The projections of noradrenergic neurons in the A5 catecholamine cell group to the spinal cord in the rat: anatomical evidence that A5 neurons modulate nociception

Clark, Frank M.; Proudfit, Herbert K.

doi:10.1016/0006-8993(93)90210-e

Cited by 157 publications

(116 citation statements)

References 33 publications

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“…The A5 neurons studied included those with identified axonal projections to the RVLM and NTS. Thus REM sleep is associated with silencing of noradrenergic A5 neurons and, presumably, a reduction of norepinephrine release in the NTS and RVLM (and probably also in the region of spinal preganglionic sympathetic, dorsal horn sensory neurons and other major projection sites of A5 neurons) (8,9,26). Because we found no A5 cells with axonal projections to the XII motor nucleus, the contribution of these cells to the noradrenergic excitation of XII motoneurons appears to be negligible.…”

Section: Discussionmentioning

confidence: 62%

“…The function(s) of A5 neurons is not well established, but their axonal projections suggest a major involvement of the A5 group in cardiorespiratory regulation and/or nociception (8,9,26,48). Recordings from these cells and local lesions or suppression of neuronal activity in the A5 region with muscimol show that they mediate a part of sympathoexcitatory response to stimulation of arterial chemoreceptors (30, 31; see, how- ever, Ref.…”

Section: Discussionmentioning

confidence: 99%

“…In the neonatal rat brain stem in vitro, local application of clonidine into the A5 region results in slowing of respiratory rate (15,28). Neuroanatomic studies show that descending projections of A5 cells include the dorsal horn and intermediolateral cell column in the spinal cord, ventrolateral medulla (RVLM as well as the pre-Bötzinger region containing neurons important for respiratory rhythmogenesis), NTS (a viscerosensory nucleus), and brain stem motor nuclei (1,8,9,23,26,48). However, similar to our results with clonidine microinjections, acute inhibition of cells within the A5 region with muscimol does not alter the resting arterial blood pressure or sympathetic activity in anesthetized rats (25).…”

Section: Discussionmentioning

confidence: 99%

“…Noradrenergic neurons may suppress nociceptive transmission in the spinal cord (9,48). Because A5 neurons project to the dorsal horn of the spinal cord, their silencing during REM sleep, along with the silencing of other noradrenergic neurons, may explain the increase in the size of the receptive field of dorsal horn neurons during this state (29).…”

Section: Discussionmentioning

confidence: 99%

“…11,24,25,45,46). They have extensive axonal projections that include cardiorespiratory and motor regions of the brain stem and spinal cord (1,8,9,23,36). Through these projections, they may control, among others, sympathetic and respiratory outputs and, via projection to the hypoglossal (XII) motor nucleus, may mediate noradrenergic excitation of XII motoneurons (5,22,27,40,49).…”

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confidence: 99%

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A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol

Fenik

Marchenko

Janssen

et al. 2002

Journal of Applied Physiology

112

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. A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol. J Appl Physiol 93: 1448-1456, 2002. First published June 14, 2002 10.1152/japplphysiol.00225.2002The A5 noradrenergic neurons are considered important for cardiorespiratory regulation. We hypothesized that A5 cells are silenced during rapid eye movement (REM) sleep, thereby contributing to cardiorespiratory changes and suppression of hypoglossal (XII) motoneuronal activity. We used an anesthetized, paralyzed, and artificially ventilated rat in which pontine microinjections of carbachol trigger signs of REM sleep, including hippocampal theta rhythm, motor suppression, and silencing of locus coeruleus neurons. All 16 putative noradrenergic A5 cells recorded were strongly suppressed when the REM sleep-like episodes were elicited and also after intravenous clonidine. Antidromic mapping showed that none of six neurons tested projected to the XII nucleus, whereas three of five projected to the nucleus of the solitary tract and two of four to the rostral ventrolateral medulla. Bilateral microinjections of clonidine into the A5 regions did not alter XII nerve activity. These data suggest that A5 neurons are silenced during natural REM sleep. This will lead to decreased norepinephrine release and may alter synaptic transmission in the nucleus of the solitary tract and rostral ventrolateral medulla without, however, a detectable impact on XII motoneurons. hypoglossal motoneurons; norepinephrine; nucleus of the solitary tract; pons; rapid eye movement sleep THE NOREPINEPHRINE-CONTAINING neurons of the A5 group, located in the ventrolateral pons between the root of the facial nerve and the superior olive, are considered important regulators of cardiorespiratory function (reviewed in Refs. 11,24,25,45,46). They have extensive axonal projections that include cardiorespiratory and motor regions of the brain stem and spinal cord (1,8,9,23,36). Through these projections, they may control, among others, sympathetic and respiratory outputs and, via projection to the hypoglossal (XII) motor nucleus, may mediate noradrenergic excitation of XII motoneurons (5,22,27,40,49). XII motoneurons are of particular interest because they innervate the genioglossus muscle of the tongue, an important airway dilator. Its decreased activity during sleep contributes, in predisposed individuals, to the pathophysiology of the obstructive sleep apnea syndrome (34).The noradrenergic neurons of the locus coeruleus (LC) and the sub-LC region show a robust relationship of their firing frequency with the sleep-wake cycle: the highest activity occurs during wakefulness, and the lowest during the rapid eye movement (REM) stage of sleep (6,43). Consistent with these findings, the extracellular level of norepinephrine is reduced in the XII nucleus during the motor atonia produced by electrical stimulation of the pontine reticular formation region implicated in the triggering of REM sleep (35). The noradrenergic cells of the A5 group may be similarly modulated with the sleep-wa...

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol

Fenik

Marchenko

Janssen

et al. 2002

Journal of Applied Physiology

112

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The ventrolateral medulla of the rat is connected with the spinal cord dorsal horn by an indirect descending pathway relayed in the A5 noradrenergic cell group

Tavares¹,

Lima²,

Coimbra³

1996

J. Comp. Neurol.

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The pathway conveying the descending inhibitory noradrenergic input elicited from the caudal ventrolateral medulla (VLM) onto the spinal cord dorsal horn was studied in the rat. Retrograde labeling with cholera toxin subunit B (CTb) injected into the dorsal horn was combined with immunostaining for dopamine-beta-hydroxylase (DBH) in the VLM and other brainstem nuclei containing noradrenergic cells. CTb-labeled neurons occurred in the lateral part of the VLM (VLMlat), located ventrolaterally to the DBH-immunoreactive cells of the A1 noradrenergic cell group. Neuronal profiles stained for CTb and DBH (double labeled) occurred in the A5 (31%), A6 (57%), and A7 (12%) noradrenergic cell groups. To ascertain whether noradrenergic cells targeting the spinal cord in those groups received projections from the VLMlat, this area was injected with the anterograde tracer biotinylated dextran amine (BDA). Labeled terminal fibers with boutons en passant were apposed to numerous double-stained neurons in the A5 cell group. Similar appositions occurred in small amounts in the ventral subcoerulear component of the A6. Correlated light and electron microscopic analyses of the labeled appositions revealed that the BDA-labeled axonal boutons contained spherical vesicles and were presynaptic at asymmetrical contacts to somata and dendritic profiles of the double-stained A5 neurons. These data indicate the occurrence of an indirect dysynaptic pathway connecting the VLM to the spinal cord, with a relay in the A5 cells. This pathway may convey the antinociceptive effects mediated by alpha 2-adrenoreceptors, which have been previously observed in the spinal cord following VLM stimulation.

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Noradrenergic input to nociceptive modulatory neurons in the rat rostral ventromedial medulla

Meng

Budra²,

Skinner³

et al. 1997

J. Comp. Neurol.

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Within the rostral ventromedial medulla (RVM), there are two classes of putative pain modulation neurons: ON cells and OFF cells, which respectively burst or pause prior to withdrawal reflexes elicited by noxious stimulation. Alpha-adrenergic agonists injected into the RVM produce changes in the latency of spinal nocifensive reflexes and, when iontophoretically applied, alter the firing of RVM ON but not OFF cells. To provide further information about the contribution of norepinephrine to RVM neuron function, we analyzed the distribution of tyrosine hydroxylase immunoreactive (TH-ir) appositions upon RVM ON and OFF cells. In the lightly anesthetized rat, seven ON and five OFF cells were identified by changes in their discharge rate in relation to nociceptive withdrawal reflexes and were labeled by intracellular injection of neurobiotin. Sections containing labeled cells were visualized by using avidin conjugated to a Texas Red fluorophore. Tissue with labeled cells was subsequently processed for TH-ir by using a Bodipy fluorophore conjugated secondary antibody. The distribution of the Bodipy-labeled fibers and terminals upon the Texas Red-labeled neurons was mapped using a confocal laser-scanning microscope. All the labeled neurons exhibited close TH-ir appositions. Appositions were of two types: swellings and fibers. Although the numbers and density of appositions varied among the cells, there were no consistent differences that correlated with physiological properties. Thus the overall density of appositions for ON cells (29.0 +/- 22.2 x 10(4) microns2) did not differ significantly from that for OFF cells (25.4 +/- 22.2 x 10(4) microns2). Tyrosine hydroxylase immunoreactive (TH-ir) appositions upon ON and OFF cells varied with their location along the dorso-ventral axis with more ventral neurons having a greater density of TH-ir swelling-type appositions. In a separate study, TH-ir and dopamine-beta-hydroxylase-like immunoreactivity (DBH-ir) were mapped in the same sections by using confocal microscopy. Nearly 97% of the TH-ir profiles co-localized with DBH-ir. These observations provide evidence that both ON and OFF cells in the RVM are targeted by noradrenergic inputs.

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The projections of noradrenergic neurons in the A5 catecholamine cell group to the spinal cord in the rat: anatomical evidence that A5 neurons modulate nociception

Cited by 157 publications

References 33 publications

A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol

A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol

The ventrolateral medulla of the rat is connected with the spinal cord dorsal horn by an indirect descending pathway relayed in the A5 noradrenergic cell group

Noradrenergic input to nociceptive modulatory neurons in the rat rostral ventromedial medulla

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