Differential innervation of superficial versus deep laminae of the dorsal horn by bulbo-spinal serotonergic pathways in the rat.

Convergent data showed that bulbo-spinal serotonergic projections exert complex modulatory influences on nociceptive signaling within the dorsal horn. These neurons are located in the B3 area which comprises the median raphe magnus (RMg) and the lateral paragigantocellular reticular (LPGi) nuclei. Because LPGi 5-HT neurons differ from RMg 5-HT neurons regarding both their respective electrophysiological properties and responses to noxious stimuli, we used anatomical approaches for further characterization of the respective spinal projections of LPGi versus RMg 5-HT neuron subgroups. Adult Sprague-Dawley rats were stereotaxically injected into the RMg or the LPGi with the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L). The precise location of injection sites and RMg vs LPGi spinal projections into the different dorsal horn laminae were visualized by PHA-L immunolabeling. Double immunofluorescent labeling of PHA-L and the serotonin transporter (5-HTT) allowed detection of serotonergic fibers among bulbo-spinal projections. Anterograde tracing showed that RMg neurons project preferentially into the deep laminae V-VI whereas LPGi neuron projections are confined to the superficial laminae I-II of the ipsilateral dorsal horn. All along the spinal cord, double-labeled PHA-L/5-HTT immunoreactive fibers, which represent only 5-15% of all PHA-L-immunoreactive projections, exhibit the same differential locations depending on their origin in the RMg versus the LPGi. The clear-cut distinction between dorsal horn laminae receiving bulbo-spinal serotonergic projections from the RMg versus the LPGi provides further anatomical support to the idea that the descending serotonergic pathways issued from these two bulbar nuclei might exert different modulatory influences on the spinal relay of pain signaling neuronal pathways.

Activation of nucleus tractus solitarius 5-HT2A but not other 5-HT2 receptor subtypes inhibits the sympathetic activity in rats.

Our first aim was to elucidate the mechanisms underlying the hypotensive response elicited by 5-HT(2) receptor activation in the nucleus tractus solitarius (NTS). In pentobarbitone-anaesthetized rats, intra-NTS administration of 2,5-dimethoxy-4-iodoamphetamine (DOI), a wide spectrum 5-HT(2) receptor agonist, but not an antagonist of selective 5-HT(2B) and 5-HT(2C) receptors, produced a decrease in blood pressure and heart rate. The maximal cardiovascular changes obtained by DOI (0.5 pmol) could be almost completely abolished by prior intra-NTS microinjection (10 pmol) of MDL-100907, a selective 5-HT(2A) receptor antagonist, but not by 5-HT(2B) or 5-HT(2C) receptor antagonists. In addition, using extracellular recordings we found that the large majority of identified cardiovascular rostroventrolateral medulla (RVLM) neurons were almost totally inhibited by NTS 5-HT(2A) receptor stimulation. We then investigated whether intra-NTS administration of a subthreshold dose (0.05 pmol) of DOI, known to facilitate the cardiovagal component of the baroreflex, could also modulate the sympathoinhibitory component of this reflex. These experiments showed that neither the decrease in the activity of the cardiovascular RVLM neurons and lumbar sympathetic nerve activities produced by aortic occlusion (gain of the baroreflex), nor the hypotensive response elicited by aortic nerve stimulation, were potentiated by the microinjection of DOI under such conditions. These data show that activation of 5-HT(2A), but not 5-HT(2B) or 5-HT(2C), receptors, located on NTS neurons, elicits depressor and bradycardic responses, and that this 5-HT(2A)-mediated hypotension is produced via the inhibition of RVLM cardiovascular neurons. In addition, NTS 5-HT(2A) receptor activation facilitates the cardiac but not the sympathetic baroreflex response.

Cardiac baroreflex facilitation evoked by hypothalamus and prefrontal cortex stimulation: role of the nucleus tractus solitarius 5-HT2A receptors.

We previously showed that serotonin (5-HT2) receptor activation in the nucleus of the tractus solitarius (NTS) produced hypotension, bradycardia, and facilitation of the baroreflex bradycardia. Activation of the preoptic area (POA) of the hypothalamus, which is involved in shock-evoked passive behaviors, induces similar modifications. In addition, previous studies showed that blockade of the infralimbic (IL) part of the medial prefrontal cortex, which sends projections to POA, produced an inhibitory influence on the baroreflex cardiac response. Thus, to assess the possible implication of NTS 5-HT2 receptors in passive cardiovascular responses, we analyzed in anesthetized rats the effects of NTS inhibition and NTS 5-HT2 receptor blockade on the cardiovascular modifications induced by chemical (0.3 M D,L-homocysteic acid) and electrical (50 Hz, 150-200 microA) stimulation of IL or POA. Intra-NTS microinjections of muscimol, a GABAA receptor agonist, prevented the decreases in blood pressure and heart rate normally evoked by IL or POA activation. In addition, we found that intra-NTS microinjection of R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol, a specific 5-HT2A receptor antagonist, did not affect the decreases in cardiovascular baseline parameters induced by IL or POA stimulation but prevented the facilitation of the aortic baroreflex bradycardia normally observed during IL (+65 and +60%) or POA (+70 and +69%) electrical and chemical stimulation, respectively. These results show that NTS 5-HT2A receptors play a key role in the enhancement of the cardiac response of the baroreflex but not in the changes in basal heart rate and blood pressure induced by IL or POA stimulation.

High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study.

An open-label, phase II non-randomised trial was conducted with darbepoetin (DAR), an erythropoiesis-stimulating factor with prolonged half-life, at a weekly dose of 300 mug subcutaneously in 62 anaemic patients with myelodysplastic syndrome (MDS) with an endogenous erythropoietin (EPO) level <500 mU/ml. Most of the patients were classified as low or intermediate 1 according to the International Prognostic Scoring System. After 12 weeks, 44 (71%) patients had an erythroid response (34 major and 10 minor), including eight of 13 patients who were previous non-responders to conventional EPO. Two additional responses (one minor and one major) occurred, in 10 non-responders, after the addition of granulocyte colony-stimulating factor (G-CSF). Thirty-six of the 46 total responders (31/35 major and 5/11 minor) continued to respond on maintenance DAR after a median of 40 weeks (range 4-84). Median dose of DAR required to maintain response was 300 microg every 14 d. The only prognostic factors of favourable response were low endogenous EPO level and low or absent red blood cell transfusion requirement. Those results suggest that high-dose DAR alone yields high erythroid response rates in anaemia of lower risk MDS, possibly equivalent to those obtained with conventional EPO + G-CSF, although this will need to be confirmed in larger and randomised trials.

Epidemiology of invasive aspergillosis in France: a six-year multicentric survey in the Greater Paris area.

Invasive aspergillosis is the most prevalent mould infection. An epidemiological surveillance network was set up in 18 teaching hospitals in Paris and the Greater Paris area. Prospective surveillance was conducted between 1994 and 1999. Between 1994 and 1997 cases were categorized as proven or probable aspergillosis and then the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria were used. The authors analysed 621 cases (115 proven, 506 probable). No seasonal variation was found. Haematological disorders (73%) including stem-cell transplantation (36%), solid-organ transplantations (10%) and AIDS (9%) were the main underlying conditions. The crude mortality was 63%. Incidence of IA was 8% (CI(95): 6.5-9.5) in acute myelocytic leukaemia and 6.3% (CI(95): 4.3-8.3) in acute lymphocytic leukaemia. Incidence was 12.8% (CI(95): 10.8-14.8) following allogeneic stem-cell transplantation and 1.1% (CI(95): 0.7-1.5) following autologous stem-cell transplantation. In solid-organ recipients incidence ranged from 11% following heart-lung transplantation and small bowel to 0.4% following kidney transplantation. Incidence in HIV infected patients ranged from 0.02 to 0.13% per annum. This large series confirmed that patients with haematologic disorders and transplantations are the most at risk for IA.

Projections from the nociceptive area of the central nucleus of the amygdala to the forebrain: a PHA-L study in the rat.

The lateral capsular division (CeLC) of the central nucleus (Ce) of the amygdala, in the rat, has been shown to be the main terminal area of a spino(trigemino)-parabrachio-amygdaloid nociceptive pathway [Bernard & Besson (1990) J. Neurophysiol. 63, 473-490; Bernard et al. (1992) J. Neurophysiol. 68, 551-569; Bernard et al. (1993) J. Comp. Neurol. 329, 201-229]. The projections to the forebrain from the CeLC and adjacent regions were studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin (PHA-L) restricted in subdivisions of the Ce and the basolateral amygdaloid nucleus anterior (BLA). Our data showed that the entire CeLC projects primarily and extensively to the substantia innominata dorsalis (SId). The terminal labelling is especially dense in the caudal aspect of the SId. The other projections of the CeLC in the forebrain were dramatically less dense. They terminate in the bed nucleus of the stria terminalis (BST) and the posterior hypothalamus (pLH). No (or only scarce) other projections were found in the remaining forebrain areas. The Ce lateral division (CeL) and the Ce medial division (CeM), adjacent to the CeLC, also project to the SId with slightly lower density labelling. However, contrary to the case of the CeLC, both the CeL and the CeM extensively project to the ventrolateral subnucleus of the BST (BSTvl) with a few additional terminals found in other regions of the lateral BST. Only the CeM projects densely to both the interstitial nucleus of the posterior limb of the anterior commissure and the caudal most portion of the pLH. The projections of the BLA are totally different from those of the Ce as they terminate in the dorsal striatum, the accumbens nucleus, the olfactory tubercle, the nucleus of olfactory tract and the rostral pole of the cingulate/frontal cortex. This study demonstrates that the major output of the nociceptive spino(trigemino)-parabrachio-CeLC pathway is to the SId. It is suggested that the CeLC-SId pathway could have an important role in anxiety, aversion and genesis of fear in response to noxious stimuli.

Parabrachial internal lateral neurons convey nociceptive messages from the deep laminas of the dorsal horn to the intralaminar thalamus.

This study investigates the physiological properties of parabrachial internal lateral (PBil) neurons that project to the paracentral thalamic (PC) nucleus using antidromic activation and single-unit recording techniques in anesthetized rat. We reported here that most of these neurons responded exclusively to the nociceptive stimulation of large receptive fields with a sustained firing that often outlasted the stimulus up to several minutes. These responses were depressed by intravenous morphine. Our results demonstrated a novel spino-PBil-PC pathway, which transmits nociceptive messages to the PC nucleus, which in turn projects to the prefrontal cortex. Recent clinical imaging studies showed the important participation of prefrontal cortex in emotional response to pain. This spino-PBil-PC pathway may explain how nociceptive messages reach the prefrontal cortex and thus trigger unbearable aversive aspects of pain.

Physiological properties of the lamina I spinoparabrachial neurons in the rat.

Single-unit extracellular recordings of spino-parabrachial (spino-PB) neurons (n = 53) antidromically driven from the contralateral parabrachial (PB) area were performed in the lumbar cord in anesthetized rats. All the spino-PB neurons were located in the lamina I of the dorsal horn. Their axons exhibited conduction velocities between 2.8 and 27.8 m/s, in the thin myelinated fibers range. They had an extremely low spontaneous activity (median = 0. 064 Hz) and a small excitatory receptive field (

Ventromedial thalamic neurons convey nociceptive signals from the whole body surface to the dorsolateral neocortex.

The somatosensory properties of ventromedial (VM) thalamic neurons were investigated in anesthetized rats by examining their responses to calibrated cutaneous stimuli. A population of neurons within the lateral part of the ventromedial thalamus (VMl) showed two peaks of activation after percutaneous electrical stimuli, regardless of which part of the body was stimulated. The early and late peaks were elicited by Adelta- and C-fiber activities with mean conduction velocities of 12.9 +/- 0.9 and 1 +/- 0.2 m/sec, respectively. These responses were strongly depressed or blocked after microinjections within the medullary subnucleus reticularis dorsalis of xylocaine or the NMDA antagonist MK-801. None of the VMl neurons responded to innocuous cutaneous or proprioceptive stimuli. In contrast, all these neurons responded to noxious mechanical and thermal stimulation of the limbs and showed monotonic increases in their discharges to increasingly strong noxious cutaneous stimuli. In addition, some VMl neurons were antidromically activated by stimulation in layer I of the dorsolateral frontal cortex. These findings suggest that the rat VMl conveys and encodes cutaneous nociceptive inputs from any part of the body surface to layer I of the dorsolateral neocortex. This reticulo-thalamo-cortical network may allow any signal of pain to gain access to widespread areas of the neocortex and thus help prime the cortex for attentional reactions and/or the coordination of motor responses.

Differential projections to the intralaminar and gustatory thalamus from the parabrachial area: a PHA-L study in the rat.

The organization of projections from the parabrachial (PB) area to the ventral posterior parvicellular (VPpc) "gustatory" and intralaminar nuclei of the thalamus was studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin (PHA-L), into subregions of the PB area. The present study is a follow-up of three former studies (Bernard et al. [1993] J. Comp. Neurol. 329:201-229; Aldén et al. [1994] J. Comp. Neurol. 341:289-314; Bester et al. [1997a] J. Comp. Neurol. 383:245-281) that examined PB projections onto the amygdala, the bed nucleus of the stria terminalis, and the hypothalamus. Our data showed that (1) the region centered in the internal lateral PB subnucleus projects densely with a bilateral and symmetric pattern to the caudal portion of the paracentral and, to a lesser extent, to the adjacent portion of the central and parafascicular medial thalamic nuclei; (2) the mesencephalic PB region centered in the ventral lateral subnucleus and scattered neurons in the subjacent brachium conjunctivum project primarily, although diffusely, to the central medial thalamic nucleus. The third region includes two subgroups: (3a) the medial subgroup, including the medial, the waist area, and the ventral lateral subnuclei of the pontine PB area, projects bilaterally but with a weak ipsilateral predominance to the VPpc, terminals bearing large varicosities. Additionally, a diffuse projection with small varicosities spreads in the area between the two VPpc nuclei and the central medial nucleus. (3b) The lateral subgroup, centered in the external medial subnucleus, projects with a contralateral predominance in the periphery of the VPpc nuclei, most terminals being located around the dorsomedial tip. It is suggested that the PB projections to the intralaminar nucleus could be involved in cortical limbic arousal processing in relation with nociceptive, (somatic, visceral, and intraoral) and gustatory aversive stimuli. The projection with large varicosities inside the VPpc could process gustatory discrimination.

VAD or VMBCP in multiple myeloma refractory to or relapsing after cyclophosphamide-prednisone therapy (protocol MY 85).

263 patients (median age 65+/-10 years) with multiple myeloma were treated with cyclophosphamide-prednisone. Out of this cohort, 103 patients had progressive disease and were randomly assigned to either VAD (vincristine, doxorubicin, dexamethasone; 50 cases) or VMBCP (vincristine, BCNU, cyclophosphamide, melphalan and prednisone; 53 cases). There were no statistical differences between the two groups with the respect to clinical, biological and radiological parameters. There was no difference in survival between the VAD and VMBCP groups. The 4 months response rate was similar in the two groups (50% VAD, 56% VMBCP). With multivariate analysis for survival (Cox model), two factors had a statistically significant impact: Karnofsky index (> 60) and albuminaemia (< 34 g/l). With both Karnofsky index > 60 and albuminaemia > or = 34 g/l, the median survival was 29 months v 2 months with a Karnofsky index < or = 60 and albuminaemia < 34 g/l (P<0.05). In conclusion, VAD or VMBCP had similar activity for salvage treatment in MM refractory or relapsing to first-line treatment with cyclophosphamide-prednisone.

Involvement of the spinoparabrachial pathway in inflammatory nociceptive processes: a c-Fos protein study in the awake rat.

The effect of graded inflammatory stimuli (intraplantar-carrageenan, 0.2, 1, and 6 mg/150 microl) on paw edema and c-Fos protein expression at two levels of the spinoparabrachial pathway, the spinal cord and parabrachial area (PB), were studied. The present study, in awake rats, is an extension of previous study (Bester et al. [1997] J. Comp. Neurol. 383:439-458) which evaluated, in anesthetized rats, the effect of graded cutaneous heat stimulation on c-Fos-expression at the same levels. At the spinal level, the c-Fos-protein-like-immunoreactive (c-Fos-LI) neurons were located primarily in superficial laminae ipsilateral to intraplantar carrageenan. The number of c-Fos-LI neurons increased dose dependently (r = 0.973, n = 24) for carrageenan, from a number close to zero for the saline injection. At the PB level, c-Fos was predominantly expressed contralateral to intraplantar carrageenan. c-Fos-LI neurons were located primarily around the pontomesencephalic junction in (i) a restricted pontine area, centered in the lateral crescent, and including an adjacent part of the outer portion of the external lateral subnucleus, and (ii) the mesencephalic superior lateral subnuclei. The number of c-Fos-LI neurons in the PB area was correlated with that in the superficial laminae (r = 0.935, n = 24) and with the paw edema (r = 0.931, n = 24). No significant changes in c-Fos expression were observed in the nucleus of the solitary tract and ventrolateral medulla. The close correlation between c-Fos expression at both the spinal and PB levels and inflammatory edema provides further evidence for the involvement of spinoparabrachial pathway in inflammatory nociceptive processes. The present results are congruent with the existence of electrophysiologically demonstrated spinoparabrachio-amygdaloid and -hypothalamic nociceptive pathways.

Organization of diencephalic projections from the medullary subnucleus reticularis dorsalis and the adjacent cuneate nucleus: a retrograde and anterograde tracer study in the rat.

The distribution and organization of diencephalic projections from the subnucleus reticularis dorsalis (SRD) and the neighbouring cuneate nucleus (Cu) were studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin in SRD and Cu and wheat germ agglutinin-apo horseradish peroxidase-gold in some selected thalamic areas. As previously reported, the efferent projections from the Cu were essentially contralateral and terminated mainly in the ventroposterolateral thalamic nucleus. Less dense terminals from the Cu were also observed in the posterior thalamic group, the ventral aspect of the zona incerta and the caudal and dorsal portion of the reuniens area. Retrograde tracer injections in the medial ventroposterolateral thalamic nucleus labeled numerous cells in the contralateral Cu, with a smaller number in the gracile nucleus. From the SRD, terminals were observed in the lateral aspect of the ventromedial thalamic nucleus, the lateral parafascicular area and, to a lesser extent, in the ventral aspect of the zona incerta and the core of the reuniens area. Retrograde tracer injections in the lateral part of the ventromedial thalamic nucleus labeled cells in the caudal medulla, many of which were located in the dorsal-most aspect of the SRD throughout its caudo-rostral extent. The existence of SRD-thalamic connections reinforces the idea that the caudal reticular formation is an important nociceptive relay to the thalamus. Our data shed new light on old hypotheses suggesting that, in addition to spino-thalamic pathways, spino-reticulo-thalamic pathways may play an important role in distributing pain signals to the forebrain.

Further evidence for the involvement of the spinoparabrachial pathway in nociceptive processes: a c-Fos study in the rat.

We have analysed in briefly anaesthetised rats (1% halothane for 18 minutes) the effects of innocuous and noxious heat, applied to the hindpaw, on evoked c-Fos immunoreactivity at the levels of the parabrachial area (PB), spinal cord, and nucleus of the solitary tract (NTS). After anaesthesia recovery, animals were left to move freely for 2 hours. At the spinal level, c-Fos was expressed primarily in the ipsilateral superficial laminae, increasing with the applied temperatures in a dependent manner in the noxious range (correlation coefficient r = 0.954, n = 20). At the NTS level, no noxiously evoked c-Fos expression was observed. At the PB level, c-Fos was expressed preferentially contralaterally, increasing with the applied temperatures in a dependent manner in the noxious range (r = 0.971, n = 25). The maximum expression was observed in the outer portion of the external lateral, the lateral crescent, and the superior lateral subnuclei around the pontomesencephalic junction. This was congruent with the densest supraspinal projection of lamina I neurones of the dorsal horn. Labelling in the PB area was highly correlated (r = 0.936, n = 20) with labelling in the superficial laminae. We conclude that, under our experimental procedures, noxious heat-induced c-Fos expression at the PB level depends on the intensity of the noxious stimulation. These data further support the relevance of the recently described spino-PB pain pathway. Because of their location, the Fos-immunoreactive neurones observed in the pontine and the mesencephalic divisions of the PB area were likely PB-amygdaloid and PB-hypothalamic nociceptive neurones, respectively.

Organization of efferent projections from the parabrachial area to the hypothalamus: a Phaseolus vulgaris-leucoagglutinin study in the rat.

The organization of projections from the parabrachial (PB) area to the hypothalamus was studied in the rat by using microinjections of Phaseolus vulgaris-leucoagglutinin (PHA-L) into subregions of the PB area. The present study is a follow-up of two former studies (Bernard et al. [1993] J. Comp. Neurol. 329:201-229; Aldén et al. [1994] J. Comp. Neurol. 341:289-314) that examined PB projections onto the amygdala and the bed nucleus of the stria terminalis. The results demonstrate that 1) the mesencephalic PB region, centered in the lateral portion of the superior lateral subnucleus projects extremely densely to almost the entire dorsomedial subdivision of the ipsilateral ventromedial hypothalamic nucleus; 2) the mesencephalic PB region, located in the medial portion of the superior lateral subnucleus and weakly overflowing into the rostralmost dorsal lateral pontine subnucleus, projects densely to the retrochiasmatic area and, to a lesser extent, to the ipsilateral ventromedial nucleus of the hypothalamus; 3) the PB region, including the central lateral, a portion of the superior lateral, and the outer external lateral subnuclei, projects densely to the ipsilateral median, anteroventral, and periventricular preoptic hypothalamic nuclei and projects more weakly to the dorsal border of the paraventricular nucleus (PVN). No consistent projection was found in the magnocellular PVN. All of these PB regions also project diffusely to the dorsomedial area and to a small tuberal subfornical hypothalamic area. In addition, the medial half of the PB area projects consistently to the posterior lateral hypothalamus. It is suggested that these pathways may be involved in aversive-defensive behavior, in autonomic and neuroendocrine aspects of pain, and in feeding and energy metabolism regulation.

Changes in the responsiveness of parabrachial neurons in the arthritic rat: an electrophysiological study.

1. Rats rendered polyarthritic by injection of Mycobacterium butyricum into the tail were used as a model for the study of "chronic pain". In such rats, anesthetized with halothane in a nitrous oxide-oxygen mixture, spontaneous activity and responses of parabrachial (PB) neurons to somatic stimulations were studied in comparison with those in a control group of healthy animals processed under the same experimental conditions. 2. The size of the somatic receptive field of PB neurons was similar in both arthritic and control groups. In the control group 13%, 55%, and 32% of the receptive fields were small, medium, and large, respectively. Similarly, in the arthritic group, 10%, 60%, and 30% of the receptive fields were small, medium, and large, respectively. 3. The spontaneous activity was significantly (P < 0.001) increased in the arthritic rats (0.1 < 3 < 16 Hz, n = 31; 10th percentile < median < 90th percentile) in comparison with the healthy rats (0.03 < 0.3 < 5 Hz, n = 22). 4. The sensitivity to mechanical stimuli was markedly increased in arthritic compared with healthy rats: 1) although PB neurons in normal rats never responded to innocuous stimuli, several PB neurons in arthritic rats responded to touch and/or joint movement; 2) the mean mechanical threshold decreased from 15.8 N/cm2 in normal rats to 5.9 N/cm2 in arthritic rats; 3) the mean pressure evoking 50% of the maximum response decreased from 34 N/cm2 in normal rats to 21 N/cm2 in arthritic rats; and 4) the intensity of the maximum response increased from 15.7 Hz in normal rats to 26.3 Hz in arthritic rats. 5. The mechanical encoding properties were clearly modified in arthritic rats compared with healthy rats. In this latter group, the PB neurons exhibited a clear capacity to encode mechanical stimuli in the noxious range: 1) the stimulus-response curves were always positive and monotonic until 48 N/cm2; and 2) the slope of the mean curve increased progressively from 2 to 8 N/cm2 before reaching a roughly linear maximum for a wide range of pressure (8-64 N/cm2) and plateauing beyond. In the arthritic rat, the PB neurons also encoded mechanical stimuli, but clearly from a lower pressure range: the slope of the mean curve was maximum and remained steep from the lowest pressure tested (1 N/cm2) up to 16 N/cm2; afterward the slope decreased progressively from 16 to 64 N/cm2 before plateauing. 6. The sensitivity to heat stimuli was only weakly modified. The thermal threshold was weakly, but significantly, increased from 44 degrees C in the normal rat to 45.8 degrees C in the arthritic rat. Other parameters for thermal modality were not changed, with the mean stimulus-response curves being similar in both arthritic and normal groups. 7. In conclusion, these experiments demonstrate that the activity of PB neurons is clearly changed in arthritic rats. These changes are reminiscent of some behavioral and electrophysiological modifications observed during arthritis. Considering the current literature, it is hypothesized that the PB relay could be responsible, at least in part, for several affective-emotional, behavioral, autonomic, and energy metabolism changes observed in arthritic rats.

Parabrachial area: electrophysiological evidence for an involvement in cold nociception.

1. Thirty-five percent of 120 neurons recorded extracellularly in the parabrachial (PB) area of anesthetized rats responded to a peripheral cold stimulus (0 degrees C). The cold-sensitive neurons were located in the lateral PB area, and most of those exhibiting a strong response to cold stimuli were inside or in close vicinity to the area receiving a high density of projections from superficial neurons of the dorsal horn. 2. The receptive fields for cold stimulation often were restricted to one or two parts of the body with a contralateral predominance for the limbs. No side predominance was observed for the face. 3. From a low spontaneous activity (10th percentile < median < 90th percentile: 0.1 < 1.5 < 5 Hz), the PB neurons responded to cold noxious stimuli (0 degree C water bath or waterjet, 20 s), without observable delay, with a sustained discharge. The mean maximal response to the stimulus was 16.1 +/- 1.2 Hz (mean +/- SE; n = 42). 4. About one-half (45%) of these cold-sensitive neurons were activated specifically by cold stimulation and did not respond or were inhibited by noxious heat and/or pinch. The remaining (55%) cold-sensitive neurons were also driven by heat and/or pinch. 5. The cold-sensitive neurons exhibited a clear capacity to encode cold stimuli in the noxious range: the stimulus-response function was always positive and monotonic from 30 to 0 degrees C; the mean curve was linear between 20 and 0 degrees C before plateauing between 0 to -10 degrees C; the mean threshold to cold stimulation was 17.1 +/- 1 degrees C (n = 21) and the mean t50 was 10.7 +/- 1.1 degrees C (n = 13). 6. The cold-sensitive neurons responded to intense transcutaneous electrical stimulation with an early and/or a late peak of activation, the latencies of which were in the 15-50 ms and 80-170 ms ranges (n = 8), respectively, i.e., compatible with the activation of A delta and C fibers. Interestingly, the cold-specific neurons predominantly responded with a late peak, suggesting these neurons were primarily driven by peripheral C fibers. 7. The intravenous injection of morphine depressed the responses of PB neurons to cold noxious stimuli in a dose-related (1, 3, and 9 mg/kg) and naloxone reversible fashion. The ED50 value was estimated approximately 2 mg/kg. Furthermore, two populations of neurons could be separated according to their morphine sensitivity. 8. It is concluded that PB cold-nonspecific neurons could be involved in affective-emotional, autonomic and neuroendocrine reactions in response to noxious cold events. The PB cold-specific neurons could be, in addition, involved in some thermoregulatory processes.

Organization of efferent projections from the spinal cervical enlargement to the medullary subnucleus reticularis dorsalis and the adjacent cuneate nucleus: a PHA-L study in the rat.

The distribution and organization of projections from the spinal cervical enlargement to subnucleus reticularis dorsalis (SRD) and the neighbouring Cuneate nucleus (Cu) area was studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin (PHA-L) into different laminae around the C7 level. The Cu received very dense projections from the dorsal horn, with the highest density being observed following injections into the medial part of laminae III-IV. The SRD received dense projections from laminae V-VII of the cervical enlargement, particularly from the reticular and medial aspects of lamina V, lamina VI, and the dorsal part of lamina VII. By contrast, the superficial part of the dorsal horn (laminae I to IV) and the dorsal part of lamina X provided only sparse projections to the SRD. Clusters of labelled terminals and boutons were observed mainly in the SRD areas subjacent to the Cu. In the caudorostral axis, labelled terminals were spread along the whole SRD from the cervicomedullary junction up to the caudal-most part of the area postrema. Contralateral projections to the SRD were scarce and were observed mainly after injections into the medial part of laminae VI-VII. These data give further support to the proposal that there are two parallel systems in neighbouring structures of the caudal medulla, viz. the Cu and the SRD, which, respectively, relay lemniscal and nociceptive information from the spinal cord to the thalamus.