-
[show abstract]
[hide abstract]
ABSTRACT: Elevating body temperature or just the temperature of the dorsal medulla by approximately 2°C prolongs the laryngeal chemoreflex (LCR) in decerebrate neonatal piglets. We tested the hypothesis that transient receptor potential vanilloid 1 (TRPV1) receptors in the nucleus of the solitary tract (NTS) mediate thermal prolongation of the LCR. We studied the effect of a selective TRPV1 receptor antagonist on thermal prolongation of the LCR, and we tested the effect of a TRPV1 agonist on the duration of the LCR under normothermic conditions. We studied 37 decerebrate neonatal piglets between the ages of post-natal days 4 and 7. The TRPV1 receptor antagonist, 5'-iodoresiniferatoxin (65μM/L in 100nL), blocked thermal prolongation of the LCR when injected bilaterally into the region of the NTS. The TRPV1 agonist, resiniferatoxin (0.65-1.0mM/L in 100nL), prolonged the LCR after bilateral injection into the NTS even when the body temperature of each piglet was normal. The effect of the TRPV1 agonists could be blocked by treatment with the GABA(A) receptor antagonist, bicuculline, whether given intravenously (0.3mg/kg) or focally injected bilaterally into the NTS (10mM in 100nL). We conclude that TRPV1 receptors in the NTS mediate thermal prolongation of the LCR.
Respiratory Physiology & Neurobiology 01/2011; 176(1-2):21-31. · 2.24 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hyperthermic prolongation of the laryngeal chemoreflex (LCR) in decerebrate piglets is prevented or reversed by GABA(A) receptor antagonists and adenosine A(2A) (Ad-A(2A)) receptor antagonists administered in the nucleus of the solitary tract (NTS). Therefore, we tested the hypothesis that enhanced GABA(A) activity and administration of the Ad-A(2A) agonist, CGS-21680, would prolong the LCR in normothermic conditions. We studied 46 decerebrate piglets ranging from 3 to 8 postnatal days of age. Focal injection into the NTS of 100 nl of 0.5 m nipecotic acid, a GABA reuptake inhibitor, significantly (P < 0.05) prolonged the LCR in normothermic conditions in 10 of 11 animals tested. Injecting 100 nl of 5-12.5 microm CGS-21680 unilaterally or bilaterally into the NTS also prolonged the LCR in normothermic conditions (n = 15), but the effect was smaller than that of unilateral injection of nipecotic acid. Systemic administration of the GABA(A) receptor antagonist, bicuculline, prevented the CGS-21680-dependent prolongation of the LCR in normothermic animals (n = 11). We conclude that thermal prolongation of the LCR depends on a thermally sensitive process or set of neurons in the NTS, which, when activated by elevated brain temperature, enhances adenosinergic and GABAergic function in the region of the NTS. These results emphasize the importance of a thermally sensitive integrative site in the dorsal medulla that, along with sites in the ventral medulla, determine the response to laryngeal chemoreflex stimulation.
Experimental physiology 04/2010; 95(7):774-87. · 3.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Laryngeal chemoreflex (LCR) apnea occurs in infant mammals of many species in response to water or other liquids in the laryngeal lumen. The apnea can last for many seconds, sometimes leading to dangerous hypoxemia, and has therefore been considered as a possible mechanism in the Sudden Infant Death Syndrome (SIDS). We have found recently that this reflex is markedly prolonged in decerebrate piglets and anesthetized rat pups that are warmed 1-3 degrees C above their normal body temperatures. We intermittently exposed pregnant rats to cigarette smoke and examined the LCR in their four- to fifteen-day-old offspring under general anesthesia, with and without whole body warming. During warming, pups of gestationally smoke-exposed dams had significantly longer LCR-induced respiratory disruption than similarly warmed control pups. The results may be significant for the pathogenesis and/or prevention of SIDS as maternal cigarette smoking during human pregnancy and heat stress in infants are known risk factors for SIDS.
Respiratory Physiology & Neurobiology 12/2008; 165(2-3):161-6. · 2.24 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hyperthermia prolongs the laryngeal chemoreflex (LCR). Under normothermic conditions, adenosine antagonists shorten and adenosine A(2A) (Ad-A(2A)) agonists prolong the LCR. Therefore, we tested the hypothesis that SCH-58261, an Ad-A(2A) receptor antagonist, would prevent thermal prolongation of the LCR when injected unilaterally within the nucleus of the solitary tract (NTS). We studied decerebrate piglets aged 4-13 days. We elicited the LCR by injecting 0.1ml of water into the larynx and recorded integrated phrenic nerve activity. The laryngeal chemoreflex was prolonged when the body temperature of each piglet was raised approximately 2.5 degrees C, and SCH-58261 reversed the thermal prolongation of the LCR when injected into the NTS (n=13), but not when injected in the nucleus ambiguus (n=9). Injections of vehicle alone into the NTS did not alter the thermal prolongation of the LCR (n=9). We conclude that activation of adenosine receptors, perhaps located on GABAergic neurons in the NTS, contributes to thermal prolongation of the LCR.
Respiratory Physiology & Neurobiology 09/2008; 164(3):358-65. · 2.24 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We investigated the interaction between body temperature and the duration of the laryngeal chemoreflex (LCR) in decerebrate piglets. Elevating body temperature by approximately 2 degrees C prolongs the duration of the LCR and the length of apnea associated with the reflex. This thermal prolongation seems to arise within the nucleus of the solitary tract in the brainstem, and we believe the thermal effect is mediated by enhanced GABAergic neurotransmission.
Advances in experimental medicine and biology 02/2008; 605:249-54. · 1.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In neonatal mammals of many species, including human infants, apnea and other reflex responses frequently arise from stimulation of laryngeal receptors by ingested or regurgitated liquids. These reflexes, mediated by afferents in the superior laryngeal nerves (SLNs), are collectively known as the laryngeal chemoreflex (LCR) and are suspected to be responsible for some cases of the sudden infant death syndrome (SIDS). The LCR is strongly enhanced by mild increases in body temperature in decerebrate piglets, a finding that is of interest because SIDS victims are often found in overheated environments. Because of the experimental advantages of studying reflex development and mechanisms in neonatal rodents, we have developed methods for eliciting laryngeal apnea in anesthetized rat pups and have examined the influence of mild hyperthermia in animals ranging in age from 3 to 21 days. We found that apnea and respiratory disruption, elicited either by intralaryngeal water or by electrical stimulation of the SLN, occurred at all ages studied. Raising body temperature by 2-3 degrees C prolonged the respiratory disturbance in response to either stimulus. This effect of hyperthermia was prominent in the youngest animals and diminished with age. We conclude that many studies of the LCR restricted to larger neonatal animals in the past can be performed in infant rodents using appropriate methods. Moreover, the developmental changes in the LCR and in the thermal modulation of the LCR seem to follow different temporal profiles, implying that distinct neurophysiological processes may mediate the LCR and thermal prolongation of the LCR.
Journal of Applied Physiology 02/2008; 104(1):269-74. · 3.75 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The laryngeal chemoreflex (LCR) is elicited by water in the larynx and leads to apnea and respiratory disruption in immature animals. The LCR is exaggerated by the elevation of brain temperature within or near the nucleus of the solitary tract (NTS) in decerebrate piglets. Thermal prolongation of reflex apnea elicited by superior laryngeal nerve stimulation is reduced by systemic administration of GABA(A) receptor antagonists. Therefore, we tested the hypothesis that microdialysis within or near the NTS of gabazine, a GABA(A) receptor antagonist, would reverse thermal prolongation of the LCR. We examined this hypothesis in 21 decerebrate piglets (age 3-13 days). We elicited the LCR by injecting 0.1 ml of water into the larynx before and after each piglet's body temperature was elevated by approximately 2.5 degrees C and before and after 2-5 mM gabazine was dialyzed unilaterally and focally in the medulla. Elevated body temperature failed to prolong the LCR in one piglet, which was excluded from analysis. Elevated body temperature prolonged the LCR in all the remaining animals, and dialysis of gabazine into the region near the NTS (n = 10) reversed the thermal prolongation of the LCR even though body temperature remained elevated. Dialysis of gabazine in other medullary sites (n = 10) did not reverse thermal prolongation of the LCR. Gabazine had no consistent effect on baseline respiratory activity during hyperthermia. These findings are consistent with the hypothesis that hyperthermia activates GABAergic mechanisms in or near the NTS that are necessary for the thermal prolongation of the LCR.
Journal of Applied Physiology 12/2007; 103(5):1864-72. · 3.75 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We tested the hypotheses that elevated body temperature would prolong reflex apnea following electrical stimulation of the superior laryngeal nerve (SLN) in decerebrate neonatal piglets and that thermal prolongation of reflex apnea after stimulation of the SLN depended on GABAergic mechanisms. These studies were conducted in 13 decerebrate piglets (age 3-15 days). The SLN was stimulated at approximately 1.5 times the threshold stimulus level for 10 s starting at the beginning of inspiration. We measured the duration of the apnea and respiratory disruption that followed SLN stimulation. Elevating body temperature prolonged the duration of the apnea and respiratory disruption that followed SLN stimulation, and treatment with antagonists of gama-aminobutyric acid A-type (GABAA) receptors reversed the thermal prolongation of reflex apnea and the period of respiratory disruption even though body temperature remained elevated. We conclude that elevated body temperature enhances or amplifies GABAergic mechanisms that prolong the respiratory inhibition following electrical stimulation of the SLN.
Respiratory Physiology & Neurobiology 06/2007; 156(2):229-33. · 2.24 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Previously, we have identified a class of retinal degeneration mutants in Drosophila in which the normally transient interaction between arrestin2 (Arr2) and rhodopsin is stabilized and the complexes are rapidly internalized into the cell body by receptor-mediated endocytosis. The accumulation of protein complexes in the cytoplasm eventually results in photoreceptor cell death. We now show that the endocytic adapter protein AP-2 is essential for rhodopsin endocytosis through an Arr2-AP-2beta interaction, and mutations in Arr2 that disrupt its interaction with the beta subunit of AP-2 prevent endocytosis-induced retinal degeneration. We further demonstrate that if the interaction between Arr2 and AP-2 is blocked, this also results in retinal degeneration in an otherwise wild-type background. This indicates that the Arr2-AP-2 interaction is necessary for the pathology observed in a number of Drosophila visual system mutants, and suggests that regular rhodopsin turnover in wild-type photoreceptor cells by Arr2-mediated endocytosis is essential for photoreceptor cell maintenance.
Journal of Cell Science 09/2006; 119(Pt 15):3141-8. · 6.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: TGF-beta1 plays a critical role in restraining pathogenic Th1 autoimmune responses in vivo, but the mechanisms that mediate TGF-beta1's suppressive effects on CD4(+) T cell expression of IFN-gamma expression remain incompletely understood. To evaluate mechanisms by which TGF-beta1 inhibits IFN-gamma expression in CD4(+) T cells, we primed naive wild-type murine BALB/c CD4(+) T cells in vitro under Th1 development conditions in the presence or the absence of added TGF-beta1. We found that the presence of TGF-beta1 during priming of CD4(+) T cells suppressed both IFN-gamma expression during priming as well as the development of Th1 effector cells expressing IFN-gamma at a recall stimulation. TGF-beta1 inhibited the development of IFN-gamma-expressing cells in a dose-dependent fashion and in the absence of APC, indicating that TGF-beta1 can inhibit Th1 development by acting directly on the CD4(+) T cell. During priming, TGF-beta1 strongly inhibited the expression of both T-bet (T box expressed in T cells) and Stat4. We evaluated the importance of these two molecules in the suppression of IFN-gamma expression at the two phases of Th1 responses. Enforced expression of T-bet by retrovirus prevented TGF-beta1's inhibition of Th1 development, but did not prevent TGF-beta1's inhibition of IFN-gamma expression at priming. Conversely, enforced expression of Stat4 partly prevented TGF-beta1's inhibition of IFN-gamma expression during priming, but did not prevent TGF-beta1's inhibition of Th1 development. These data show that TGF-beta1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4(+) T cells at priming and at recall.
The Journal of Immunology 06/2005; 174(10):5950-8. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We tested the hypotheses that elevated body temperature would prolong reflex apnea following electrical stimulation of the superior laryngeal nerve (SLN) in decerebrate neonatal piglets and that thermal prolongation of reflex apnea after stimulation of the SLN depended on GABAergic mechanisms. These studies were conducted in 13 decerebrate piglets (age 3–15 days). The SLN was stimulated at ∼1.5 times the threshold stimulus level for 10 s starting at the beginning of inspiration. We measured the duration of the apnea and respiratory disruption that followed SLN stimulation. Elevating body temperature prolonged the duration of the apnea and respiratory disruption that followed SLN stimulation, and treatment with antagonists of gama-aminobutyric acid A-type (GABAA) receptors reversed the thermal prolongation of reflex apnea and the period of respiratory disruption even though body temperature remained elevated. We conclude that elevated body temperature enhances or amplifies GABAergic mechanisms that prolong the respiratory inhibition following electrical stimulation of the SLN.
Respiratory Physiology & Neurobiology.
-
[show abstract]
[hide abstract]
ABSTRACT: Hyperthermia prolongs the laryngeal chemoreflex (LCR). Under normothermic conditions, adenosine antagonists shorten and adenosine A2A (Ad-A2A) agonists prolong the LCR. Therefore, we tested the hypothesis that SCH-58261, an Ad-A2A receptor antagonist, would prevent thermal prolongation of the LCR when injected unilaterally within the nucleus of the solitary tract (NTS). We studied decerebrate piglets aged 4–13 days. We elicited the LCR by injecting 0.1 ml of water into the larynx and recorded integrated phrenic nerve activity. The laryngeal chemoreflex was prolonged when the body temperature of each piglet was raised ∼2.5 °C, and SCH-58261 reversed the thermal prolongation of the LCR when injected into the NTS (n = 13), but not when injected in the nucleus ambiguus (n = 9). Injections of vehicle alone into the NTS did not alter the thermal prolongation of the LCR (n = 9). We conclude that activation of adenosine receptors, perhaps located on GABAergic neurons in the NTS, contributes to thermal prolongation of the LCR.
Respiratory Physiology & Neurobiology.
-
[show abstract]
[hide abstract]
ABSTRACT: Elevating body temperature or just the temperature of the dorsal medulla by approximately 2 °C prolongs the laryngeal chemoreflex (LCR) in decerebrate neonatal piglets. We tested the hypothesis that transient receptor potential vanilloid 1 (TRPV1) receptors in the nucleus of the solitary tract (NTS) mediate thermal prolongation of the LCR. We studied the effect of a selective TRPV1 receptor antagonist on thermal prolongation of the LCR, and we tested the effect of a TRPV1 agonist on the duration of the LCR under normothermic conditions. We studied 37 decerebrate neonatal piglets between the ages of post-natal days 4 and 7. The TRPV1 receptor antagonist, 5′-iodoresiniferatoxin (65 μM/L in 100 nL), blocked thermal prolongation of the LCR when injected bilaterally into the region of the NTS. The TRPV1 agonist, resiniferatoxin (0.65–1.0 mM/L in 100 nL), prolonged the LCR after bilateral injection into the NTS even when the body temperature of each piglet was normal. The effect of the TRPV1 agonists could be blocked by treatment with the GABAA receptor antagonist, bicuculline, whether given intravenously (0.3 mg/kg) or focally injected bilaterally into the NTS (10 mM in 100 nL). We conclude that TRPV1 receptors in the NTS mediate thermal prolongation of the LCR.
Respiratory Physiology & Neurobiology.
