral medullary neurons that project to the intermediolateral cell column in the rat

The present study was conducted to determine if substance P-, thyrotropin-releasing hormone and/or serotonin-immunoreactivities coexist in ventral medullary neurons that project to the intermediolateral cell column in the rat. Neurons that projected to the intermediolateral cell column were identified by the presence of retrogradely transported rhodamine bead-labeled microspheres in the cell body after an injection of the microspheres into the intermediolateral cell column of the third thoracic spinal cord segment. Co-existence was determined by using a combination of dual color immunohistochemistry and serial 4-μm sections that were immunostained with different antibodies. Antibodies to substance P, serotonin, and pre-pro-thyrotropin releasing hormone 160–169 were used to identify substance P, serotonin and thyrotropin-releasing hormone, respectively. Neurons that contained substance P-, thyrotropin-releasing hormone- and/or serotonin-immunoreactivities and that projected to the intermediolateral cell column were present in the nucleus raphe magnus, the nucleus raphe pallidus, the nucleus reticularis magnocellularis pars alpha, the paragigantocellular reticular nucleus and the parapyramidal region. Neurons that projected to the intermediolateral cell column, in each of these regions, were found to contain each of the following combinations of immunoreactive neurochemicals: substance P and thyrotropin-releasing hormone; substance P and serotonin; thyrotropin-releasing hormone and serotonin; or substance P, thyrotropin-releasing hormone and serotonin. In addition, most of the regions also contained neurons that appeared to contain only one of the neurochemicals and that also projected to the intermediolateral cell column. The greatest number of neurons that projected to the intermediolateral cell column and that also contained two or more co-existing neurochemicals was present in the midline regions. This study demonstrates the presence of neurons in the ventral medulla that project to the intermediolateral cell column and contain three co-existing neurochemicals. This study also demonstrates the use of a new method for the localization of three neurochemicals in single projection-specific neurons.

Enkephalin‐immunoreactive neuronal projections from the medulla oblongata to the intermediolateral cell column: Relationship to substance P–immunoreactive neurons

The present study investigated the ventral medullary distribution of enkephalin-immunoreactive neurons that project to the intermediolateral cell column and the relationship of these neurons to substance P-immunoreactive neurons. Neurons that projected to the intermediolateral cell column were identified by the presence of rhodamine-labeled microspheres within the neuronal cell body after an injection of the microspheres into the intermediolateral cell column of the third thoracic spinal cord segment. Enkephalin- and substance P-immunoreactivities were identified by dual-color immunohisto-chemistry. Enkephalin-immunoreactive neurons that projected to the intermediolateral cell column were present in the raphe magnus, the nucleus reticularis magnocellularis pars alpha, the paragigantocellular reticular nucleus, and the parapyramidal region. These neurons were present throughout the rostrocaudal extent of each of these nuclei. However, in the raphe magnus the greatest number was present at more rostral levels of the nucleus. The morphology and distribution of enkephalin-immunoreactive neurons that projected to the intermediolateral cell column were similar to those of enkephalin-immunoreactive neurons that were not observed to contain rhodamine-labeled microspheres. Substance P- and enkephalin-immunoreactive neurons that projected to the intermediolateral cell column were present in similar distributions in each of the nuclei studied, except the raphe magnus. The raphe magnus contained more enkephalin- than substance P-immunoreactive neurons at rostral levels and more substance P-immunoreactive neurons than enkephalin-immunoreactive neurons at caudal levels. Coexistence of substance P- and enkephalin-immunoreactivities in ventral medullary neurons that projected to the intermediolateral cell column was rarely seen. These studies support the hypothesis that ventral medullary enkephalinergic neurons project to the intermediolateral cell column where they could act to modulate preganglionic sympathetic activity.

The nuclei of origin of monoaminergic, peptidergic, and cholinergic afferents to the cat nucleus reticularis magnocellularis: a double-labeling study with cholera toxin as a retrograde tracer.

Using a sensitive double-immunostaining technique with nonconjugated cholera toxin B subunit (CT) as a retrograde tracer, we examined the cells of origin and the histochemical nature of afferents to the cat nucleus reticularis magnocellularis (Mc) of the medulla oblongata. After injections of CT confined to the Mc, we found that the major afferents to the Mc arise from: (1) the lateral part of the bed nucleus of the stria terminalis, the nucleus of the anterior commissure, the preoptic area, the central nucleus of the amygdala, the posterior hypothalamus, and the nucleus of the fields of Forel; (2) the Edinger-Westphal nucleus, the mesencephalic reticular formation, and the ventrolateral part of the periaqueductal grey; (3) the nuclei locus coeruleus alpha (LC alpha), peri-LC alpha, locus subcoeruleus, and reticularis pontis oralis and caudalis; (4) the caudal raphe nuclei; and (5) the nucleus reticularis ventralis of the medulla.(ABSTRACT TRUNCATED AT 400 WORDS)

Bulbospinal thyrotropin-releasing hormone projections to the intermediolateral cell column: A double fluorescence immunohistochemical-retrograde tracing stdy in the rat

Whereas the neurochemistry of the peripheral autonomic nervous system has been well characterized, less is known concerning the neurotransmitters utilized by medullary projections onto sympathetic preganglionic neurons residing in the thoracolumbar spinal intermediolaleral cell column. Retrograde transport of rhodamine-labeled fluorescent microspheres following discrete microinjection into the thoracic intermediolateral cell column was combined with immunohistochemistry to determine neuroanatomic location of thyrotropin-releasing hormone-immunoreactive neurons which project to the intermediolateral cell column in the rat. The ventromedial group of raphe nuclei including the nucleus raphe pallidus. obscurus, and magnus possessed the greatest number of medullary thyrotropin-releasing hormone-immunoreactive neurons which also contained rhodamine-labeled microspheres. High numbers of intermediolateral cell column-projecting thyrotropin-releasing hormone-immunoreactive neurons were also observed in nucleus reticularis paragigantocellularis lateralis and magnocellularis, the lateral reticular nucleus, and the superficial ventral (arcuate) medullary surface. Despite the observations that nucleus reticularis gigantocellularis, paramedianus, and ventralis pars beta project to the intermediolateral cell column, double-labeled cells were not observed in these nuclei. Furthermore, whereas the nucleus reticularis magnocellularis and gigantocellularis, and the lateral reticular nucleus displayed strong ipsilateral predominance in projecting to the intermediolateral cell column, other medullary reticular and raphe nuclei displayed bilateral projections. The present findings support the hypothesis that thyrotropin-releasing hormone-containing neurons in the ventral medulla project to the intermediolateral cell column and may influence sympathetic preganglionic neurons.

Projections of the medial preoptic nucleus: a Phaseolus vulgaris leucoagglutinin anterograde tract-tracing study in the rat.

The projections of the medial preoptic nucleus (MPN) were examined by making injections of the anterogradely transported lectin Phaseolus vulgaris leucoagglutinin (PHA-L) into the MPN and charting the distribution of labeled fibers. The evidence indicates that the MPN projects extensively to widely distributed regions in both the forebrain and brainstem, most of which also supply inputs to the nucleus. An important neuroendocrine role for the MPN is underscored by its extensive projections to almost all parts of the periventricular zone of the hypothalamus, including the anteroventral periventricular, anterior part of the periventricular, paraventricular (PVH), and arcuate nuclei, and a role in autonomic mechanisms is indicated by projections to such regions as the dorsal and lateral parvicellular parts of the PVH, the lateral parabrachial nucleus, and the nucleus of the solitary tract. Other projections of the MPN suggest participation in the initiation of specific motivated behaviors. For example, inputs to two nuclei of the medial zone of the hypothalamus, the ventromedial and dorsomedial nuclei, may be related to the control of reproductive and ingestive behaviors, respectively, although the possible functional significance of a strong projection to the ventral premammillary nucleus is presently unclear. The execution of these behaviors may involve activation of somatomotor regions via projections to the substantia innominata, zona incerta, ventral tegmental area, and pedunculopontine nucleus. Similarly, inputs to other regions that project directly to the spinal cord, such as the periaqueductal gray, the laterodorsal tegmental nucleus, certain medullary raphe nuclei, and the magnocellular reticular nucleus may also be involved in modulating somatic and/or autonomic reflexes. Finally, the MPN may influence a wide variety of physiological mechanisms and behaviors through its massive projections to areas like the ventral part of the lateral septal nucleus, the bed nucleus of the stria terminalis, the lateral hypothalamic area, the supramammillary nucleus, and the ventral tegmental area, all of which have extensive connections with regions along the medial forebrain bundle. Although the PHA-L method does not allow a clear demonstration of possible differential projections from each subdivision of the MPN, our results suggest that each of them does give rise to a unique pattern of outputs.(ABSTRACT TRUNCATED AT 400 WORDS)

Studies on the reticulospinal tract and the vestibulospinal tract using HRP method

In 1972, Tokita et al reported that the hyperextended posture which appears after bilateral destruction of the labyrinth is due to increased antigravity muscular tonus, and they suggested that contralateral inhibition is greater than ipsilateral excitation in the vestibulospinal system. The author studied the anatomical basis of contralateral control of the vestibulospinal system in the cat.After the injection of HRP in the cervical, thoracic and lumbar spinal cord, labeled neurons were observed in the pontine and medullary reticular formation and vestibular nuclei.1) The reticulospinal tract which originates in the nucleus reticularis magnocellularis descended almost entirely ipsilaterally along the whole spinal cord. The number of fibers descending ipsilaterally was 10 to 20 times that descending contralaterally.2) The reticulospinal tract which originates in the nucleus reticularis gigantocellularis descended bilaterally along the whole spinal cord. The number of fibers descending ipsilaterally was twice that descend-ing contralaterally.3) The reticulospinal tract which originates in the nucleus reticularis pontis caudalis descended bilaterally along the whole spinal cord. The number of fibers descending ipsilaterally was the same as that descending contralaterally.4) The vestibulospinal tract which originates in the rostral portion of the descending vestibular nucleus and the medial vestibular nucleus descended bilaterally only to the cervical spinal cord.5) The vestibulospinal tract which originates in the caudal portion of the descending vestibular nucleus and the medial vestibular nucleus descended bilaterally along the whole spinal cord.6) The vestibulospinal tract which originates in the lateral vestibular nucleus descended entirely ipsilaterally along the whole spinal cord.The reticulospinal tract which originates in the nucleus reticularis gigantocellularis is important as a system which relays information from the labyrinth of one side to both ipsi- and contralateral sites along the whole spinal cord.

The distribution of substance P-, enkephalin-and dynorphin-immunoreactive neurons in the medulla of the rat and their contribution to bulbospinal pathways

This study examined the medullary distribution of peptide-containing neurons at the origin of bulbospinal pathways in the rat. Antisera directed against substance P, methionine-enkephalin-arg-glγ-leu and dynorphin B were used on sections in which spinally projecting brainstem neurons had been identified by the retrograde transport of a protein-gold complex that was injected into the spinal cord. Both the relative numbers and distribution of the different peptide-immunoreactive spinally projecting neurons differed. Methionine-enkephalin-immunoreactive neurons were twice as numerous as the substance P-immunoreactive cells and seven times more numerous than the dynorphin B-positive neurons. The methionine-enkephalin cells were found in all medullary raphénuclei, and in the ventromedial and ventrolateral medullary reticular formation. Caudally, the methionine-enkephalin cells were concentrated laterally; more rostrally, they were located more medially. Three major loci of methionine-enkephalin-immunoreactive cells were found: (1) the nucleus reticularis paragigantocellularis lateralis, at levels caudal to the facial nucleus, (2) the B3 cell group (nucleus raphémagnus and the nucleus reticularis magnocellularis, pars alpha) and the most rostral part of the B1 and B2 cell groups (nuclei raphépallidus and obscurus), (3) a dense cluster of cells that flanks the dorsal surface of the dorsal accessory olive (referred to as the nucleus interfascicularis hypoglossi, pars dorsalis). Substance P-like cells were seen in all raphénuclei except for the most anterior portion of the B3 cell group. Substance P-immunoreactive cells were also seen in both the ventromedial (nuclei reticularis ventralis and magnocellularis) and ventrolateral medulla (nucleus reticularis paragigantocellularis lateralis). Finally there was a dense concentration of substance P neurons in the nucleus interfascicularis hypoglossi, pars ventralis. The distribution of dynorphin-immunoreactive neurons differed significantly from that of methionine-enkephalin and substance P. Dynorphin cells were almost exclusively found in the ventrolateral medulla (nucleus reticularis paragigantocellularis lateralis), at all Ievels between the lateral reticular nucleus and the caudal pole of the facial nucleus. The proportion of each of these peptidergic-immunoreactive cells at the origin of bulbospinal pathways differed considerably. Substance P spinally projecting neurons were more numerous than methionine-enkephalin spinally projecting neurons. The majority of the substance P projection neurons were found in the Bl and B2 cell groups, in the adjacent ventromedial medulla and in the nucleus interfascicularis hypoglossi, pars ventralis. A few substance P projection neurons were also found in the caudal reaches of the B3 cell group. Methionine-enkephalin projection neurons were located in the rostral B1/B2 cell groups, B3 cell group and in the nucleus interfascicularis hypoglossi, pars dorsalis. None were found in caudal B1/B2 cell groups. Methionine-enkephalin projecting neurons were thus located rostral to the majority of the double-labelled substance P cells. Only scattered projection neurons were found among the methionine-enkephalin- and substance P-immunoreactive cells of the nucleus reticularis paragigantocellularis lateralis. In contrast to the large numbers of double-labelled methionine-enkephalin and substance P cells, no spinally projecting dynorphin neurons were found. We suggest that there are differential methionine-enkephalin 5-hydroxytryptamine inhibitory and substance P/5 hydroxytryptamine excitatory influences that issue from different medullary areas and are, respectively, exerted upon dorsal horn nociceptive neurons, and visceral/somatic motoneurons and intermediolateral preganglionic neurons.

Endogenous inhibitory system in pain

Electrical stimulation of several brain sites produces profound analgesia in humans, and inhibits nocifensor reflexes in animal studies. Responses of the dorsal horn nociceptive neurons evoked by stimulation onto the receptive fields are also inhibited by brain stimulation. These brain sites are Periaqueductal Gray Matter (PAG), Nucleus Raphe Magnus (NRM), Nucleus Reticularis magnocellularis (NRmc), Locus Coeruleus (LC), Lateral Hypothalamus, and others. We have explained in a general way the mechanism of these stimulation produced analgesia. The mechanism of PAG stimulation analgesia is partly due to an activation of serotonin containing neurons which descend from NRM to the spinal dorsal horn and activated by PAG stimulation. Activation of NRM neurons may produce inhibition of the nociceptive neurons of the dorsal horn by the mechanism of direct postsynaptic inhibition. Currently there is no evidence to support the theory of presynaptic inhibition. Endogenous opioid peptides do not play an important role in PAG stimulation analgesia. On the other hand, the mechanism of NRmc or LC stimulation analgesia may be due to an activation of noradrenaline containing neurons which similarly inhibit the dorsal horn nociceptive neurons in the spinal cord. At present, it still remains unknown whether endogenous opioid peptides play an important role in this type of analgesia.

Developmental abnormalities of medullary “respiratory centers” in sudden infant death syndrome

Dendritic development and gliosis in the medullary magnocellular reticular nucleus and solitary and dorsal vagal nuclei of 15 cases with sudden infant death syndrome (SIDS) and 23 control subjects were compared using morphometric Golgi and immunohistochemical methods. Developmental delay of the normal diminution of dendritic spines was found in the magnocellular reticular nucleus and/or vagal nuclei of 50 to 80% of SIDS infants. Astrocytes reactive with antisera to glial fibrillary acidic protein also increased in those regions, although dendritic spine density was inconsistent with the presence of astrogliosis in 20 to 40% of the cases. This delayed neuronal maturation of dendritic spines suggests there are immature neural respiratory control mechanisms in SIDS.

Analgesia after lesions of nucleus reticularis magnocellularis: differential effect on supraspinal versus spinal pain reflexes

The present studies examine the effect of bilateral electrolytic lesions of descending fibers arising from nucleus reticularis magnocellularis (NMC) on responding to noxious peripheral thermal or mechanical stimulation and on spinal cord mono-amine levels. The lesion effects were quantified by examining two supraspinally organized pain responses, the hot plate latency and vocalization threshold and two spinally organized nociceptive reflexes, tail flick latency and hind limb flexion threshold. Following interruption of descending NMC fibers, a profound analgesia was observed on supraspinally organized pain responses. Assay of spinal cord serotonin (5-HT) indicated that the NMC lesions also destroyed appreciable numbers of descending 5-HT fibers of passage originating in nucleus raphe magnus (RM). A modest hypersensitivity to pain occurred after control lesions in RM suggesting that the analgesia observed after NMC lesions would have been even more pronounced if RM fibers of passage had not been concomitantly destroyed. To assess whether the analgesia observed after NMC lesions was due to non-specific destruction of a given volume of reticular tissue, control lesions were placed in nucleus subcoeruleus (NSC). NSC lesions resulted in a hypersensitivity to pain and significant depletion of spinal cord noradrenaline (NA). These data suggest both that the analgesia observed after NMC lesions was not due to non-specific destruction of the reticular formation, and that descending NSC NA fibers tonically suppress pain. The above analgesic effects were observed exclusively on supraspinally organized pain responses, not spinally organized nociceptive reflexes. This supports previous studies demonstrating differential descending control of nociception in the spinal versus intact preparations. In summary, the present data suggest that descending NMC fibers tonically suppress ascending pain transmission.

Ascending and descending projections from nucleus reticularis magnocellularis and nucleus reticularis gigantocellularis: an autoradiographic and horseradish peroxidase study in the rat

The projections of the rostal medulla were studied using retrograde and orthograde transport techniques in the rat. The present horseradish peroxidase (HRP) studies indicate that the ventral portion of nucleus reticularis (NGC) and nucleus reticularis magnocellularis (NMC) project to both rostral and caudal levels of the spinal cord, while dorsal NGC projects only to the rostral cord. A differential density distribution of labeled cells was observed, with the greatest density of NGC-spinal neurons located rostral to the level of the inferior olive; and the greatest density of NMC-spinal neurons located caudally. This differential density distribution, when coupled with microiontophoretic application of [ 3H]amino acids allowed relatively independent labeling of the adjacent NGC- and NMC-spinal systems. On the basis of the HRP and autoradiographic studies 3 separate regions were delineated: dorsal NGC, ventral NGC and NMC. Descending projections from NGC were observed to the lateral vestibular nucleus, facial nucleus, hypoglossal nucleus and cuneatus. At cervical levels NGC fibers projected through the ventral and ventrolateral columns. Terminal fields were observed in laminae VII, VIII and to a lesser extent in IX. Labeled NGC fibers became difficult to follow by thoracic levels, which is consistent with the present HRP results. A continuum of descending NGC projections was observed with dorsally located NGC neurons projecting bilaterally through the ventral columns, and ventrally located NGC cells projecting through the ipsilateral ventrolateral columns. Ascending projections from NGC to the motor nucleus of V, trochlear nucleus, oculomotor nucleus, Edinger-Westphal nucleus, the ventral aspect of the periaqueductal gray, the deep and intermediate layers of the superior colliculus, nucleus parafasicularis and centromedianus, the Fields of Forel and the dorsal and lateral hypothalamic nuclei were observed. Descending projections from NMC to the dorsal nucleus of the vagus, hypoglossal nucleus, nucleus commissuralis and intercalatus were observed. At cervical levels, fibers project through the ipsilateral lateral columns, particularly its dorsal aspect. Terminal fields are located ipsilaterally in lamonae IV, V and VI, and bilaterally in VII, VIII and X. NMC projections continue through cadual levels of the spinal cord including a projection to the ipsilateral intermediolateral columns. Ascending NMC projections are limited to the ventral pontine reticular formation. The differing projections and cytoarchitecture of the rostral medulla of the rat observed in the present study are compared to that of the cat and opossum, with implications for the subdivision of this region discussed. The possible involvement of NMC and NGC projections in the modulation of pain is reviewed.

The role of 5-HT, GABA and opioid peptides in presynaptic inhibition of tooth pulp input from the medial brainstem

In decerebrate or chloralose-anaesthetized cats electrical stimulation in the spinal trigeminal nucleus evoked antidromic responses in the mandibular canine tooth pulp. Conditioning stimulation in nucleus raphe magnus (NRM) and in the adjacent contralateral medullary reticular formation, nucleus reticularis gigantocellularis (NRGC) and nucleus reticularis magnocellularis (NRMC), produced a decrease in the threshold for the antidromic responses in a proportion of the tooth pulp inputs. This was interpreted as being due to depolarization of the tooth pulp afferent terminals, reflecting presynaptic inhibition. The primary afferent depolarization (PAD) of tooth pulp afferent terminals by NRM stimulation could be selectively blocked by bicuculline applied intravenously or by iontophoresis in the terminal region. Intravenous naloxone, cinanserin and methysergide had no effect on the PAD evoked from NRM, NRGC or NRMC. Thus NRM appears to exert presynaptic inhibitory control of Aδ tooth pulp input to the spinal trigeminal nucleus via GABA-containing neurones.

Effect of interruption of bulbospinal pathways on lordosis, posture, and locomotion

The effect of interruption of descending bulbospinal projections arising from (i) the medial medullary reticular formation: nucleus reticularis gigantocellularis (NGC) and nucleus reticularis magnocellularis (NMC), (ii) nucleus raphe magnus, and (iii) nucleus subceruleus on the lordosis reflex, posture, and locomotion was examined. After interruption of descending NGC-NMC fibers, time-dependent deficits in lordosis were observed during the first two postoperative weeks with subsequent reflex recovery. A syndrome of postural and locomotor deficits occurred after NGC-NMC lesions. Postoperatively, postural reflexes were dominated by increased extensor tone which resulted in limb hyperextension. Specific time-dependent deficits in the control of extensor and flexor muscle groups involved in locomotion resulted in a motor syndrome that is detailed. After interruption of NMC fibers alone, no postural or locomotor deficits occurred and effects on lordosis were limited to the first few postoperative days. The NMC data suggested that the majority of the functional deficits seen after NGC plus NMC lesions were due to destruction of the NGC descending projections. Interruption of NSC bulbospinal fibers resulted in a significant depletion of spinal cord noradrenaline (NA) but not serotonin (5-HT). Functional deficits, when present, were limited to the first few postoperative days. Although interruption of descending NRM fibers resulted in a significant depletion of spinal cord 5-HT concentrations, greater depletions occurred in the NGC plus NMC group. No functional deficits were observed in the NRM group. These data suggest that interruption of NGC-NMC fibers destroyed the descending output from neurons which integrate the hormonal and sensory information necessary for lordosis.

Systematic mapping of descending inhibitory control by the medulla of nociceptive spinal neurones in cats

Inhibition descending the spinal cord from the medullary brainstem was systematically mapped in two dimensions in anaesthetized cats. Fifty-four ipsi- and contralateral sites and 27 ipsilateral sites were electrically stimulated with concentric bipolar or with monopolar electrodes, respectively, whilsr extracellularly recording firing of dorsal horn neurones to noxious heat. Effective bipolar stimulation, but not monopolar stimulation caused gross lesions at the stimulated sites. There were 3 ipsilateral sites at which descending inhibition was evoked with the smallest stimuli. These areas corresponded to nucleus raphe magnus, nucleus reticularis magnocellularis and the lateral tegmental field. Contralateral stimulation was as effective or more effective than ipsilateral stimulation. The inhibition of dorsal horm neurones was not due to the cardiovascular changes which sometimes accompanied stimulation of the brainstem. The data are discussed in relation to the analgesia which results from stimulating these areas of the brainstem.

Projections from the reticular formation of the medulla, the spinal trigeminal and lateral reticular nuclei to the inferior olive

Injections of tritiated l-leucine were placed in the reticular formation of the medulla, the spinal trigeminal and lateral reticular nuclei of cats and silver grain accumulations in the inferior olivary nucleus were demonstrated by autoradiography. Cells of the reticular formation located at the junction of nuclei reticularis magnocellularis and reticularis parvocellularis in the rostral medulla and within nucleus reticularis ventralis in the caudal medulla contribute four distinct projections to the olive. Three projections are distributed ipsilaterally in the caudal part of the medial accessory olive, at mid-level of the dorsal accessory olive and in the ventrolateral bend of the principal olive, at rostral levels. There is also a small contralateral projection to the caudal part of the medial accessory olive. The spinal trigeminal nucleus sends crossed projections to the rostral part of the dorsal accessory olive and adjacent ventral lamella as well as to the caudal part of the medial accessory olive. The lateral reticular nucleus sends an extensive ipsilateral projection to the caudal part of the medial accessory olive and provides a small contribution to the same subdivision, contralaterally. All these projections converge with other known afferents to the olive.

The antinociceptive action of etorphine in the dorsal horn is due to a direct spinal action and not to activation of descending inhibition

1--Etorphine, microinjected into the brainstem or administered intravenously, inhibited the firing of dorsal horn neurones to noxious heat in spinal or non-spinal anaesthetized cats and in decerebrate, non-anaesthetized cats with intact spinal cords. 2--Small doses of etorphine sometimes caused facilitation, especially when the cord was intact, but this was invariably followed by inhibition at higher doses. 3--The ED50 for inhibition (mean 3.9 micrograms/kg) after microinjection into nucleus raphe magnus, nucleus reticularis magnocellularis or the lateral tegmental field was similar at all sites in anaesthetized, non-spinal cats. 4--The ED50 for microinjection was not increased by spinal transection in anaesthetized cats (mean ED50, 2.6 micrograms/kg) and was similar to the ED50 in decerebrate, non-anaesthetized cats. 5--Intravenous administration was 2 to 3 times more effective than microinjection and the time course of inhibition was faster after intravenous administration than after microinjection. 6--It is concluded that etorphine inhibits dorsal horn neurones after microinjection or intravenous administration by a direct action on the spinal cord and not by activating a descending inhibition. After microinjection it rapidly enters the general circulation and subsequently distributes into the spinal cord. 7--It is also concluded that naloxone readily gains entry to the circulation from the brain because microinjection antagonized the effects of systemic etorphine on dorsal horn neurones in spinal cats.

Stimulation sites in periaqueductal gray, nucleus raphe magnus and adjacent regions effective in suppressing oral-facial reflexes

Electrode penetrations were made in the mesencephalon and caudal brainstem at the levels of the periaqueductal gray matter (PAG) and nucleus raphe magnus (NRM) in chloralose-anaesthetized or decerebrate cats. In a systematic fashion, mesencephalic and brainstem loci at every 1 mm of vertical depth were electrically stimulated in a series of mediolateral or anteroposterior electrode penetrations to determine the lowest stimulation threshold at eachlocus for suppressing the digastric jaw-opening reflex evoked by tooth pulp or infraorbital nerve stimulation; at some loci, the threshold current required for suppressing infraorbital nerve-evoked neck reflexes was also determined. Stimulation at sites within large regions of the mesencephalon and caudal brainstem was effective in suppressing these reflexes at less than 4 × the lowest threshold for reflex suppression in each animal. However, in these regions the areas of lowest threshold in the mesencephalon generally corresponded to the ventrolateral PAG and adjacent nucleus cuneiformis and part of the lateral reticular formation (LRF) and in the caudal brainstem they corresponded to NRM and the adjacent nuclei reticularis magnocellularis (RMC) and gigantocellularis (RGC). These findings suggest that there may be mesencephalic and caudal brainstem areas in addition to PAG and NRM that are equally effective in modulating reflex activity.

Postsynaptic inhibition of cat medullary dorsal horn neurons by stimulation of nucleus raphe magnus and other brain stem sites

Sensory responses of neurons in the medullary and spinal cord dorsal horn can be inhibited by stimulation of a number of brain stem regions. These regions include the nucleus raphe magnus (NRM), the nucleus reticularis gigantocellularis (NGC), the nucleus reticularis magnocellularis (NMC), the periaqueductal gray (PAG), and the nucleus cuneiformis (CU). The purpose of this study was to determine whether or not this inhibition is mediated by postsynaptic processes. Experiments were carried out on chloralose-anesthetized cats. The responses of 29 medullary dorsal horn (trigeminal subnucleus caudalis) cells were recorded with carbon-fiber microelectrodes. Included were cells which responded to noxious stimulation (nine cells) as well as cells which responded only to nonnoxious input. The presence of postsynaptic inhibition was tested by two indirect techniques. We studied the effects of conditioning stimulation of the five regions on the latency of antidromically activated cells and also on the firing rate of neurons excited by iontophoretically applied glutamate. Conditioning stimulation was associated with a block or increased latency of antidromic activation in 15 of 18 nociceptive and nonnociceptive neurons. These effects reflect membrane hyperpolarization, presumably resulting from postsynaptic inhibition. Furthermore, conditioning stimulation of these regions inhibited the glutamate-evoked firing of all 11 cells tested, also indicating a postsynaptic type of inhibition of medullary dorsal horn cells. Thus these results indicate that at least part of the inhibition induced by stimulation of the NRM, NGC, NMC, PAG, and the CU probably results from postsynaptic inhibitory mechanisms.

Afferent connections of the rostral medulla of the cat: a neural substrate for midbrain-medullary interactions in the modulation of pain.

In order to study the organization of the rostral medulla of the cat and its contribution to pain control mechanisms, we have examined the afferent connections of the midline nucleus raphe magnus (NRM), the laterally located nucleus reticularis magnocellularis (Rmc), and the nucleus reticularis gigantocellularis (Rgc) located dorsal to Rmc. Iontophoretic injections of HRP were made into the three regions; the distribution of retrogradely labeled neurons in brainstem and spinal cord was then mapped. While significant differences characterize the source of afferents to Rgc and NRM/Rmc, there is little to distinguish that between NRM and Rmc. The predominant spinal projection is to Rgc; fewer labeled neurons were recorded after injections into Rmc. In contrast, no significant direct spinal projection to NRM was found. All three regions receive input from widespread areas within the medullary and pontine reticular formation. The most pronounced differences in the distribution of retrogradely labeled neurons were found in the midbrain. The major projection to both NRM and Rmc derives from the periaqueductal gray (PAG) and from the adjacent nucleus cuneiformis. Labeled cells are concentrated in the dorsal and lateral PAG; few are found in the ventrolateral PAG. In contrast, Rgc receives few afferents from the PAG; however, after Rgc injections, many cells were recorded in the deep layers of the contralateral tectum. None of the injection sites produced significant labeling of the catecholamine-rich dorsolateral pontine tegmentum or of the nucleus raphe dorsalis. The demonstration of significant PAG projections to NRM/Rmc provides anatomical evidence for the hypothesis that opiate and stimulation-produced analgesia involves connections from PAG to neurons of NRM and Rmc which, in turn, inhibit spinal nociceptors.