Visual and auditory inputs into the cuneate nucleus.

Sound clicks or light flashes modify somatic sensory activity in the cuneate nucleus of the cat. The techniques of gross potential recording in the cuneate nucleus or medial lemniscal tract, of single unit recording in the cuneate nucleus, and of excitability testing of cuneate terminals demonstrate this heterosensory interactionsensory interaction.

Early neurologic complications following coronary bypass surgery.

BACKGROUND: Coronary artery bypass surgery is associated with central and peripheral nervous system complications in the period following surgery. Recognising these complications may help in their prevention or early treatment. METHODS: We reviewed medical records of all the patients who underwent coronary artery bypass surgery at our institution over a period of two years. We studied their risk factors, reasons for surgery, operative variables, and post operative neurologic complications. RESULTS: Of the 587 coronary artery bypass surgeries performed at our centre over a two year period. We found that 2.04% of these patients developed neurologic complication in the two weeks following the surgery. Fifty percent of these patients suffered from cerebrovascular insults and 50% suffered from cognitive decline. No patients in this group developed seizures or peripheral nerve lesions. Patients with renal failure, carotid stenosis, history of cerebral strokes, and redo coronary bypass surgery were more predisposed to develop neurologic complications after bypass surgery. Furthermore, a longer stay in the coronary care unit and the development of arrhythmias predisposed patients to neurologic complications. Mortality for patients who developed neurologic complications post bypass surgery ranged between 16.7% and 33.4%. CONCLUSIONS: Around 2% of patients who undergo coronary artery bypass surgery develop neurologic complications in the period directly after the surgery. Patients with previous history of cerebral, coronary, or carotid disease are more predisposed for such complications, as well as patients who spend more time in the intensive units after the surgery.

Effects of lesions in the anterolateral columns and dorsolateral funiculi on self-mutilation behavior in rats.

The possible role of the anterolateral columns (ALCs) and dorsolateral funiculi (DLF) in pain mechanisms was examined from the effects of lesions in these tracts (alone or combined) on tests for chronic deafferentation pain (autotomy) in rats. Spinal lesions alone (i.e., without denervation) in either ALC or DLF or combined DLF-ALC did not lead to any form of self-mutilation behavior. Cervical surgery, without spinal lesion, followed by limb denervation (sham) resulted in similar autotomy characteristics to those observed following limb denervation alone (control). Both results were considered as one set of controls. ALC lesions simultaneous with, or 1-2 weeks prior to limb denervation (ipsilaterally or contralaterally) produced significant delay in onset of autotomy and decrease in percentage of rats showing this behavior. DLF lesions followed by limb denervation produced significant acceleration of onset of autotomy and increase in percentage of rats showing this behavior. Combined DLF-ALC lesions with limb denervation produced intermediate effects between those observed following either ALC or DLF lesions alone. These results give further support to the concept that autotomy is related to rostral transmission of nociceptive information and that a spino-bulbo-spinal inhibitory loop involving the DLF and ALC is triggered by chronic deafferentation pain.

Endotoxin-induced local inflammation and hyperalgesia in rats and mice: a new model for inflammatory pain.

Lipopolysaccharide, also known as endotoxin (ET), is a major constituent of the outer membrane of the cell wall of most gram negative bacteria. ET is known to cause a number of pathophysiological changes associated with illness including inflammatory pain. The aim of this study is to characterize the peripheral hyperalgesia induced by ET in rats and mice. Different groups of rats and mice received different doses of ET ranging from 0.6 microgram to 40 micrograms dissolved in 50 microliters saline and injected in the plantar area of the left hind legs. All animals were subjected to tail immersion (TF), hot plate (HP) and paw pressure (PP) tests, 2-3 days prior to ET injection and during the following 1-2 days. ET injections produced a dose-dependent decrease in the latencies of the HP and PP tests of the injected leg reaching a maximum decrease of 50-60% of the control with 20-40 micrograms ET at 9 h (rats) and 24 h (mice) after the injection. Almost complete recovery was observed after 24 h in rats and 48 h in mice. TF latencies showed a less but a significant decrease while PP of the opposite leg and all tests in saline-injected animals did not elicit significant variations and served as additional controls. Our results indicate that the use of ET-produced hyperalgesia is a valid model for local and reversible inflammatory pain, with minimal distress to the animal. This model can also be used to study the efficacy of various anti-inflammatory and analgesic drugs and the molecular mechanisms of inflammation induced by bacterial invasion.

The role of cytokines and prostaglandin-E(2) in thymulin induced hyperalgesia.

We have recently reported that intraperitoneal (i.p.) injection of thymulin at low doses (50 ng) resulted in thermal and mechanical hyperalgesia and upregulation of the level of interleukin-1beta in the liver. In this study, we demonstrate that such injections of thymulin result in a significant elevation in the levels of TNF-alpha (P<0.01), NGF (P<0.01) and PGE(2) (P<0.01) in the liver of the treated rats, in addition to the increase in the levels of IL-1beta. Pretreatment with specific antagonists to each of these factors (polyclonal anti-TNF-alpha, anti-NGF antiserum and IL-1 receptor antagonist) did not result in the abolition of the hyperalgesia as assessed by the paw pressure, hot plate, paw immersion and tail flick tests. However, pretreatment with a combination of the above antagonist and antisera almost completely prevented thymulin-induced hyperalgesia. The cyclooxygenase inhibitor, meloxicam, reversed in a dose dependent manner (0.2, 0.4 and 2 mg/kg) thymulin effects as assessed by the different pain tests. It also abolished the thymulin-induced increase in the level of cytokines and NGF in the liver. Our results indicate that PGE(2) could be the key mediator of the hyperalgesic action of thymulin and the observed upregulation of proinflammatory cytokines and NGF.

Involvement of substance P, CGRP and histamine in the hyperalgesia and cytokine upregulation induced by intraplantar injection of capsaicin in rats.

Intraplantar (i.pl.) injection of small doses of capsaicin has been shown to produce hyperalgesia and upregulation of the levels of proinflammatory cytokines. The present work aimed at investigating the possible mediation of these effects by sensory neuropeptides and mast cells. Various groups of rats received i.pl. injection of capsaicin alone or preceded by the injection of antagonists to substance P (SP), calcitonin gene-related protein (CGRP) and histamine (H1, H2) or the mast cell blocker ketotifen. All pretreatments prevented, in a dose-related manner, the capsaicin-induced hyperalgesia. The SP, H2 antagonists and ketotifen prevented the upregulation of all cytokines and nerve growth factor (NGF) levels, while the CGRP and H1 antagonists showed only attenuation of the NGF level.

Thymulin induces c-fos expression in the spinal cord of rats which is reversed by meloxicam and morphine.

Intraplantar (i.pl.) injections of thymulin have been shown to produce hyperalgesia in rats through a prostaglandin E2-dependent mechanism. This study aimed at investigating if such injections can produce sustained activation of spinal neurons by mapping the fos-like-immunoreactivity (FLI) as a marker for this activation. Our results showed that thymulin produces significant and sustained FLI in neurons located in spinal laminae known to be involved in nociception. Pretreatment with either morphine or meloxicam (a cyclooxygenase inhibitor) revealed differential effects on FLI and the hyperalgesia induced by thymulin. These findings support the hypothesis that thymulin can affect central neurons either directly or through the peripheral nerve terminals.

Involvement of capsaicin sensitive primary afferents in thymulin-induced hyperalgesia.

Intraplantar (5 ng) or intraperitoneal (50 ng) injections of thymulin, produced both thermal and mechanical hyperalgesia in rats. In this report, we show that ablation of capsaicin sensitive primary afferents (CSPA) can alter or abolish thymulin-induced hyperalgesia. Different groups of rats were subjected to either treatment with capsaicin or to surgical subdiaphragmatic vagotomy (SDV). Both capsaicin and SDV reduced significantly thymulin-induced hyperalgesia. On the other hand, these treatments elicited differential effects on the modulation by thymulin of the levels of nerve growth factor and interleukin 1beta. We conclude that the hyperalgesic effects of i.p. thymulin are mainly mediated through the CSPA fibers.

Attenuation of neuropathic pain by segmental and supraspinal activation of the dorsal column system in awake rats.

In addition to its involvement in the transmission of neuropathic pain, the dorsal column system has been shown to have analgesic effects when electrically stimulated. The segmental or supraspinal origin of the analgesia, however, has not been clearly delineated. The aim of this study is to demonstrate the contribution of supraspinal mechanisms to the inhibition of allodynia and hyperalgesia in two different rat models of mononeuropathy. Mononeuropathy was induced, under deep anesthesia, in several groups of rats (n=7 each) following either the chronic constriction injury or the spared nerve injury model. Mechanical and cold allodynia were assessed by the Von Frey monofilaments and by the acetone drop test, respectively. Thermal hyperalgesia was assessed by the paw withdrawal and hot plate tests. Bipolar electrodes for dorsal column stimulation were implanted chronically in all rats on the dorsal aspect of the medulla at the level of the obex. Selective dorsal column bilateral lesions were performed at the upper cervical level in some groups of rats. Dorsal column nuclear stimulation, rostral to selective dorsal spinal lesions, produced strong inhibitory effects on the allodynia and hyperalgesia observed in both models of mononeuropathy. These effects were comparable to those observed following similar stimulations in rats with an intact spinal cord. Our results demonstrate strong inhibitory effects of dorsal column stimulation on neuropathic pain. This inhibition can be attributed to the activation of brainstem pain-modulating centers via rostral projections of the dorsal column nuclei.

Thymulin reverses inflammatory hyperalgesia and modulates the increased concentration of proinflammatory cytokines induced by i.c.v. endotoxin injection.

The immunomodulatory thymic hormone thymulin has been shown previously to possess anti-inflammatory actions in the periphery. In this study, we have examined the effect of i.c.v. injections of either endotoxin (ET) or thymulin, in separate groups of conscious rats, on pain-related behavior and cytokine levels in different areas of the brain. Furthermore, we investigated the effect of pretreatment with either i.c.v. or i.p. injections of thymulin on endotoxin-induced hyperalgesia and the effect of pretreatment with i.c.v. thymulin on endotoxin-induced up-regulation of cytokine levels. Our results demonstrate that i.c.v. injection of endotoxin (1 microg in 5 microl saline) resulted in a significant decrease in the nociceptive thresholds as assessed by different pain tests, with peak hyperalgesia at 3 h. However, thymulin at different doses, when injected (i.c.v.), had no significant effect on pain related behavior. Pretreatment (i.c.v.) with thymulin (0.1, 0.5 and 1 microg in 5 microl saline) 20 min before endotoxin (i.c.v.) injection (1 microg in 5 microl saline) reduced, in a dose dependent manner, the endotoxin-induced hyperalgesia and exerted differential effects on the up-regulated levels of cytokines in different areas of the brain. The results provide behavioral and immunochemical characterization of a rat model for intracerebral inflammation and indicates a neuroprotective role for thymulin in the CNS.

Attenuation of neuropathic manifestations by local block of the activities of the ventrolateral orbito-frontal area in the rat.

Clinical and recent imaging reports demonstrate the involvement of various cerebral prefrontal areas in the processing of pain. This has received further confirmation from animal experimentation showing an alteration of the threshold of acute nociceptive reflexes by various manipulations in the orbito-frontal cortical areas. The present study investigates the possible involvement of this area in the modulation of neuropathic manifestations in awake rats. Several groups of rats were subjected to mononeuropathy following the spared nerve injury model, known to produce evident tactile and cold allodynia and heat hyperalgesia. The activity of the ventrolateral orbital areas was selectively blocked by using either chronic or acute injection of lidocaine, electrolytic lesion, or chemical lesion with kainic acid or 6-hydroxydopamine (6-OHDA). The effects of these manipulations were compared with those following lesion of the somatic sensorimotor cortical areas. Local injection of lidocaine resulted in a reversible depression of all neuropathic manifestations while electrolytic or chemical lesions elicited transient attenuation affecting mainly the heat hyperalgesia and to a lesser extent the cold allodynia. The magnitude of the observed effects with the different procedures used can be ranked as follows: 6-OHDA

The role of the dorsal columns in neuropathic behavior: evidence for plasticity and non-specificity.

Despite conflicting clinical and experimental evidence, textbook description of somatic sensations continues to follow a rigid dichotomy based on the concept that pain sensation is transmitted cephalad primarily through anterolateral pathways, while touch is mediated through the dorsal column pathway. This study provides an example of the dynamic rerouting in the transmission of the nociceptive signals following injuries to the peripheral and central processes of sensory neurons. In two rat models for mononeuropathy, the chronic constriction injury model [Bennett, G.J., Xie, Y.K., Pain 33 (1988) 87-107] and the spared nerve injury model [Decosterd, I., Woolf, C.J., Pain 87 (2000) 149-158], we demonstrate that selective dorsal columns lesion produced significant decrease of tactile and cold allodynias and thermal hyperalgesia which were assessed by the Von Frey hair filaments, the acetone drop test and the heat-induced paw withdrawal, respectively. These manifestations, however, can reappear 2 weeks after bilateral dorsal column lesion in rats subjected to spared nerve injury mononeuropathy and appear also in animals sustaining chronic bilateral dorsal column lesion followed by either model of mononeuropathy. Lesion of the dorsal column on the side opposite to the neuropathic leg did not alter the neuropathic manifestations in both animal models. Changes in the sequence of timing of the dorsal column lesion and induction of mononeuropathy, suggest that the effects of the former last for 1 to 2 weeks. The results of this study show that the dorsal columns are involved in neuropathic manifestations and at the same time are not necessary for their full development and persistence. Furthermore, these results shade doubts on the validity of the concept of segregation of pathways involved in the transmission of neuropathic manifestations. Therefore, principles governing acute pain transmission are not necessarily applicable to chronic pain situations. The latter conditions seem to engage other available pathways to reestablish the pain signaling system.

A thymulin analogue peptide with powerful inhibitory effects on pain of neurogenic origin.

The effects of a synthetic peptide analog of thymulin (PAT) were tested on nociceptive behavior in two animal models for peripheral mononeuropathy and in another two models for capsaicin-induced hyperalgesia. Treatment with PAT (0.25-25 microg/rat, i.p.) produced significant reduction of the mechanical allodynia and heat hyperalgesia in rats subjected to either chronic constriction injury (CCI) or spared nerve injury (SNI) models for mononeuropathy. Cold allodynia was moderately reduced in the CCI model. The inhibition of neuropathic manifestations peaked at 1-2 h post-treatment and disappeared in 3-4 h. Daily treatment with PAT, however, produced progressive attenuation of all neuropathic manifestations in the SNI model. On the other hand, pretreatment with similar doses of PAT produced dose-dependent reduction of the hyperalgesia induced by intraplantar injection of capsaicin (10 microg in 50 microl). The highest dose of PAT (50 microg) produced significant reduction of abdominal aversive behavior induced by i.p injection of capsaicin (20 microg in 100 microl). Compared with the effects of treatment with morphine or meloxicam (injected at single doses known to produce analgesia), PAT exerted equal or stronger inhibitory effects on neuropathic manifestations. The reported results suggest a possible direct action of PAT on afferent nerve fibers but its mechanisms remain to be determined.

Calcitonin gene-related peptide regulates amino acid absorption across rat jejunum.

The calcitonin gene related peptide (CGRP) is widely distributed in the enteric nervous system and gut afferents. Its role in normal digestion and absorption is not characterised. This study is conducted to elucidate whether CGRP regulates amino acid absorption in the small intestine. In in vivo experiments using the single-pass perfusion technique, intravenous infusion of CGRP (250-750 pmol/kg-min) reduced alanine absorption by 35-40%. The effects were completely blocked by the antagonist hCGRP (8-37). Moreover, intravenous infusion of CGRP antagonist blocked the inhibitory effect of intraluminal capsaicin perfusion on alanine absorption. Similarly, intracerebral injection of CGRP decreased alanine absorption, an effect which was reduced by vagotomy. In vitro experiments using isolated jejunal strips showed that CGRP reduced alanine absorption in a dose-dependent manner. At 6 pM, CGRP decreased alanine absorption by 33%. Similarly, CGRP reduced the absorption of proline and taurine by 20 and 11.5%, respectively. Kinetic studies revealed that CGRP reduces alanine influx into intestinal epithelial cells by inhibiting the affinity of the carriers. It is demonstrated that CGRP is involved in the regulation of jejunal amino acid absorption through intrinsic (enteric) and extrinsic (central) neural mechanisms.

Effects of intracerebral injections of VIP on jejunal alanine absorption and gastric acid secretion in rats.

The effects of intracerebral injections of VIP on jejunal alanine absorption and gastric acid secretion, and its association with vagal outflow were examined in Sprague-Dawley rats. Intracerebroventricular injection of VIP (2 ng) decreased significantly (P < 0.05) alanine absorption across the jejunum, whereas similar injections in vagotomized rats did not show further decrease in absorption beyond that noticed by vagotomy only. Moreover, VIP injected in the Nucleus Tractus Solitarius-Dorsal Motor Nucleus (NTS-DMN) complex (1 ng) produced also a significant inhibition of Ala absorption which was reduced but remained significant (P < 0.05) after vagotomy. Water movement was not affected by VIP injection in the lateral ventricle, while VIP injections in the NTS-DMN inhibited significantly (P < 0.05) jejunal water absorption by 10-12%. Vagotomy increased water absorption by 15-20% above control (P < 0.05) which was not altered by injecting VIP in the NTS-DMN complex. On the other hand, VIP injection in the NTS-DMN produced a 25.7% increase in gastric acid output in the first hour of the experiment followed by a non-significant decrease (P > 0.05) in the second hour. Same injections done in vagotomized animals produced similar effects to those elicited by vagotomy only. It can be suggested that NTS-DMN complex could be a site of action of VIP since injection of VIP in it produced a more pronounced inhibitory effect on water and Ala absorption than that produced by VIP injection in the LV. These effects were reduced or abolished by vagotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intravenous vasoactive intestinal peptide injection on jejunal alanine absorption and gastric acid secretion in rats.

The effect of intravenous vasoactive intestinal polypeptide (VIP) injection on jejunal L-alanine absorption and gastric acid secretion in the rat was investigated. Continuous intravenous VIP infusion (11.2 ng/kg per min) throughout the experimental period (160 min) produced 60% decrease in alanine absorption and 40% decrease in gastric acid secretion during the second hour of the experiment. Subdiaphragmatic vagotomy reduced alanine absorption to 91% (P > 0.05) and 71.3% (P < 0.05) of control value during the first and second hours of perfusion, respectively. VIP infusion following vagotomy elicited a reduced effect when compared to that produced by similar injections in normal rats. Gastric secretion in vagotomized rats was reduced by 40% (P < 0.05) below control. VIP infusion in vagotomized rats exerted a significant decrease (P < 0.05) of gastric acid secretion. Moreover, water absorption was decreased by almost 10% (P < 0.05) after i.v. injection of VIP and was increased by 20-24% above control value following vagotomy. However, i.v. administration of VIP following vagotomy did not elicit any further change in water absorption. It can be concluded that VIP inhibits alanine absorption and gastric acid secretion in the rat and that these inhibitory effects might be partially mediated by the vagus nerve.

Autoradiographic localization of opiate receptors in rat brain. II. The brain stem.

The distribution of opiate receptors, determined by the autoradiographic localization of stereospecific [3H]diprenorphine binding sites, was studied in the brain stem. Areas showing very dense or dense localizations of receptors included the parabrachial nuclei, the superior colliculus, the ventral median raphe nucleus, components of the accessory optic system, portions of the habenulo-interpeduncular complex, the pretectal nuclei and the ventral lateral geniculate, the infundibulum and the medial thalamus. Moderate grain densities were found in broad areas of the upper medulla, midbrain and diencephalon. The significance of these findings are discussed in terms of pain mechanisms, association of some receptors with small diameter axons, pupillary reflexes, hormonal control, and effects of opiates on neurotransmitter systems.

Autoradiographic localization of opiate receptors in rat brain. I. Spinal cord and lower medulla.

The localization of opiate receptors in the spinal cord and lower medulla has been elucidated by the autoradiographic identification of stereospecific [3H]diprenorphine (a potent opiate antagonist) binding sites. The opiate receptors were higly localized to: layers I (marginal cell zones) and II (substantia gelatinosa) of the dorsal horn of the spinal cord; the substantia gelationsa of the spinal trigeminal nucleus; components of the vagal system, including the vagus nerve, nucleus tractus solitarius, nucleus commissuralis, nucleus intercalatus, nucleus ambiguus and nucleus originis dorsalis vagus; the area postrema. Examination of [3H]etorphine (a potent opiate agonist) binding sites showed the same distribution. We conclude that, in these brain regions, opiate receptors are (1) highly associated with areas receiving small, afferent primary fibers, (2) strategically placed to modulate noxious stimuli as well as explain some visceral side effects of opiate administration.

Autoradiographic localization of opiate receptors in rat brain. III. The telencephalon.

Opiate receptor distribution, determined by the autoradiographic localization of stereospecific [3H]diprenorphine binding sites, was examined in the telencephalon. Areas showing very dense or dense localization of receptors included parts of the presubiculum and amygdala, patchy areas in the caudate-putamen and accumbens, the subfornical organ, the interstriatal nucleus of the striae terminalis and the anterior olfactory nucleus, pars externa. Lower densities were found in other parts of the hippocampal formation, the deeper part of the cerebral cortex, the entopeduncular nucleus, globus pallidus, nucleus triangularis septi and nucleus paratenialis. The significance of these findings is discussed in terms of the biochemical and physiological actions of opiates.

Inhibitory effects from various types of dorsal column and raphe magnus stimulations on nociceptive withdrawal flexion reflexes.

Most of the clinical and research reports agree about the analgesic effects of dorsal column (DC) stimulation, but there is no unanimity about the neural mechanisms involved in this stimulation. The aim of the present study was to compare the effects of segmental and rostral activation of the DCs and to investigate whether these effects are mediated through a brainstem spinal loop. Decerebrate-decerebellate cats were subjected to selective DC lesions at C(1) and C(3) spinal cervical levels and their reflex reactions to natural or electrical nociceptive stimuli were monitored either as withdrawal flexion reflexes or as motorneuronal discharges. Conditioning stimulation was performed as train of shocks (100 Hz, for 1 to 10 min or 300 Hz for 30 ms) applied on the DCs either rostral (DCr) or caudal (DCc) to the spinal lesions or on the raphe magnus (RM). Conditioning trains for 5-10 min applied on DCr inhibited the withdrawal flexion reflexes recorded as toe flexion (90% of the control). Comparisons of the effects of DCr, DCc or RM of conditioning stimuli were made on the discharges of 110 motorneurons recorded in isolated ventral root fibers. Conditioning stimulation applied to DCc produced short lived inhibition (in about 60%) or facilitation (in about 30% of the neurons) while DCr or RM conditioning produced inhibition in 90% of neurons which outlasted the duration of the conditioning trains. It was also shown that repetitive application of conditioning train on either DCr or RM resulted in longer duration of inhibition than that observed following DCc conditioning. We conclude that the stronger inhibition of motorneuronal discharges, evoked by nociceptive stimuli, is obtained by rostral activation of the DCs and that long term effects of DCst are mediated through a DC-brainstem-spinal loop.