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35 publication(s) since Avril 1987:

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Vasopressin (antidiuretic hormone) release has been thought to be controlled by interacting osmoreceptors and Na(+)-detectors for > 20 years. Only recently, however, have molecular and cellular advances revealed how changes in the external concentration of Na+ and osmolality are detected during acute and chronic osmotic perturbations. In rat vasopressin-containing neurons, local osmosensitivity is conferred by intrinsic stretch-inactivated cation channels and by taurine release from surrounding glia. Na+ detection is accomplished by acute regulation of the permeability of stretch-inactivated channels and by changes in Na+ channel gene expression. These features provide a first glimpse of the integrative processes at work in a central osmoregulatory reflex.

Rat magnocellular neurosecretory cells (MNCs) show an intrinsic sensitivity to acute changes in fluid osmolality. Experiments in acutely isolated supraoptic MNCs have shown that these responses are due to in part to the cell volume-dependent modulation of gadolinium-sensitive 33 pS stretch-inactivated cation (SIC) channels. Previous studies in vivo have shown that the slope (i.e. gain) of the 'osmosensory' relation between VP release and plasma osmolality can be increased or decreased under various physiological and pathological conditions. Here, we review recent work that shows how changes in external [Na] and excitatory neuropeptides such as angiotensin II (Ang II), cholecystokinin (CCK) and neurotensin (NT), may influence osmosensory gain in acutely isolated MNCs. Whole-cell and single-channel recording experiments have revealed that changes in external Na cause proportional changes in osmosensory gain as a result of modified SIC channel permeability and not by affecting mechanotransduction. In contrast, Ang II, CCK, or NT appear to convergently, and directly, stimulate the osmosensory cation conductance in MNCs. Preliminary analysis in current clamp further suggests that osmosensory gain may be increased upon exposure to these excitatory peptides. Whether such mechanisms contribute to the modulation of osmosensory gain in vivo remains to be established.

2002 | Neuroscience
Ascending connections from the caudal part to the oral part of the spinal trigeminal nucleus in the rat.
Voisin DL, Domejean-Orliaguet S, Chalus M, Dallel R, Woda A

The brainstem trigeminal somatosensory complex, while sharing many common aspects with the spinal somatosensory system, displays features specific to orofacial information processing. One of those is the redundant representation of peripheral structures within the various subnuclei of the complex. A functional redundancy also exists since a single sensory modality, e.g. nociception, may be processed within different subnuclei. In the present study, we addressed the question whether anatomical connections from the caudal part to the oral part of the spinal trigeminal nucleus may support topographical and functional redundancy within the rat trigeminal somatosensory complex. The retrograde tracer tetramethylrhodamine-dextran was injected iontophoretically into the oral subnucleus of anaesthetised rats. Cell bodies labelled retrogradely from the oral subnucleus were observed in laminae III-IV and V of the ipsilateral caudal subnucleus consistently, and to a lesser degree in lamina I. Such a distribution of retrogradely labelled cells suggested that specific subsets of neurones may relay nociceptive information, and others non-nociceptive information. Furthermore, intratrigeminal connections conserved the somatotopic distribution of primary afferents in the two subnuclei. First, injections of tracer in the dorsomedial and ventrolateral parts of the oral subnucleus resulted in retrograde labelling of the dorsal and ventral parts of the caudal subnucleus respectively. Second, animals that received tracer into the ventrolateral oral subnucleus displayed more caudal labelling than animals that were injected into the dorsomedial oral subnucleus. These findings show the existence of anatomical connections from the caudal part to the oral part of the spinal trigeminal nucleus in the rat. The connections conserve the somatotopic distribution of primary afferents in the two subnuclei. They provide an anatomical substrate for the indirect activation of trigeminal oral subnucleus neurones by somatosensory stimuli through the caudal subnucleus.

Despite continuous improvements in available pain treatments, many patients with chronic pain still remain insufficiently relieved. Although such therapeutic failures are often ascribed to pharmacological or psychological factors, difficulties in elucidating pain-generating mechanisms may be the main cause of insufficient pain management. These difficulties arise from several origins, including the unsuitability of the usual classification of pain, the exclusive use of etiology or symptom criteria as the main dimension of pain to guide the choice of therapeutic agents, the inadequate interpretation of sensory deficit, the lack of identification of the injured tissues, the absence of objective pain assessment by psychophysical methods. In this paper, we review briefly some fundamental knowledge to determine pain treatment based on the identification of the physiopathological mechanisms of pain. We advocate that once pain-generating mechanisms are known, it becomes possible to establish the appropriate treatment of pain.

Deep dorsal horn neurons present plateau properties involved in non-linear integration of nociceptive inputs, in the windup of the discharge, and in the expression of long-lasting afterdischarges. In vitro experiments using intracellular recordings in a slice preparation of the rat spinal cord have established that they are supported in part by voltage-dependent calcium currents, and positively modulated by metabotropic glutamate receptor activation. In the present study, whole-cell patch-clamp recordings in acutely isolated soma of dorsal horn neurons (n=48) were used to analyse the voltage-dependent calcium currents involved.Deep dorsal horn neurons expressed both inactivating and non-inactivating calcium currents with Ca(2+) or Ba(2+) used as a charge carrier. The non-inactivating component activated at intermediate threshold (-55mV), and was blocked mostly by nifedipine (61+/-6%). Although voltage-dependent facilitation of whole-cell calcium currents could be obtained by prepulses to +100mV, repetitive depolarization at potentials compatible with the plateau (-45mV and -10mV) failed to induce facilitation of calcium currents. No direct modulation of somatic calcium currents by application of (S)-3,5-dihydroxyphenylglycine, a selective group I metabotropic glutamate receptor agonist and 1S,3R-1-amino-1,3-cyclopentanedicarboxylic acid, a group I and II metabotropic glutamate receptor agonist, was found, while application of the metabotropic GABA(B) receptor agonist baclofen induced a significant decrease in calcium currents.Thus, the present voltage-clamp study shows that rat deep dorsal horn neurons express a non-inactivating, nifedipine sensitive, intermediate threshold (-55mV) calcium current which could provide the depolarizing drive to generate plateau potentials near threshold. Our results also indicate that calcium currents are not sensitized following repetitive stimulation, and not modulated by metabotropic glutamate receptor activation. They provide, however, the first evidence for a direct modulation of voltage-gated calcium channels in dorsal horn neurons by GABA(B) receptor activation, which may contribute to the mechanism of baclofen's antinociceptive activity.

Behavioral and neuroendocrine responses underlying systemic osmoregulation are under the concerted control of centrally located osmoreceptors and cerebrospinal fluid (CSF) Na+ concentration ([Na+]) detectors. Although the process underlying osmoreception is understood, the mechanism by which [Na+] is detected and integrated with cellular information derived from osmoreceptors is unknown. Here, we show that shifts in extracellular [Na+] ([Na+]0) cause proportional changes in the relative Na+ permeability of mechanosensitive cation channels responsible for signal transduction in the osmosensory neurons of the supraoptic nucleus. This effect causes the generation of Na+ specific receptor potentials under isotonic conditions and modulates osmoreceptor potentials and electrical responsiveness during osmotic perturbation. These results provide a cellular basis for Na+-sensing and for the coordinated detection of CSF [Na+] and osmolality in central osmoregulatory neurons.

1. The transient outward K+ current (ITO) was studied using whole-cell recording in immunocytochemically identified oxytocin (OT; n = 23) and vasopressin (VP; n = 67) magnocellular neurosecretory cells (MNCs) acutely isolated from the supraoptic nucleus of adult rats. 2. The peak density of ITO during steps to -10 mV was 26 % smaller in OT-MNCs (355 +/- 23 pA pF-1; mean +/- s.e. m.; n = 18) than in VP-MNCs (478 +/- 17 pA pF-1; n = 52). No differences were observed in the voltage dependence of activation or inactivation. 3. Kinetic analysis revealed two components of ITO inactivation in both OT-MNCs (tau1 = 9.2 +/- 0.4 ms and tau2 = 41.2 +/- 1.6 ms; n = 18) and VP-MNCs (tau1 = 12.4 +/- 0.4 ms and tau2 = 37.1 +/- 1.2 ms; n = 52). Although the density of the rapid component (tau1) was not different (275 +/- 13 versus 265 +/- 16 pA pF-1, respectively), the slow component (tau2) was markedly smaller in OT-MNCs (183 +/- 19 versus 331 +/- 16 pA pF-1 in VP-MNCs). 4. In unidentified MNCs, 0.5 mM 4-aminopyridine reduced ITO amplitude by 29% and decreased the latency to spike discharge by about 70% during depolarization from -70 mV. Latency to discharge from potentials less negative than -60 mV, where ITO is inactivated, was unaffected. 5. Comparison of latency to spike discharge in identified cells showed that OT-MNCs achieve spike threshold twice as fast as VP-MNCs when depolarized from -70 mV. The lower density of ITO in OT-MNCs, therefore, accelerates the rate at which excitation can occur in response to depolarizing stimuli and may facilitate the occurrence of higher frequency discharges in OT-MNCs during physiological activation.

Circulating estrogens influence the electrical and biosynthetic activity of the hypothalamic magnocellular neurons which synthesize vasopressin or oxytocin and regulate body fluid homeostasis and reproduction. As none of these magnocellular neurons express nuclear estrogen receptor in the rat, the present study has combined estrogen receptor immunocytochemistry with retrograde tracing techniques to examine whether the first-order neurons projecting to magnocellular neurons in the supraoptic nucleus may be receptive to estrogen. Green fluorescent latex microspheres (50 nl) were injected into the supraoptic nucleus of five ovariectomized rats. The largest numbers of retrogradely-labelled cells expressing estrogen receptor immunoreactivity were detected in the organum vasculosum of the lamina terminalis, anteroventral periventricular nucleus and medial preoptic nucleus where approximately 15% of all retrogradely-labelled cells were estrogen receptor-immunoreactive. Other prominent sites where double-labelled cells were detected were the median preoptic nucleus, subfornical organ, ventrolateral division of the hypothalamic ventromedial nucleus and the brainstem nucleus tractus solitarii. Triple labelling experiments in the caudal medulla revealed that the estrogen-receptive neurons of the nucleus tractus solitarii and ventrolateral medulla projecting to the supraoptic nucleus were not noradrenergic. These findings show that sub-populations of neurons projecting to the supraoptic nucleus express estrogen receptors. This provides immunocytochemical evidence that estrogen may regulate the activity of magnocellular oxytocin and vasopressin neurons in an indirect, trans-synaptic manner by influencing the activity of first-order neurons projecting to the supraoptic nucleus. The predominance of estrogen-receptive lamina terminalis and preoptic area inputs to the supraoptic nucleus suggests respective sites of estrogen action on magnocellular neurons in modulating fluid balance and reproductive function.

03/1997 | Neuroscience
Up-regulation of nitric oxide synthase messenger RNA in an integrated forebrain circuit involved in oxytocin secretion.
Luckman SM, Huckett L, Bicknell RJ, Voisin DL, Herbison AE

The hypothalamo-neurohypophysial system contains high levels of neuronal nitric oxide synthase and this increases further during times of neurohormone demand, such as that following osmotic stimulation. Using double in situ hybridization, we demonstrate here an increase in the expression of nitric oxide synthase messenger RNA by oxytocin neurons, but not vasopressin neurons, of the supraoptic nucleus at the time of lactation, when oxytocin is in demand due to another neuroendocrine stimulus, the milk-ejection reflex. In addition, using immunocytochemical retrograde tracing, we show that neurons of the subfornical organ, median preoptic nucleus and organum vasculosum of the lamina terminalis, which project to the supraoptic nucleus, contain nitric oxide synthase. These three structures of the lamina terminalis, together with the hypothalamo-neurohypophysial system, make up the forebrain osmoresponsive circuit that controls osmotically-stimulated release of oxytocin in the rat. The expression of nitric oxide synthase messenger RNA in the lamina terminalis was also shown to increase during lactation. The increases in nitric oxide synthase messenger RNA were not apparent during pregnancy. These results provide evidence for an integrated nitric oxide synthase-containing neural network involved in the regulation of the hypothalamo-neurohypophysial axis. The expression of nitric oxide synthase messenger RNA increases in this circuit during lactation and correlates with a reduction in the sensitivity of the circuit to osmotic stimuli also present in lactation but not pregnancy. As nitric oxide is believed to attenuate neurohormone release, it seems that the increased nitric oxide synthase messenger RNA expression detected here during lactation at a time of high oxytocin demand may be involved in reducing the sensitivity of the whole forebrain circuit to osmotic stimuli.

01/1997 | Endocrinology
Profile of monoamine and excitatory amino acid release in rat supraoptic nucleus over parturition.
Herbison AE, Voisin DL, Douglas AJ, Chapman C

The magnocellular oxytocin neurons of the hypothalamic supraoptic (SON) and paraventricular nuclei play an important role in the initiation and maintenance of parturition in the rat. As little is known about the neural inputs responsible for activating oxytocin neuron activity at this time, we used the technique of microdialysis to examine the profile of monoamine and excitatory amino acid neurotransmitter release within the SON before and during parturition. Microdialysis probes were implanted into the SON of anesthetized pregnant rats (n = 8) on the morning of the day preceding parturition (day 20), and 15-min dialysate samples were collected from freely moving animals over the following 2 days until 3 h after birth of the last pup. On the day of parturition (day 21), dialysate concentrations of norepinephrine were significantly increased (P < 0.05) in the hour leading up to the expulsion of the first pup and, compared with those on the previous day, remained at significantly (P < 0.05) elevated levels throughout the course of parturition. A significant (P < 0.01) increase in glutamate concentrations was also detected, although in this case, it was only elevated transiently in the 15-min period immediately before the onset of pup expulsion. Mean levels of dopamine were not different between days 20 and 21, but a significant increase in dopamine release was detected specifically during the second half of parturition. No significant changes in serotonin and aspartate concentrations were observed on days 20 and 21 or in relation to parturition. This study provides an analysis of neurotransmitter release in the SON over parturition and indicates that norepinephrine concentrations are elevated well in advance of the onset of pup expulsion, whereas a burst of glutamate release occurs immediately before the birth of the first pup. Such changes are likely to reflect activity in afferent inputs to the SON and may represent neurochemical events involved in the initiation and maintenance of parturition.