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.

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.

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.

Topographical organization of olivocerebellar and corticonuclear connections in the rat--an WGA-HRP study: I. Lobules IX, X, and the flocculus.

The organization of the olivocerebellar and corticonuclear relations for vermal lobules IX and X and the flocculus has been studied in the rat by using microinjections of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP). This axonal tracer allowed us to study simultaneously the olivocortical connections (revealed by retrograde transport) and corticonuclear connections (revealed by anterograde transport) from a single injection in the cerebellar cortex. The results indicate that four modules can be distinguished, each of which consists of a region of cerebellar cortex receiving afferents from a single small region of the inferior olive (IO) and sending efferents to one or several portions of the cerebellar nuclei and/or vestibular nuclei. The first module includes a medial part of lobule X as well as all the flocculus. It receives afferents from the dorsal cap (dc) and sends efferents to the small cell (s) zone of the dentate nucleus as well as to the medial vestibular (VM) nucleus and subnucleus y. The second module includes a medial parasagittal region located in lobules IX and X. It receives afferents from the ventrolateral outgrowth (vlo) and/or beta nucleus (vlo + beta nucleus) and sends efferents principally to the ventrolateral part of fastigial nucleus and to the superior vestibular (VS), inferior vestibular (VI), and VM nuclei. The third module includes a lateral parasagittal region in lobules IX and X. It receives afferents from the dorsomedial cell column (dmcc) of IO and sends efferents principally to the interpositus nucleus and subnucleus y. The fourth module includes the most lateral part of lobules IX and Xa. It receives afferents from the principal olive (PO) and sends efferents to the s zone of the dentate nucleus. These results are comparable to those obtained in the cat although a few differences are discussed.

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.

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.

Distribution of spinal cord projections from the medullary subnucleus reticularis dorsalis and the adjacent cuneate nucleus: a Phaseolus vulgaris-leucoagglutinin study in the rat.

The distribution and organization of descending spinal projections from the dorsal part of the caudal medulla were studied in the rat following injections of Phaseolus vulgaris-leucoagglutinin into small areas of the subnucleus reticularis dorsalis (SRD) and the adjacent cuneate nucleus (Cu). The caudal aspect of the Cu projected only to the dorsal horn of the ipsilateral cervical cord via the dorsal funiculus. These projections were mainly to laminae I, IV, and V. More ventrally located reticular structures projected to the full length of the cord. Fibers originating from the SRD travelled through the ipsilateral dorsolateral funiculus and terminated within the deep dorsal horn and upper layers of the ventral horn, mainly in laminae V-VII. Fibers originating from subnucleus reticularis ventralis (SRV) travelled ipsilaterally through the lateral and ventrolateral funiculi and bilaterally through the ventromedial funiculus. These fibers terminated within the ventral horn. The density of labeling within the gray matter varied at different levels of the cord was as follows: cervical > sacral > thoracic > lumbar. The reciprocal connections between the caudal medulla and the spinal cord suggest that the former is an important link in feedback loops that regulate spinal outflow.

The organization of the efferent projections from the pontine parabrachial area to the amygdaloid complex: a Phaseolus vulgaris leucoagglutinin (PHA-L) study in the rat.

The organization of the efferent projections from the pontine parabrachial (pPB) area to the amygdala has been studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin (PHA-L), a sensitive and selective anterograde axonal marker, into restricted subregions of the pPB area. The results confirmed that the pPB area primarily projected onto the ipsilateral nucleus centralis of the amygdala (Ce), and to a lesser extent onto the ipsilateral posterior basolateral (BLP), anterior basomedial (BMA), and amygdaloid cortical (ACo) nuclei of the amygdala. Substantial projections were also found in the substantia innominata dorsal/ventral portion of the globus pallidus (SId/GPv), substriatal (SStr), and fondus striatal (FStr) regions which continue the amygdala rostrally. The results demonstrated that the projections of the pPB area onto the Ce were topically organized: 1) The region of the pPB area mainly including the medial subnucleus (pPBm), the waist area (pPBwa), and a thin rostral lamina of the ventral lateral subnucleus (pPBvl) projects primarily to the medial portion of the Ce (CeM). Dense projections were also found in the BLP, BMA, and ACo nuclei of the amygdala, and in the SId/GPv, SStr, and FStr rostral areas. 2) The region of the pPB mainly including the rostral portion of the central lateral subnucleus (pPBcl) and the outer-rostral portion of the external lateral subnucleus (pPBel) projects primarily to the lateral portion of the Ce (CeL). 3) The region of the pPB mainly including the dorsolateral subnucleus (pPBdl), the remaining pPBel, and the external medial (pPBem) subnuclei projects primarily to the lateral capsular portion of the Ce (CeLC) and bilaterally to its rostral portion. Dense projections were also found in the regions which extend the CeLC rostrally and in the SId/GPv, SStr, and FStr rostral areas. The possible role of each of the three parabrachio-amygdaloid pathways described is discussed. It was suggested that the pPB-CeM pathway is mainly implicated in gustatory processes; the pPB-CeL pathway is mainly implicated in visceral and chemosensitive processes; and the pPB-CeLC pathway is mainly implicated in respiratory, cardiovascular, and nociceptive processes.

Organization of the efferent projections from the pontine parabrachial area to the bed nucleus of the stria terminalis and neighboring regions: a PHA-L study in the rat.

The organization of efferent projections from the pontine parabrachial (pPB) area to the forebrain rostral to the central nucleus of the amygdala (Ce) was studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin (PHA-L), into subregions of the pPB area. The present study is a follow-up of a former study (Bernard et al. [1993] J. Comp. Neurol. 329:201-229) which examines pPB projections onto the Ce. The results demonstrate that: (1) the pPB(m) region (the medial, the ventral lateral subnuclei and the waist area) diffusely projects to the lateral division (BSTL) of the bed nucleus of the stria terminalis (BST), the Ce-BSTL continuum (including, the dorsal portion of substantia innominata, the ventral portion of globus pallidus, the fundus striatum, and the substriatal area) and to a lesser extent the agranular insular cortex; (2) the pPB(1) region [the central lateral (pPBcl) and the outer portion of external lateral subnuclei] densely projects to the dorsal lateral subnucleus of BST (BSTdl); only the pPBcl subnucleus projects to the median, the anteroventral and the periventricular nuclei of the preoptic hypothalamus; and (3) the remaining pPB area (the dorsal lateral, part of the external lateral and the external medial subnuclei) projects to the nucleus of horizontal limb of diagonal band but does not project onto the BST and the preoptic hypothalamus. It is suggested that the pPB(m)-BSTL "diffuse pathway" is mainly implicated in motivational and autonomic aspects of taste. The pPB(1)-BSTdl and hypothalamic "concentrated pathways" could be implicated in autonomic and nociceptive processes.

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 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.

Organization of the efferent projections from the spinal cervical enlargement to the parabrachial area and periaqueductal gray: a PHA-L study in the rat.

The organization of efferent projections from the spinal cervical enlargement to the parabrachial (PB) area and the periaqueductal gray (PAG) was studied in the rat by using microinjections of Phaseolus vulgaris-leucoagglutinin (PHA-L) into different laminae around the C7 level. The results demonstrated two areas of cervical enlargement which project in different ways to the PB area and PAG. First, the superficial laminae (I, II) showed a very dense projection, with a clear contralateral dominance at the coronal level where the inferior colliculus merges with the pons, to a restricted "superficial" portion of the PB area, namely the lateral crescent area, the dorsal lateral, the superior lateral (PBsl), and the outer portion of the external lateral PB subnuclei. Less dense projections were observed in the Kölliker-Fuse nucleus (KF) and in the ventrolateral/lateral quadrant of the caudal and mid PAG. By contrast, the labeling was weak or absent in the other PB subnuclei and the outer adjacent regions; in particular, no, or very little, labeling was found in the cuneiform nucleus. The PB area appeared to be the supraspinal target that received the densest projection from laminae I and II. Projections were less dense in the PAG and the thalamus and markedly less in other sites such as the ventrolateral medulla, the subnucleus reticularis dorsalis, and the nucleus of the solitary tract. Second, the reticular portion of lamina V, the medial portion of laminae IV-VI up to X and lamina VIII, showed bilateral projections with a weak ipsilateral dominance and a high to medium density on a very restricted portion of the PB area, namely the internal lateral PB subnucleus. A lesser projection was also observed in the adjacent portion of the PBsl, the KF, and the lateral quadrant of the PAG. These results suggest that signals carried by neurons from lamina I-II converge on a restricted superficial portion of the PB area and the ventral part of the lateral quadrant of the PAG. These results are discussed in the context of the role of the spino-PB and spino-PAG pathways in nociception.

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.

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.

Age as the main prognostic factor in adult aggressive non-Hodgkin's lymphoma.

From 1975 to 1983, 73 patients with aggressive non-Hodgkin's lymphoma were treated with a first-generation program including Adriamycin, VM 26, cyclophosphamide, and prednisone. Thirty-nine patients were under 60 years of age, and 34 were 60 years or older. The clinical and histologic characteristics of the two groups were similar. Using either univariate or multivariate analysis, age appeared as the only prognostic factor. Patients under 60 had a median survival of 48 months, with a five-year survival rate of 47 percent and a five-year disease-free survival rate for complete-remission patients of 72 percent. Patients 60 years or older had a median survival of 18 months with a five-year survival rate of 18 percent and a five-year disease-free survival rate for complete-remission patients of 24 percent. These highly significant differences were related to a non-significantly decreased complete-remission rate and a significantly higher relapse rate in elderly patients. Since patient selection according to age could play a role in the results achieved with intensive chemotherapy programs, randomized trials comparing the various chemotherapy programs for aggressive non-Hodgkin's lymphoma are warranted.

Afferents and efferents of the rat cuneiformis nucleus: an anatomical study with reference to pain transmission.

Small iontophoretic application of wheat-germ-agglutinin conjugated to horseradish peroxidase, was used to simultaneously observe, in the rat, the afferent and the efferent connections of the cuneiformis nucleus (Cnf), in the same animal. The results demonstrate that the main Cnf afferent connections originate from: (1) 6 regions of the forebrain: the nucleus centralis of the amygdala, the zona incerta, the dorsomedial, ventromedial and the lateral area of the hypothalamus and the periventricular gray matter and (2) 4 regions of the midbrain: the substantia nigra pars lateralis, the peripeduncular area, the periaqueductal gray matter and the other side Cnf. In contrast to the wealth of origins of afferent fibers, most projections of the Cnf are concentrated to the B3 area and the bordering reticular nuclei. It is proposed that the Cnf, which mostly receives afferent connections from the forebrain and the midbrain, and which in turn densely projects on the B3 area, is a relay for the modulation of pain processes.

Inferior olivary neurons: 3-acetylpyridine effects on glucose consumption, axonal transport, electrical activity and harmaline-induced tremor.

The effects of 3-acetylpyridine (3-AP) on the neurons in the inferior olive (IO) were studied by several methods to establish the time-order of events due to the neurotoxicity of 3-AP in the rat. It was found that IO metabolism, studied with [14C]2-deoxyglucose, began to decrease detectably 1 h after 3-AP and was totally suppressed at 3 h. Retrograde axonal transport of lectin horseradish peroxidase (HRP) from cerebellar cortex to the IO was also totally suppressed 3 h after 3-AP and in fact showed a time course similar to that for the suppression of metabolism. Harmaline produced tremor has been shown to induce rhythmic activity and increase glucose consumption in the IO. When injected in 3-AP treated animals, harmaline produced its usual effects at 2 h after the 3-AP but had no effects after 3 h. The present results indicate that the neurotoxic effects of 3-AP are not simply graded in time, but tend to have the greatest effects between the 2nd and 3rd hour following its administration.

Effect of noxious somesthetic stimulation on the activity of neurons of the nucleus centralis of the amygdala.

Neurons (n = 107) were recorded, in anaesthetized rats, with extracellular micropipettes, in the nucleus centralis of the amygdala (Ce). The activity of a large majority (77%) was exclusively or preferentially affected by noxious stimuli applied in any area of the body. The rest of the neurons was not activated by any stimuli (21%) or responded only to innocuous stimuli (2%). The nociceptive neurons were classified into two groups: the neurons in the first group (34% of the whole population) were activated by mechanical and thermal noxious stimuli; the neurons in the second group (43% of the whole population) were inhibited by noxious stimuli. Neurons in two groups precisely encoded thermal stimuli in the noxious range. Transcutaneous electrical stimulation suggested that the Ce nociceptive neurons were under the influence of A delta and C fibers. These results demonstrate important nociceptive input to the Ce which according to previous studies probably relays in the pontine parabrachial nucleus. In addition, they are in good agreement with the involvement of the amygdala in emotional, autonomic and/or behavioral reactions to noxious events.

Morphine depresses the transmission of noxious messages in the spino(trigemino)-ponto-amygdaloid pathway.

We had recently demonstrated that a subregion of the parabrachial area relays nociceptive information in the spino(trigemino)-ponto-amygdaloid pathway. The aim of the present study was to investigate, in halothane-anesthetized rats, the effect of i.v. administration of morphine on nociceptive specific neurons located in the parabrachial area with some cells being antidromically driven from the amygdala. Morphine induced a marked depression of responses elicited by noxious thermal stimuli (waterbath, 50 degrees C) dose relatedly (1, 3, 9 mg/kg) and naloxone reversibly, with an ED50 = 1.8 mg/kg. This effect of morphine probably not only reflects the direct action of this drug at the spinal level, but could also involve a direct action at the parabrachial level. These results could account at least in part for the effect of morphine on the emotional-affective aspects of pain.

Intravenous morphine depresses the transmission of noxious messages to the nucleus centralis of the amygdala.

It has recently been demonstrated that the nucleus centralis of the amygdala contains numerous neurons specifically driven by noxious stimuli. The aim of the present study was to investigate the effect of i.v. morphine on responses of neurons located in the nucleus centralis of the amygdala to noxious mechanical or thermal stimuli. It was observed, in halothane-anesthetized rats, that i.v. morphine caused a marked depression of responses induced by noxious thermal (waterbath, 50 degrees C) and mechanical (pinch) stimuli and caused a moderate depression of spontaneous activity in a dose-related (1, 3, 9 mg/kg) and naloxone reversible fashion. The ED50 value was 1.2 and 9 mg/kg for i.v. morphine for the evoked activity and spontaneous activity, respectively. The strong depressive effect of morphine on evoked activity probably reflects a direct action of this drug at both spinal and parabrachial levels. These results could account, at least in part, for the effect of morphine on the emotional-affective aspects of pain.