Maria C Almeida

St. Joseph's Hospital and Medical Center (AZ, USA), Phoenix, Arizona, United States

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Publications (12)55.76 Total impact

  • 02/2010: pages 349 - 402; , ISBN: 9780470588284
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    ABSTRACT: The development of antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel as pain therapeutics has revealed that these compounds cause hyperthermia in humans. This undesirable on-target side effect has triggered a surge of interest in the role of TRPV1 in thermoregulation and revived the hypothesis that TRPV1 channels serve as thermosensors. We review literature data on the distribution of TRPV1 channels in the body and on thermoregulatory responses to TRPV1 agonists and antagonists. We propose that two principal populations of TRPV1-expressing cells have connections with efferent thermoeffector pathways: 1) first-order sensory (polymodal), glutamatergic dorsal-root (and possibly nodose) ganglia neurons that innervate the abdominal viscera and 2) higher-order sensory, glutamatergic neurons presumably located in the median preoptic hypothalamic nucleus. We further hypothesize that all thermoregulatory responses to TRPV1 agonists and antagonists and thermoregulatory manifestations of TRPV1 desensitization stem from primary actions on these two neuronal populations. Agonists act primarily centrally on population 2; antagonists act primarily peripherally on population 1. We analyze what roles TRPV1 might play in thermoregulation and conclude that this channel does not serve as a thermosensor, at least not under physiological conditions. In the hypothalamus, TRPV1 channels are inactive at common brain temperatures. In the abdomen, TRPV1 channels are tonically activated, but not by temperature. However, tonic activation of visceral TRPV1 by nonthermal factors suppresses autonomic cold-defense effectors and, consequently, body temperature. Blockade of this activation by TRPV1 antagonists disinhibits thermoeffectors and causes hyperthermia. Strategies for creating hyperthermia-free TRPV1 antagonists are outlined. The potential physiological and pathological significance of TRPV1-mediated thermoregulatory effects is discussed.
    Pharmacological reviews 09/2009; 61(3):228-61. · 17.00 Impact Factor
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    ABSTRACT: An involvement of the transient receptor potential vanilloid (TRPV) 1 channel in the regulation of body temperature (T(b)) has not been established decisively. To provide decisive evidence for such an involvement and determine its mechanisms were the aims of the present study. We synthesized a new TRPV1 antagonist, AMG0347 [(E)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide], and characterized it in vitro. We then found that this drug is the most potent TRPV1 antagonist known to increase T(b) of rats and mice and showed (by using knock-out mice) that the entire hyperthermic effect of AMG0347 is TRPV1 dependent. AMG0347-induced hyperthermia was brought about by one or both of the two major autonomic cold-defense effector mechanisms (tail-skin vasoconstriction and/or thermogenesis), but it did not involve warmth-seeking behavior. The magnitude of the hyperthermic response depended on neither T(b) nor tail-skin temperature at the time of AMG0347 administration, thus indicating that AMG0347-induced hyperthermia results from blockade of tonic TRPV1 activation by nonthermal factors. AMG0347 was no more effective in causing hyperthermia when administered into the brain (intracerebroventricularly) or spinal cord (intrathecally) than when given systemically (intravenously), which indicates a peripheral site of action. We then established that localized intra-abdominal desensitization of TRPV1 channels with intraperitoneal resiniferatoxin blocks the T(b) response to systemic AMG0347; the extent of desensitization was determined by using a comprehensive battery of functional tests. We conclude that tonic activation of TRPV1 channels in the abdominal viscera by yet unidentified nonthermal factors inhibits skin vasoconstriction and thermogenesis, thus having a suppressive effect on T(b).
    Journal of Neuroscience 08/2007; 27(28):7459-68. · 6.91 Impact Factor
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    ABSTRACT: Carbon monoxide (CO) has been identified as a diffusible signaling messenger in the brain, capable of altering body temperature by stimulating soluble guanylate cyclase (sGC). However, its site of action remains unclear. Locus coeruleus (LC) is rich not only in sGC but also in heme oxygenase (HO; the enzyme that catalyses the metabolism of heme to CO, along with biliverdin and free iron). Therefore, the possible role of the HO-CO-cGMP pathway in the lipopolysaccharide (LPS)-induced fever regulation by LC neurones was investigated. Induction of the HO pathway using heme-lysinate (7.6 nmol, intra-LC) attenuated the febrile response, and this effect could be prevented by pretreatment with ODQ (an sGC inhibitor; given intracerebroventricularly, 1.3 nmol). Moreover, ZnDPBG (an HO inhibitor; 5 nmol, intra-LC) augmented the febrile response. Taken together, these data suggest that CO in the LC produced by the HO pathway and acting via cGMP plays an antipyretic role during LPS-fever in rats.
    Pflügers Archiv - European Journal of Physiology 02/2007; 453(4):471-6. · 4.87 Impact Factor
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    ABSTRACT: The systemic induction of cytokines and prostaglandins plays a key role in the development of fever. However, whether fever is triggered by local injection of lipopolysaccharide (LPS) and the involvement of locally produced prostaglandins in periodontal tissue has never been assessed. Thus, we tested the hypothesis that the trigeminal nerve is a neuronal pathway that signals the brain during acute periodontitis, and this response involves prostaglandin induction. Rats were given a gingival intra-pouch injection of sterile saline or Escherichia coli lipopolysaccharide, at doses of 10 and 100 microg/kg. Some animals were pre-treated with the local anesthetic mepivacaine or had the peripheral branches of the trigeminal nerves transected. Another group of animals were pre-treated (locally or systemically) with the nonselective inhibitor of cyclooxygenases diclofenac. Body core temperature (T (b)) was measured by means of biotelemetry before and after injections. LPS elicited a dose-dependent increase in T (b), which was abolished by mepivacaine, bilateral transection of the peripheral branches of the trigeminal nerve, or local treatment with diclofenac. The results indicate that there is an activation of periodontal nerves to induce fever by LPS. It also shows that local formation of prostaglandins plays a role in fever development. Moreover, immunohistochemistry detected c-fos expression in the subnucleus caudalis of spinal trigeminal nucleus and in the preoptic area of the hypothalamus 2 and 3 h after LPS injection, further confirming the role of trigeminal nerve signaling brain in acute periodontitis.
    Pflügers Archiv - European Journal of Physiology 11/2006; 453(1):73-82. · 4.87 Impact Factor
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    ABSTRACT: Systemic inflammation (SI) is a leading cause of hospital death. Although fever and hypothermia are listed as symptoms in every definition of SI, how SI affects thermoregulatory behavior is unclear. SI is often modeled by systemic administration of bacterial lipopolysaccharide (LPS) to rats. When rats are not allowed to regulate their body temperature (Tb) behaviorally, LPS causes either fever or hypothermia, and the direction of the response is determined by LPS dose and ambient temperature (Ta). However, in many studies in which rats were allowed to regulate Tb behaviorally (by selecting their preferred Ta in a thermogradient apparatus), they consistently expressed warmth-seeking behavior and developed fever. We hypothesized that SI can cause not only warmth-seeking behavior but also cold-seeking behavior; we then tested this hypothesis by studying LPS-induced thermoregulatory behavior in adult Wistar rats. A multichannel thermogradient apparatus, implantable data loggers and infrared thermography were used; multiple control experiments were conducted; and the ability of the apparatus to reliably register the changes in rats' preferred Ta induced by thermal (external cooling or heating) or chemical (TRPV1 or TRPM8 agonist) stimuli was confirmed. The rats responded to a low dose of LPS (10 microg/kg i.v.) with warmth-seeking behavior and a polyphasic fever, but to a high dose (5 mg/kg i.v.) with marked cold-seeking behavior and hypothermia followed by warmth-seeking behavior and fever. This is the first well-controlled study to report SI-associated cold-seeking behavior in rats. Cold-seeking behavior is likely to be an important defense response in severe SI.
    European Journal of Neuroscience 07/2006; 23(12):3359-67. · 3.75 Impact Factor
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    ABSTRACT: Systemic inflammation is a leading cause of hospital death. Mild systemic inflammation is accompanied by warmth-seeking behavior (and fever), whereas severe inflammation is associated with cold-seeking behavior (and hypothermia). Both behaviors are adaptive. Which brain structures mediate which behavior is unknown. The involvement of hypothalamic structures, namely, the preoptic area (POA), paraventricular nucleus (PVH), or dorsomedial nucleus (DMH), in thermoregulatory behaviors associated with endotoxin (lipopolysaccharide [LPS])-induced systemic inflammation was studied in rats. The rats were allowed to select their thermal environment by freely moving in a thermogradient apparatus. A low intravenous dose of Escherichia coli LPS (10 microg/kg) caused warmth-seeking behavior, whereas a high, shock-inducing dose (5,000 microg/kg) caused cold-seeking behavior. Bilateral electrocoagulation of the PVH or DMH, but not of the POA, prevented this cold-seeking response. Lesioning the DMH with ibotenic acid, an excitotoxin that destroys neuronal bodies but spares fibers of passage, also prevented LPS-induced cold-seeking behavior; lesioning the PVH with ibotenate did not affect it. Lesion of no structure affected cold-seeking behavior induced by heat exposure or by pharmacological stimulation of the transient receptor potential (TRP) vanilloid-1 channel ("warmth receptor"). Nor did any lesion affect warmth-seeking behavior induced by a low dose of LPS, cold exposure, or pharmacological stimulation of the TRP melastatin-8 ("cold receptor"). We conclude that LPS-induced cold-seeking response is mediated by neuronal bodies located in the DMH and neural fibers passing through the PVH. These are the first two landmarks on the map of the circuitry of cold-seeking behavior associated with endotoxin shock.
    PLoS ONE 02/2006; 1:e1. · 3.73 Impact Factor
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    ABSTRACT: The injection of repeated doses of lipopolysaccharide (LPS) results in attenuation of the febrile response, which is called endotoxin tolerance. We tested the hypothesis that nitric oxide (NO) arising from inducible NO synthase (iNOS) plays a role in endotoxin tolerance, using not only pharmacological trials but also genetically engineered mice. Body core temperature was measured by biotelemetry in mice treated with NG-monomethyl-L-arginine (L-NMMA, 40 mg/kg; a nonselective NO synthase inhibitor) or aminoguanidine (AG, 10 mg/kg; a selective iNOS inhibitor) and in mice deficient in the iNOS gene (iNOS KO) mice. Tolerance to LPS was induced by means of three consecutive LPS (100 microg/kg) intraperitoneal injections at 24-h intervals. In wild-type mice, we observed a significant reduction of the febrile response to repeated administration of LPS. Injection of L-NMMA and AG markedly enhanced the febrile response to LPS in tolerant animals. Conversely, iNOS-KO mice repeatedly injected with LPS did not become tolerant to the pyrogenic effect of LPS. These data are consistent with the notion that NO modulates LPS tolerance in mice and that iNOS isoform is involved in NO synthesis during LPS tolerance.
    Journal of Applied Physiology 05/2005; 98(4):1322-7. · 3.48 Impact Factor
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    ABSTRACT: Systemic inflammation is accompanied by changes in body temperature, either fever or hypothermia. Over the past decade, the rat and mouse have become the predominant animal models, and new species-specific tools (recombinant antibodies and other proteins) and genetic manipulations have been applied to study fever and hypothermia. Remarkable progress has been achieved. It has been established that the same inflammatory agent can induce either fever or hypothermia, depending on several factors. It has also been established that experimental fevers are generally polyphasic, and that different mechanisms underlie different febrile phases. Signaling mechanisms of the most common pyrogen used, bacterial lipopolysaccharide (LPS), have been found to involve the Toll-like receptor 4. The roles of cytokines (such as interleukins-1beta and 6 and tumor necrosis factor-alpha) have been further detailed, and new early mediators (e.g., complement factor 5a and platelet-activating factor) have been proposed. Our understanding of how peripheral inflammatory messengers cross the blood-brain barrier (BBB) has changed. The view that the organum vasculosum of the lamina terminalis is the major port of entry for pyrogenic cytokines has lost its dominant position. The vagal theory has emerged and then fallen. Consensus has been reached that the BBB is not a divider preventing signal transduction, but rather the transducer itself. In the endothelial and perivascular cells of the BBB, upstream signaling molecules (e.g., pro-inflammatory cytokines) are switched to a downstream mediator, prostaglandin (PG) E2. An indispensable role of PGE2 in the febrile response to LPS has been demonstrated in studies with targeted disruption of genes encoding either PGE2-synthesizing enzymes or PGE2 receptors. The PGE2-synthesizing enzymes include numerous phospholipases (PL) A2, cyclooxygenases (COX)-1 and 2, and several newly discovered terminal PGE synthases (PGES). It has been realized that the "physiological," low-scale production of PGE2 and the accelerated synthesis of PGE2 in inflammation are catalyzed by different sets of these enzymes. The "inflammatory" set includes several isoforms of PLA2 and inducible isoforms of COX (COX-2) and microsomal (m) PGES (mPGES-1). The PGE2 receptors are multiple; one of them, EP3 is likely to be a primary "fever receptor." The effector pathways of fever start from EP3-bearing preoptic neurons. These neurons have been found to project to the raphe pallidus, where premotor sympathetic neurons driving thermogenesis in the brown fat and skin vaso-constriction are located. The rapid progress in our understanding of how thermoeffectors are controlled has revealed the inadequacy of set point-based definitions of thermoregulatory responses. New definitions (offered in this review) are based on the idea of balance of active and passive processes and use the term balance point. Inflammatory signaling and thermoeffector pathways involved in fever and hypothermia are modulated by neuropeptides and peptide hormones. Roles for several "new" peptides (e.g., leptin and orexins) have been proposed. Roles for several "old" peptides (e.g., arginine vasopressin, angiotensin II, and cholecystokinin) have been detailed or revised. New pharmacological tools to treat fevers (i.e., selective inhibitors of COX-2) have been rapidly introduced into clinical practice, but have not become magic bullets and appeared to have severe side effects. Several new targets for antipyretic therapy, including mPGES-1, have been identified.
    Frontiers in Bioscience 02/2005; 10:2193-216. · 3.29 Impact Factor
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    ABSTRACT: It is known that brain noradrenaline (norepinephrine) mediates fever, but the neuronal group involved is unknown. We studied the role of the major noradrenergic nucleus, the locus coeruleus (LC), in lipopolysaccharide (LPS)-induced fever. Male Wistar rats had their LC completely ablated electrolytically or their catecholaminergic LC neurones selectively lesioned by microinjection of 6-hydroxydopamine; the controls were sham-operated. Both lesions resulted in a marked attenuation of LPS (1 or 10 microg kg(-1), i.v.) fever at a subneutral (23 degrees C) ambient temperature (Ta). Because electrolytic and chemical lesions produced similar effects, the role of the LC in fever was further investigated using electrolytic lesions only. The levels of prostaglandin (PG) E2, the terminal mediator of fever, were equally raised in the anteroventral third ventricular region of LC-lesioned and sham-operated rats during the course of LPS fever, indicating that LC neurones are not involved in febrigenic signalling to the brain. To investigate the potential involvement of the LC in an efferent thermoregulatory neuronal pathway, the thermoregulatory response to PGE(2) (25 ng, i.c.v.) was studied at a subneutral (23 degrees C, when fever is brought about by thermogenesis) or neutral (28 degrees C, when fever is brought about by tail skin vasoconstriction) Ta. The PGE2-induced increases in metabolic rate (an index of thermogenesis) and fever were attenuated in LC-lesioned rats at 23 degrees C, whereas PGE2-induced skin vasoconstriction and fever normally developed in LC-lesioned rats at 28 degrees C. The LC-lesioned rats had attenuated PGE2 thermogenesis despite the fact that they were fully capable of activating thermogenesis in response to noradrenaline and cold exposure. It is concluded that LC neurones are part of a neuronal network that is specifically activated by PGE2 to increase thermogenesis and produce fever.
    The Journal of Physiology 08/2004; 558(Pt 1):283-94. · 4.38 Impact Factor
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    ABSTRACT: It has been reported that systemic injection of arginine vasopressin (AVP) induces a drop in body core temperature (T(c)), but little is known about the mechanisms involved. Because glutamate is an important excitatory neurotransmitter involved in a number of thermoregulatory actions, in the present study, we tested the hypothesis that glutamate plays a role in systemic AVP-induced hypothermia. Wistar rats were pretreated intracerebroventricularly (icv) with kynurenic acid, an antagonist of l-glutamate ionotropic receptors, alpha-methyl-(4-carboxyphenyl)glycine (MCPG), an antagonist of l-glutamate metabotropic receptors, or saline 15 min before intravenous injection of AVP (2 microg/kg) or saline. T(c), brown adipose tissue (BAT) temperature, blood pressure, heart rate, and tail skin temperature were measured continuously. Administration of saline icv followed by intravenous AVP caused a significant drop in T(c) brought about by a reduction in BAT thermogenesis and an increase in heat loss through the tail. MCPG treatment (icv) did not affect the fall in T(c) induced by AVP. Treatment with kynurenic acid (icv) abolished AVP-induced hypothermia but did not affect the AVP-evoked rise in blood pressure or drop in heart rate and BAT temperature. Heat loss through the tail was significantly reduced in animals injected with AVP and pretrated with kynurenic acid. These data indicate that ionotropic receptors of l-glutamate in the central nervous system participate in peripheral AVP-induced hypothermia by affecting heat loss through the tail.
    Journal of Applied Physiology 02/2003; 94(1):271-7. · 3.48 Impact Factor

Publication Stats

408 Citations
55.76 Total Impact Points

Institutions

  • 2006–2010
    • St. Joseph's Hospital and Medical Center (AZ, USA)
      Phoenix, Arizona, United States
    • St. Joseph Medical Center
      Houston, Texas, United States
  • 2007
    • St. Joseph's Hospital
      Savannah, Georgia, United States
  • 2003–2007
    • University of São Paulo
      • Faculdade de Medicina de Ribeirão Preto (FMRP)
      São Paulo, Estado de Sao Paulo, Brazil
    • Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
      San Paulo, São Paulo, Brazil