Biomedical subjects

Shaun F Morrison

Publications and source records attributed to Shaun F Morrison.

15 recordsLinked to original sources

PubMed2006

Kappa opioid receptor (KOR) and GAD67 immunoreactivity are found in OFF and NEUTRAL cells in the rostral ventromedial medulla.

This study combines functional and anatomical characterization of neurons in the rostral ventromedial medulla (RVM) to show distinct neurochemical phenotypes between functional classes of neurons. The RVM contains three functional classes of neurons: off cells show a pause in spontaneous activity prior to a nociceptive withdrawal reflex; on cell activity increases prior to a nociceptive reflex; and neutral cell activity does not change significantly during the nociceptive reflex. We determined if serotonin, glutamate decarboxylase (GAD67), or the kappa opioid receptor (KOR) were differentially located within these cell types as predicted by previous studies. In this study, RVM neurons were recorded extracellularly, functionally characterized, and juxtacellularly labeled with biotinamide. Fixed sections were processed for detection of biotinamide and immunfluorescence either for serotonin or for KOR and GAD67. In the first study, serotonin was found exclusively in a subset of neutral cells (33%). These data substantiate previous findings that serotonin is found in some neutral cells whose role in nociception remains unclear. In the second study, we found KOR immunoreactivity in most off (86%) and neutral (80%) cells but rarely in on (13%) cells. We also found GAD67 immunoreactivity in most off (93%) and neutral cells (80%) but less frequently in on cells (63%). Most KOR-immunoreactive cells (16 of 17) also contained GAD67 immunoreactivity regardless of cell classification. These findings support the hypothesis that KOR agonists directly inhibit off and neutral cell activity. The majority of the off and neutral cells are GABAergic, and some on cells are also GABAergic.

Animals↗

PubMed2006

Serotonin potentiates sympathetic responses evoked by spinal NMDA.

In urethane-chloralose anaesthetized, neuromuscularly blocked, ventilated rats, we examined the effects on sympathetic outflow to brown adipose tissue (BAT) of separate and simultaneous spinal microinjections of NMDA and serotonin. Microinjection of NMDA (12 pmol) into the right T4 spinal intermediolateral nucleus (IML) immediately increased ipsilateral brown adipose tissue (BAT) sympathetic nerve activity (SNA; peak: +546% of control), BAT thermogenesis (+0.8 degrees C) and heart rate (+53 beats min-1), whereas microinjection of a lower dose of NMDA (1.2 pmol) did not change any of the recorded variables. Microinjection of 5-hydroxytryptamine (5-HT, 2 nmol) into the T4 IML increased BAT SNA (peak: +342% of control) at a long latency (mean onset: 23 min). The long latency 5-HT-evoked increase in BAT SNA was prevented by microinjection of methysergide (600 pmol) into the T4 IML. The increases in BAT SNA evoked by T4 IML microinjections of NMDA (12 pmol) were significantly potentiated (two to three times larger than the response to NMDA alone) following T4 IML microinjections of 5-HT (100 pmol to 2 nmol, but not 20 pmol). Also, microinjection of 5-HT (200 pmol) converted the subthreshold dose of NMDA (1.2 pmol) into an effective dose for increasing BAT SNA and heart rate. The 5-HT-mediated potentiation of the increase in BAT SNA evoked by microinjection of NMDA into the T4 IML was reversed by microinjection of methysergide (600 pmol) into the T4 IML. These results demonstrate that BAT SNA and thermogenesis can be driven by activation of spinal excitatory amino acid or 5-HT receptors and that concomitant activation of spinal NMDA and 5-HT receptors can act synergistically to markedly increase BAT SNA and thermogenesis.

Action Potentials↗

PubMed2006

Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue.

Control of thermoregulatory effectors by the autonomic nervous system is a critical component of rapid cold-defense responses, which are triggered by thermal information from the skin. However, the central autonomic mechanism driving thermoregulatory effector responses to skin thermal signals remains to be determined. Here, we examined the involvement of several autonomic brain regions in sympathetic thermogenic responses in brown adipose tissue (BAT) to skin cooling in urethane-chloralose-anesthetized rats by monitoring thermogenic [BAT sympathetic nerve activity (SNA) and BAT temperature], metabolic (expired CO(2)), and cardiovascular (arterial pressure and heart rate) parameters. Acute skin cooling, which did not reduce either rectal (core) or brain temperature, evoked increases in BAT SNA, BAT temperature, expired CO(2), and heart rate. Skin cooling-evoked thermogenic, metabolic, and heart rate responses were inhibited by bilateral microinjections of bicuculline (GABA(A) receptor antagonist) into the preoptic area (POA), by bilateral microinjections of muscimol (GABA(A) receptor agonist) into the dorsomedial hypothalamic nucleus (DMH), or by microinjection of muscimol, glycine, 8-OH-DPAT (5-HT(1A) receptor agonist), or kynurenate (nonselective antagonist for ionotropic excitatory amino acid receptors) into the rostral raphe pallidus nucleus (rRPa) but not by bilateral muscimol injections into the lateral/dorsolateral part or ventrolateral part of the caudal periaqueductal gray. These results implicate the POA, DMH, and rRPa in the central efferent pathways for thermogenic, metabolic, and cardiac responses to skin cooling, and suggest that these pathways can be modulated by serotonergic inputs to the medullary raphe.

Adipose Tissue, Brown↗

PubMed2006

Glutamate receptors in the raphe pallidus mediate brown adipose tissue thermogenesis evoked by activation of dorsomedial hypothalamic neurons.

Disinhibition of DMH neurons with the GABAA receptor antagonist, bicuculline, increases heart rate (HR) and augments both brown adipose tissue sympathetic nerve activity (BAT SNA) and renal SNA (RSNA) contributing to the evoked increases in BAT thermogenesis and arterial pressure (AP). We determined the role of glutamate receptor activation in the rostral raphe pallidus (RPa) in mediating the sympathoexcitatory responses in HR, BAT SNA and RSNA following disinhibition of DMH neurons in urethane/chloralose anesthetized, artificially ventilated rats. Microinjections of either the selective NMDA receptor agonist, NMDA, or the selective non-NMDA receptor agonist, kainic acid (KA), into the RPa produced increases in BAT SNA (peak: + 502% and + 408% of control, respectively) and BAT temperature (peak: + 0.6 degrees C and + 1.0 degrees C) accompanied by rises in HR (peak: + 38 and + 63 bpm), RSNA (peak: + 57% and + 58% of control) and MAP (peak: + 12 and 15 mmHg). These responses were reversed by subsequent microinjection into RPa of the respective selective glutamate receptor antagonists, AP5 and CNQX. Microinjections of the non-selective glutamate receptor antagonist, kynurenic acid (Kyn), the NMDA receptor antagonist, AP5, or the non-NMDA receptor antagonist, CNQX, were effective in reversing the increases in BAT SNA (for Kyn, from peak of + 419% of control to + 9% of control) and BAT temperature, but not those in HR, MAP or RSNA (for Kyn, from peak of + 143% of control to + 124% of control) evoked by unilateral microinjection of bicuculline into the DMH. These results indicate that both NMDA and non-NMDA glutamate receptors in the RPa play a significant role in mediating the excitatory synaptic transmission producing the activation of BAT thermogenesis following disinhibition of DMH neurons. Glutamate receptors in the RPa may not be important for transmitting cardiovascular responses induced by activation of the DMH neurons.

Action Potentials↗

PubMed2006

Differentiated hemodynamic changes controlled by splanchnic nerve.

The splanchnic (SPL) nerve is a postganglionic sympathetic nerve involved in the tonic regulation of the cardiovascular system. Electrical stimulation of this nerve produces mesenteric vasoconstriction and it has been assumed that vasodilatory responses are dependent on inhibition of the vasoconstrictor tone. Several different central stimuli have been shown to dilate the hindquarter vascular bed and constrict the mesenteric vascular bed. To determine whether vasodilatory and vasoconstrictor effects in different vascular beds are elicited by activation of different sympathetic nerves, we investigated the hemodynamic changes in hindquarter, mesenteric and renal vascular beds evoked by electrical stimulation of the SPL nerve. Stimulation of the intact or sectioned SPL nerve in chloralose-anesthetized, artificially ventilated rats evoked increases in the hindquarter vascular conductance and simultaneously decreased the mesenteric and renal vascular conductance. Intravenous (i.v.) administration of L-NAME prior to stimulation of the proximal end of the sectioned SPL nerve abolished the increase in hindquarter conductance, suggesting the involvement of nitric oxide in this response. In assessing the hemodynamic effects of tonic activity on the SPL nerves, no significant changes were observed after unilateral section of the SPL nerve, but bilateral section of the SPL nerves decreased hindquarter conductance and did not significantly change the mesenteric conductance simultaneously. No consistent response was observed in the renal vascular bed after unilateral and subsequent contralateral section of the SPL nerves. These findings demonstrate that electrical stimulation of the SPL nerve produces mesenteric vasoconstriction and simultaneous hindquarter vasodilatation, which is mediated by nitric oxide. Moreover, the present data suggest that SPL nerves may provide a tonic vasodilatory tone in the hindquarter vascular bed and simultaneously a vasoconstrictor tone in another, undetermined vascular bed.

Analysis of Variance↗

PubMed2006

Rostral ventromedial periaqueductal gray: a source of inhibition of the sympathetic outflow to brown adipose tissue.

Central inhibitory pathways play a significant role in determining the level of sympathetic outflow to the cold defense efferents in mammals. We tested the hypothesis that neurons in the rostral ventromedial periaqueductal gray (rvmPAG) are a source of inhibitory regulation of the sympathetic nerve activity (SNA) to brown adipose tissue (BAT). In urethane/chloralose-anesthetized, paralyzed, artificially ventilated rats, microinjection of PGE2 (200 pmol in 70 nl) into the medial preoptic area (POA) or microinjection of the GABAA antagonists, bicuculline or SR95531 (60 pmol in 60 nl), into the dorsomedial hypothalamic area (DMH) increased BAT SNA by +853 +/- 176 and +898 +/- 249% of control, respectively. These evoked increases in BAT SNA were reversed by microinjection of bicuculline (60 pmol in 60 nl) into the rvmPAG at the level of the posterior commissure. Microinjection of muscimol (160 pmol in 80 nl) into the rvmPAG increased BAT SNA by an amount (+191 +/- 92% of control) that was significantly (P < 0.05) smaller than the peak increase observed after bicuculline microinjection into the rostral raphe pallidus (+1340 +/- 547% of control), but not different from that observed after transaction of the midbrain posterior to the rvmPAG (+423 +/- 123% of control). We conclude that the rvmPAG contains neurons that exert an inhibitory influence on the sympathetic outflow to BAT. These BAT sympathoinhibitory neurons are, themselves, under a tonic GABAergic inhibition. Blockade of this tonic inhibition reveals an inhibitory influence of rvmPAG neurons that is capable of reversing BAT SNA activations from POA or from DMH. Augmenting the tonic inhibition of rvmPAG neurons elicits a modest increase in BAT SNA. Neurons in rvmPAG provide some, but not all, of the tonic inhibition regulating the discharge of BAT sympathetic premotor neurons in RPa and ultimately the level of thermogenesis in BAT.

Adipose Tissue, Brown↗

PubMed2005

Regulation of thermogenesis by the central melanocortin system.

Adaptive thermogenesis represents one of the important homeostatic mechanisms by which the body maintains appropriate levels of stored energy and its core temperature. Dysregulation of adaptive thermogenesis promotes obesity. The central melanocortin system, in particular the melanocortin 4 receptor (MC4R) signaling pathway, influences the regulation of every aspect of energy balance, including thermogenesis, and plays a critical role in energy homeostasis in both rodent and man. This review will outline our current understanding of adaptive thermogenesis, focusing on the role of the central melanocortin pathway in the regulation of thermogenesis.

Adaptation, Physiological↗

PubMed2005

Direct pyrogenic input from prostaglandin EP3 receptor-expressing preoptic neurons to the dorsomedial hypothalamus.

Fever is induced by a neuronal mechanism in the brain. Prostaglandin (PG) E2 acts as a pyrogenic mediator in the preoptic area (POA) probably through the EP3 subtype of PGE receptor expressed on GABAergic neurons, and this PGE2 action triggers neuronal pathways for sympathetic thermogenesis in peripheral effector organs including brown adipose tissue (BAT). To explore pyrogenic efferent pathways from the POA, we determined projection targets of EP3 receptor-expressing POA neurons with a special focus on rat hypothalamic regions including the dorsomedial hypothalamic nucleus (DMH), which is known as a center for autonomic responses to stress. Among injections of cholera toxin b-subunit (CTb), a retrograde tracer, into hypothalamic regions at the rostrocaudal level of the DMH, injections into the DMH, lateral hypothalamic area (LH) and dorsal hypothalamic area (DH) resulted in EP3 receptor immunolabelling in substantial populations of CTb-labeled neurons in the POA. Bilateral microinjections of muscimol, a GABA(A) receptor agonist, into the DMH and a ventral region of the DH, but not those into the LH, inhibited thermogenic (BAT sympathetic nerve activity, BAT temperature, core body temperature and expired CO2) and cardiovascular (arterial pressure and heart rate) responses to an intra-POA PGE2 microinjection. Further immunohistochemical observations revealed a close association of POA-derived GABAergic axon swellings with DMH neurons projecting to the medullary raphe regions where sympathetic premotor neurons for febrile and thermoregulatory responses are localized. These results suggest that a direct projection of EP3 receptor-expressing POA neurons to the DMH/DH region mediates febrile responses via a GABAergic mechanism.

Adipose Tissue, Brown↗

PubMed2004

Brown adipose tissue thermogenesis contributes to fentanyl-evoked hyperthermia.

Mu-opioid receptor activation increases body temperature and affects cardiovascular function. In the present study, fentanyl was administered intravenously [100 mug/kg (300 nmol/kg) iv] and intracerebroventricularly [3.4 mug (10 nmol) in 10 microl icv] in urethane-chloralose-anesthetized, artificially ventilated rats. Increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA) (peak, +326% of control), BAT temperature (peak, +0.8 degrees C), renal SNA (peak, +146% of control), and heart rate (HR; peak, +32 beats/min) produced by intravenous fentanyl were abolished by premamillary transection of the neuraxis but were mimicked by intracerebroventricular administration of fentanyl, which also increased arterial pressure (AP; peak, +12 mmHg). Pretreatment with the opioid antagonist naloxone (100 nmol in 10 microl icv) eliminated the intracerebroventricular fentanyl-evoked responses. Microinjection of glycine (0.5 M, 60 nl) to inhibit local neurons in the rostral raphe pallidus (RPa) selectively reversed the intracerebroventricular fentanyl-evoked increases in BAT SNA and HR, while the fentanyl-evoked excitation in RSNA, the pressor responses, and the tachycardic responses were reversed by inhibition of neurons in the rostral ventrolateral medulla (RVLM). Prior inhibition of neurons in the dorsomedial hypothalamus eliminated the intracerebroventricular fentanyl-evoked increases in BAT SNA, BAT temperature, and HR, but not those in RSNA or AP. These results indicate that activation of central mu-opioid receptors with fentanyl can elicit BAT thermogenesis and cardiovascular stimulation through excitation of the sympathetic outflows to BAT, kidney, and heart. Activation of neurons in the rostral RPa and RVLM are essential for the increases in BAT thermogenesis and renal sympathoexcitation, respectively, induced by activation of central mu-opioid receptors. BAT thermogenesis could contribute to fentanyl-evoked hyperthermia, particularly in infants where BAT plays a significant role in thermoregulation.

Adipose Tissue, Brown↗

PubMed2004

Activation of 5-HT1A receptors in raphe pallidus inhibits leptin-evoked increases in brown adipose tissue thermogenesis.

To elucidate the central neural pathways contributing to the thermogenic component of the autonomic response to intravenous administration of leptin, experiments were conducted in urethane-chloralose-anesthetized, ventilated rats to address 1) the role of neurons in the rostral ventromedial medulla, including raphe pallidus (RPa), in the leptin-evoked stimulation of brown adipose tissue (BAT) sympathetic nerve activity (SNA); and 2) the potential thermolytic effect of 5-hydroxytryptamine(1A) (5-HT(1A)) receptors on RPa neurons that influence BAT thermogenesis. Leptin (1 mg/kg) administration increased BAT SNA by 1,219% of control, BAT temperature by 2.8 degrees C, expired CO(2) by 1.8%, heart rate by 90 beats/min, and mean arterial pressure by 12 mmHg. Microinjection of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into RPa resulted in a prompt and sustained reversal of the leptin-evoked stimulation of BAT SNA, BAT thermogenesis, and heart rate, with these variables returning to their pre-leptin control levels. Subsequent microinjection of the selective 5-HT(1A) receptor antagonist WAY-100635 into RPa reversed the BAT thermolytic effects of 8-OH-DPAT, returning BAT SNA and BAT temperature to the elevated levels after leptin. In conclusion, activation of neurons in RPa, possibly BAT sympathetic premotor neurons, is essential for the increases in BAT SNA, BAT thermogenesis, and heart rate stimulated by intravenous administration of leptin. Neurons in RPa express 5-HT(1A) receptors whose activation leads to reversal of the BAT thermogenic and the cardiovascular responses to intravenous leptin, possibly through hyperpolarization of local sympathetic premotor neurons. These results contribute to our understanding of central neural substrates for the augmented energy expenditure stimulated by leptin.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2004

Central pathways controlling brown adipose tissue thermogenesis.

Heat production in brown adipose tissue contributes to cold defense, to stress-induced increases in body temperature, and to energy balance. Elucidating the functional organization of the central network controlling the sympathetic outflow to brown adipose tissue could provide a framework for understanding how dysregulation of thermogenesis contributes to hyperthermia and to obesity.

Adipose Tissue, Brown↗

PubMed2003

Disinhibition of rostral raphe pallidus neurons increases cardiac sympathetic nerve activity and heart rate.

We determined the cardiovascular effects of microinjecting the GABA(A) receptor antagonist, bicuculline, into the rostral raphe pallidus (RPa) on arterial pressure (AP), heart rate (HR) and cardiac sympathetic nerve activity (CSNA) in urethane-chloralose anesthetized, artificially-ventilated rats. In 26 animals, microinjection of the GABA(A) receptor antagonist, bicuculline (2 mM, 30 nl), into RPa increased CSNA (+234+/-64% of control), HR (+91+/-10 bpm) and mean AP (+16+/-3 mmHg). A similar tachycardia was evoked after removal of both adrenal glands, but was absent after beta-adrenergic receptor blockade with atenolol. Equivalent percentage increases in CSNA and HR were evoked by disinhibition of the rostral RPa neurons after inhibition of cardiovascular sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) with bilateral microinjections of the GABA(A) receptor agonist, muscimol (6 mM, 50 nl) which markedly lowered CSNA, HR and AP. These results indicate that RPa contains a population of neurons, possibly sympathetic premotor neurons with direct projections to spinal cardiac sympathetic preganglionic neurons, that receive a tonic, GABAergic inhibition and thus do not contribute markedly to resting levels of CSNA and HR, but when disinhibited, they can produce large increases in CSNA and HR comparable to those seen during certain stress responses.

Adrenal Glands↗

PubMed2003

Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure.

The thermogenic activity of interscapular brown adipose tissue (IBAT) in response to physiologic stimuli, such as cold exposure, is controlled by its sympathetic innervation. To determine which brain regions might be involved in the regulation of cold-evoked increases in sympathetic outflow to IBAT, the present study compared central nervous system (CNS) areas activated by cold exposure with brain regions anatomically linked to the sympathetic innervation of IBAT. Immunocytochemical localization of Fos was examined in the brains of rats exposed to 4 degrees C for 4 hours. In a separate group of rats, the neural circuit involved in IBAT control, including the location of sympathetic preganglionic neurons in the spinal cord, was characterized with pseudorabies virus, a retrograde transynaptic tracer. Central noradrenergic and serotonergic groups related to the sympathetic outflow to IBAT also were identified. Localization of viral antigens at different survival times (66-96 hours) revealed infection in circumscribed CNS populations, but only a subset of the regions comprising this circuitry showed cold-evoked Fos expression. The raphe pallidus and the ventromedial parvicellular subdivision of the paraventricular hypothalamic nucleus (PVH), both infected at early survival times, were the main areas containing sympathetic premotor neurons activated by cold exposure. Major cold-sensitive areas projecting to spinal interneurons or to regions containing sympathetic premotor neurons, which became infected at intermediate intervals, included lateral hypothalamic, perifornical, and retrochiasmatic areas, anterior and posterior PVH, ventrolateral periaqueductal gray, and Barrington's nucleus. Areas infected later, most likely related to reception of cold-related signals, comprised the lateral preoptic area, parastrial nucleus, dorsomedial hypothalamic nucleus, lateral parabrachial nucleus, and nucleus of the solitary tract. These interconnected areas, identified by combining functional and retrograde anatomic approaches, likely constitute the central circuitry responsible for the increase in sympathetic outflow to IBAT during cold-evoked thermogenesis.

Adipose Tissue, Brown↗

PubMed2003

Glutamate transmission in the rostral ventrolateral medullary sympathetic premotor pathway.

1. The aim of these studies was to test the hypothesis that glutamate is the principal excitatory neurotransmitter in the sympathetic premotor pathway from the rostral ventrolateral medulla (RVLM) to the sympathetic preganglionic neurons (SPNs) in the thoracic spinal cord. 2. Iontophoretic and pressure ejection of glutamate receptor agonists and antagonists was made onto antidromically identified splanchnic and adrenal SPNs before and during electrical stimulation of the RVLM in urethane/chloralose-anesthetized, artificially ventilated rats. 3. SPNs were excited by both NMDA and non-NMDA glutamate receptor agonists. Blockade of glutamate receptors in the IML interrupted the ability of electrical activation of sympathetic premotor neurons in the RVLM to excite SPNs. Within the IML, antergradely labeled terminals of RVLM neurons were found to contain glutamate immunoreactivity and to make asymmetric synapses on local dendrites. 4. These data support a significant role for glutamate neurotransmission in mediating the tonic and phasic excitation of SPNs by the sympathetic premotor pathway from the RVLM. It seems likely that stimulation of the RVLM produces glutamate release from both C1 and non-PNMT-containing axon terminals in the IML.

Action Potentials↗

PubMed2002

Inhibition of neurons in commissural nucleus of solitary tract reduces sympathetic nerve activity in SHR.

Neurons in the commissural nucleus of the solitary tract (commNTS) play an important role in certain cardiovascular responses dependent on sympathetic vasoconstrictor activation, including the arterial chemoreceptor reflex. Electrolytic lesions of the commNTS elicit a fall in arterial pressure (AP) in spontaneously hypertensive rats (SHR). To determine whether the latter result 1) arose from elimination of commNTS neuronal activity rather than en passant axons and 2) was accompanied by a reduction in sympathetic nerve activity, we evaluated the effect of inhibition of neurons in the commNTS on basal splanchnic sympathetic nerve activity (SNA), AP, and heart rate (HR) in SHR, Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats. In chloralose-anesthetized, paralyzed, and artificially ventilated SHR, microinjection of GABA into the commNTS markedly decreased splanchnic SNA, AP, and HR. The reductions in SNA and AP following similar microinjections in WKY and SD rats were significantly less than those in SHR. Our findings suggest that tonically active neurons in the commNTS contribute to the maintenance of SNA and the hypertension in SHR. The level of tonic discharge of these commNTS neurons in normotensive WKY and SD rats may be lower than in SHR.

Animals↗