Sec Trains Research Articles

Lubiprostone Increases Small Intestinal Smooth Muscle Contractions Through a Prostaglandin E Receptor 1 (EP)-mediated Pathway

Background/AimsLubiprostone, a chloride channel type 2 (ClC-2) activator, was thought to treat constipation by enhancing intestinal secretion. It has been associated with increased intestinal transit and delayed gastric emptying. Structurally similar to prostones with up to 54% prostaglandin E2 activity on prostaglandin E receptor 1 (EP1), lubiprostone may also exert EP1-mediated procontractile effect on intestinal smooth muscles. We investigated lubiprostone's effects on intestinal smooth muscle contractions and pyloric sphincter tone.MethodsIsolated murine small intestinal (longitudinal and circular) and pyloric tissues were mounted in organ baths with modified Krebs solution for isometric recording. Basal muscle tension and response to electrical field stimulation (EFS; 2 ms pulses/10 V/6 Hz/30 sec train) were measured with lubiprostone (10-10-10-5 M) ± EP1 antagonist. Significance was established using Student t test and P < 0.05.ResultsLubiprostone had no effect on the basal tension or EFS-induced contractions of longitudinal muscles. With circular muscles, lubiprostone caused a dose-dependent increase in EFS-induced contractions (2.11 ± 0.88 to 4.43 ± 1.38 N/g, P = 0.020) that was inhibited by pretreatment with EP1 antagonist (1.69 ± 0.70 vs. 4.43 ± 1.38 N/g, P = 0.030). Lubiprostone had no effect on circular muscle basal tension, but it induced a dose-dependent increase in pyloric basal tone (1.07 ± 0.01 to 1.97 ± 0.86 fold increase, P < 0.05) that was inhibited by EP1 antagonist.ConclusionsIn mice, lubiprostone caused a dose-dependent and EP1-mediated increase in contractility of circular but not longitudinal small intestinal smooth muscles, and in basal tone of the pylorus. These findings suggest another mechanism for lubiprostone's observed clinical effects on gastrointestinal motility.

Effects of chronic amphetamine treatment on cocaine‐induced facilitation of intracranial self‐stimulation in rats

Amphetamine is a monoamine releaser and candidate agonist medication for cocaine dependence. Chronic amphetamine treatment decreases cocaine self‐administration by rats, nonhuman primates and humans. This study tested the hypothesis that chronic amphetamine would decrease abuse‐related facilitation of intracranial self‐stimulation (ICSS) by cocaine in rats. Male Sprague‐Dawley rats were equipped with electrodes targeting the medial forebrain bundle and trained to respond under a fixed‐ratio 1 schedule for 0.5 sec trains of electrical stimulation. Stimulation intensity was individually determined in each rat, and frequency varied from 56–158 Hz in 0.05 log units during each session. Effects of 10 mg/kg cocaine on ICSS were determined before, during and after 14‐day continuous infusion with saline (N=5) or amphetamine (0.32 mg/kg/hr, N=5). Saline treatment had no effect on ICSS, and cocaine produced comparable facilitation of ICSS before, during and after saline treatment. Amphetamine facilitated ICSS throughout the 14‐day treatment, and termination of amphetamine decreased ICSS below pre‐treatment baseline. Cocaine facilitated ICSS before and after amphetamine, but during amphetamine treatment, it did not facilitate ICSS above levels produced by amphetamine alone. These findings suggest that chronic amphetamine decreases abuse‐related stimulus effects of cocaine. Funded by R01 DA026946

Pre‐junctional α2‐adrenoceptors modulation of the nitrergic transmission in the pig urinary bladder neck

To investigate the nitric oxide (NO)-mediated nerve relaxation and its possible modulation by pre-junctional alpha2-adrenoceptors in the pig urinary bladder neck. Urothelium-denuded bladder neck strips were dissected, and mounted in isolated organ baths containing a physiological saline solution (PSS) at 37 degrees C and continuously gassed with 5% CO2 and 95% O2, for isometric force recording. The relaxations to transmural nerve stimulation (electrical field stimulation [EFS]) or exogenously applied NO were carried out on strips pre-contracted with 1 microM phenylephrine (PhE) and treated with guanethidine (10 microM) and atropine (0.1 microM), to block noradrenergic neurotransmission and muscarinic receptors, respectively. EFS (0.2-1 Hz, 1 msec duration, 20 sec trains, current output adjusted to 75 mA) evoked frequency-dependent relaxations which were abolished by the neuronal voltage-activated Na+ channel blocker tetrodotoxin (TTX, 1 microM). These responses were potently reduced by the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOARG, 30 microM) and further reversed by the NO synthesis substrate L-arginine (L-ARG, 3 mM). The alpha2-adrenoceptor agonist BHT-920 (2 microM) reduced the electrically evoked relaxations, its effectiveness being higher on the responses induced by low frequency stimulation. BHT-920-elicited reductions were fully reversed by the alpha2-adrenoceptor antagonist rauwolscine (RAW, 1 microM). Exogenous NO (1 microM-1 mM) induced concentration-dependent relaxations which were not modified by BHT-920, thus eliminating a possible post-junctional modulation. These results indicate that NO is involved in the non-adrenergic non-cholinergic (NANC) inhibitory neurotransmission in the pig urinary bladder neck, the release of NO from intramural nerves being modulated by pre-junctional alpha2-adrenoceptor stimulation.

Recovery of Function after Vagus Nerve Stimulation Initiated 24 Hours after Fluid Percussion Brain Injury

Recent evidence from our laboratory demonstrated in laboratory rats that stimulation of the vagus nerve (VNS) initiated 2 h after lateral fluid percussion brain injury (FPI) accelerates the rate of recovery on a variety of behavioral and cognitive tests. VNS animals exhibited a level of performance comparable to that of sham-operated uninjured animals by the end of a 2-week testing period. The effectiveness of VNS was further evaluated in the present study in which initiation of stimulation was delayed until 24 h post-injury. Rats were subjected to a moderate FPI and tested on the beam walk, skilled forelimb reaching, locomotor placing, forelimb flexion and Morris water maze tasks for 2 weeks following injury. VNS (30 sec trains of 0.5 mA, 20.0-Hz biphasic pulses) was initiated 24 h post-injury and continued at 30-min intervals for the duration of the study, except for brief periods when the animals were detached for behavioral assessments. Consistent with our previous findings when stimulation was initiated 2 h post-injury, VNS animals showed significantly faster rates of recovery compared to controls. By the last day of testing (day 14 post-injury), the FPI-VNS animals were performing significantly better than the FPI-no-VNS animals and were not significantly different from shams in all motor and sensorimotor tasks. Performance in the Morris water maze indicated that the VNS animals acquired the task more rapidly on days 11-13 post-injury. On day 14, the FPI-VNS animals did not differ in the latency to find the platform from sham controls, whereas the injured controls did; however, the FPI-VNS animals and injured controls were not significantly different. Despite the lack of significant histological differences between the FPI groups, VNS, when initiated 24 h following injury, clearly attenuated the ensuing behavioral deficits and enhanced acquisition of the cognitive task. The results are discussed with respect to the norepinephrine hypothesis.

PACAP 38 is involved in the non‐adrenergic non‐cholinergic inhibitory neurotransmission in the pig urinary bladder neck

To investigate the role played by pituitary adenylate cyclase activating polypeptide 38 (PACAP 38) in the non-adrenergic non-cholinergic (NANC) neurotransmission of the pig urinary bladder neck. Urothelium-denuded bladder neck strips were dissected and mounted in organ baths containing a physiological saline solution (PSS) at 37 degrees C and gassed with 5% CO(2) and 95% O(2), for isometric force recording. The relaxations to transmural nerve stimulation (EFS) or PACAP 38 were performed on strips precontracted with 1 microM phenylephrine (PhE). EFS experiments were carried out in the absence and the presence of guanethidine (10 microM), atropine (0.1 microM), and N(G)-nitro-L-arginine (L-NOARG, 100 microM), to block noradrenergic neurotransmission, muscarinic receptors, and nitric oxide (NO) synthase, respectively. EFS (2-16 Hz, 1 ms duration, 20 sec trains, 75 mA current output) evoked frequency-dependent relaxations which were reduced by the VIP/PACAP receptor antagonist PACAP (6-38) (3 microM), and by the neurotoxin of the capsaicin-sensitive primary afferents capsaicin (10 microM), and abolished by the neuronal voltage-activated Na(+) channel blocker tetrodotoxin (TTX, 1 microM). The vasoactive intestinal peptide (VIP) receptor antagonist [Lys(1), Pro(2,5), Arg(3,4), Tyr(6)]-VIP (3 microM) failed to modify the EFS-induced relaxations. PACAP 38 (1 nM-1 microM) induced concentration-dependent relaxations which were reduced by PACAP (6-38), TTX and by the neuronal voltage-gated Ca(2+) channel inhibitor omega-conotoxin GVIA (omega-CgTX, 1 microM). The results suggest that PACAP 38, mainly released from capsaicin-sensitive primary afferents, is involved in the NANC inhibitory neurotransmission of the pig urinary bladder neck, producing relaxation through neuronal and muscle VIP/PACAP receptor activation.

Elevated Postsynaptic [Ca2+]iand L-Type Calcium Channel Activity in Aged Hippocampal Neurons: Relationship to Impaired Synaptic Plasticity

Considerable evidence supports a Ca(2+) dysregulation hypothesis of brain aging and Alzheimer's disease. However, it is still not known whether (1) intracellular [Ca(2+)](i) is altered in aged brain neurons during synaptically activated neuronal activity; (2) altered [Ca(2+)](i) is directly correlated with impaired neuronal plasticity; or (3) the previously observed age-related increase in L-type voltage-sensitive Ca(2+) channel (L-VSCC) density in hippocampal neurons is sufficient to impair synaptic plasticity. Here, we used confocal microscopy to image [Ca(2+)](i) in single CA1 neurons in hippocampal slices of young-adult and aged rats during repetitive synaptic activation. Simultaneously, we recorded intracellular EPSP frequency facilitation (FF), a form of short-term synaptic plasticity that is impaired with aging and inversely correlated with cognitive function. Resting [Ca(2+)](i) did not differ clearly with age. Greater elevation of somatic [Ca(2+)](i) and greater depression of FF developed in aged neurons during 20 sec trains of 7 Hz synaptic activation, but only if the activation triggered repetitive action potentials for several seconds. Elevated [Ca(2+)](i) and FF also were negatively correlated in individual aged neurons. In addition, the selective L-VSCC agonist Bay K8644 increased the afterhyperpolarization and mimicked the depressive effects of aging on FF in young-adult neurons. Thus, during physiologically relevant firing patterns in aging neurons, postsynaptic Ca(2+) elevation is closely associated with altered neuronal plasticity. Moreover, selectively increasing postsynaptic L-VSCC activity, as occurs in aging, negatively regulated a form of short-term plasticity that enhances synaptic throughput. Together, the results elucidate novel processes that may contribute to impaired cognitive function in aging.

Neurons of a Limited Subthalamic Area Mediate Elevations in Cortical Cerebral Blood Flow Evoked by Hypoxia and Excitation of Neurons of the Rostral Ventrolateral Medulla

Sympathoexcitatory reticulospinal neurons of the rostral ventrolateral medulla (RVLM) are oxygen detectors excited by hypoxia to globally elevate regional cerebral blood flow (rCBF). The projection, which accounts for >50% of hypoxic cerebral vasodilation, relays through the medullary vasodilator area (MCVA). However, there are no direct cortical projections from the RVLM/MCVA, suggesting a relay that diffusely innervates cortex and possibly originates in thalamic nuclei. Systematic mapping by electrical microstimulation of the thalamus and subthalamus revealed that elevations in rCBF were elicited only from a limited area, which encompassed medial pole of zona incerta, Forel's field, and prerubral zone. Stimulation (10 sec train) at an active site increased rCBF by 25 +/- 6%. Excitation of local neurons with kainic acid mimicked effects of electrical stimulation by increasing rCBF. Stimulation of the subthalamic cerebrovasodilator area (SVA) with single pulses (0.5 msec; 80 microA) triggered cortical EEG burst-CBF wave complexes with latency 24 +/- 5 msec, which were similar in shape to complexes evoked from the MCVA. Selective bilateral lesioning of the SVA neurons (ibotenic acid, 2 microg, 200 nl) blocked the vasodilation elicited from the MCVA and attenuated hypoxic cerebrovasodilation by 52 +/- 12% (p < 0.05), whereas hypercarbic vasodilation remained preserved. Lesioning of the vasodilator site in the basal forebrain failed to modify SVA-evoked rCBF increase. We conclude that (1) excitation of intrinsic neurons of functionally restricted region of subthalamus elevates rCBF, (2) these neurons relay signals from the MCVA, which elevate rCBF in response to hypoxia, and (3) the SVA is a functionally important site conveying vasodilator signal from the medulla to the telencephalon.

Comparison between monopolar and bipolar electrical stimulation of the motor cortex.

Intra-operative neurophysiological techniques allow reliable identification of the sensorimotor region and make their anatomical and functional preservation feasible. Monopolar cortical stimulation has recently been described as a new mapping technique. In the present study this method was compared to the "traditional" technique of bipolar stimulation. Functional mapping of the motor cortex was performed in 35 patients during surgery in the central region. The central sulcus (CS) was identified by somatosensory evoked potential (SEP) phase reversal. Cortical motor mapping was first performed by monopolar anodal stimulation with a train of 500 Hz (7-10 pulses) followed by bipolar stimulation (pulses at 60 Hz with max. 4 sec train duration). Surgery was performed under general anaesthesia without muscle relaxants. Of 280 motor responses elicited by bipolar cortical stimulation, 54.23% [152] were located in the primary motor cortex (PMC), 37.85% 106[ outside the motor strip in the secondary motor cortex (SMC), and 8% 22[ posterior to the CS. Of 175 motor responses elicited by monopolar cortical stimulation. 68.57% 120[ were located in the SMC, 23.42% 41[ in the SMC and 8% 14[ posterior to the CS. Contrary to the general clinical view, there is considerable overlapping of primary motor units over a cortical area much broader than the "classical" narrow motor strip along the CS. Bipolar cortical stimulation is more sensitive than monopolar for mapping motor function in the premotor frontal cortex. Both methods are equally sensitive for mapping the primary motor cortex.

Interaction between somatic and vagal afferent inputs in control of ventilation in 2-week-old rabbits

Effects of saphenous nerve stimulation (SNS) on the Hering–Breuer expiratory-promoting reflex evoked by a positive tracheal pressure (P tr; 5 cmH 2O) and on the diaphragmatic EMG (EMG di), inspiratory (T i) and expiratory (T e) time, were studied in 16 urethane-anesthetized (1.2–1.6 g/kg, i.p.) spontaneously breathing 2-week-old rabbits. Positive P tr applied at the end of T i increased the subsequent T e to 255±29% (±S.E.; P<0.0001) of control. SNS (1 sec train, 2 msec pulse, 6 Hz) applied at the onset of T e, shortened this T e by 42±3% ( P<0.0001). When SNS preceded positive P tr or positive P tr preceded SNS, the T e increased to 163±20 and 184±21% of control, respectively. These responses were not different, and smaller than that provoked by the P tr test alone ( P<0.003 and 0.05, respectively). The results show that in newborns somatic afferent stimulation attenuates the vagally mediated respiratory inhibition, whether immediately before or during the vagal stimulation.

Inflammatory Mediators Sensitize Acutely Axotomized Nerve Fibers to Mechanical Stimulation in the Rat

Many axotomized myelinated as well as unmyelinated cutaneous nerve fibers are sensitive to mechanical stimuli applied to the cut nerve end within a few hours after nerve lesion. Here we investigated the influence of inflammatory mediators on this ectopic mechanosensitivity after cutting and ligating the sural nerve in anesthetized rats. Neural activity was recorded from single axons in filaments teased from the sural or sciatic nerve proximally to the lesion site 2-33 hr after axotomy. Using calibrated von Frey hairs (1.0-128.5 mN), 30 sec trains of phasic stimuli were applied to the cut nerve end immediately before and after local application of a mixture of inflammatory mediators [inflammatory soup (IS), consisting of bradykinin, 5-HT, prostaglandin E2, histamine (all 10 microM), and K+ 7 mM, pH 7.0] for 2 min. Before as well as after IS application, von Frey thresholds were significantly lower in myelinated (A) fibers than in unmyelinated (C) fibers. IS application enhanced the ectopic mechanical excitability, as expressed in reduced von Frey thresholds and increased response magnitudes, of most severed mechanosensitive C fibers (77%) and some mechanosensitive A fibers (46%). The sensitization lasted for 10-40 min after a 2 min IS application. Additionally, among axotomized nerve fibers unresponsive to probing of the nerve lesion site before IS application, 1 of 63 (1.6%) A and 3 of 106 (2.8%) C fibers became mechanosensitive immediately after IS application. The results indicate that after axotomy, inflammatory processes augment touch-evoked ectopic activity in lesioned sensory nerve fibers. Because many affected afferents are presumably of nociceptive function, their enhanced neural barrage may contribute to neuropathic pain states.

In vitro classical conditioning of abducens nerve discharge in turtles

In vitro classical conditioning of abducens nerve activity was performed using an isolated turtle brainstem-cerebellum preparation by direct stimulation of the cranial nerves. Using a delayed training procedure, the in vitro preparation was presented with paired stimuli consisting of a 1 sec train stimulus applied to the auditory nerve (CS), which immediately preceded a single shock US applied to the trigeminal nerve. Conditioned and unconditioned responses were recorded in the ipsilateral abducens nerve. Acquisition exhibited a positive slope of conditioned responding in 60% of the preparations. Application of unpaired stimuli consisting of CS-alone, alternate CS and US, or backward conditioning failed to result in conditioning, or resulted in extinction of CRs. Latencies of CR onset were timed such that they occurred midway through the CS. Activity-dependent uptake of the dye sulforhodamine was used to examine the spatial distribution of neurons labeled during conditioning. These data showed label in the cerebellum and red nucleus during conditioning whereas these regions failed to label during unconditioned responses. Furthermore, the principal abducens nucleus labeled heavily during conditioning. These findings suggest the feasibility of examining classical conditioning in a vertebrate in vitro brainstem-cerebellum preparation. It is postulated that the abducens nerve CR represents a behavioral correlate of a blink-related eye movement. Multiple sites of conditioning are hypothesized, including the cerebellorubral circuitry and brainstem pathways that activate the principal abducens nucleus.

A computer analysis of EEG-intersignal reactions during the development of motoric alimentary conditioned reflexes in dogs.

The background electrical activity of the neocortex in the interstimulus periods at the stage of generalization during the development of alimentary motor conditioned reflexes (CR) in dogs was the investigational object. It was characterized by the appearance of brief (0.1-0.3 sec) trains of high frequencies (HF), significantly exceeding the adjacent initial baseline in frequency and amplitude. The relative variance index which we had developed made it possible to distinguish this EEG phenomenon in the initial realizations of the background activity when they were inputted into a digital computer. It was not possible to evaluate the parameters of the HF chains by means of a spectral correlation analysis. Nonstandard techniques of computer analysis directed toward the decomposition of the EEG tracing into a system of oscillations and toward the obtaining of the corresponding amplitude-frequency distributions (maps) were developed by us for the purpose of accomplishing this objective. It was demonstrated that HF trains were localized in these maps in specific, quite compact regions.

Role of the hippocampal-entorhinal loop in temporal lobe epilepsy: extra- and intracellular study in the isolated guinea pig brain in vitro

This article introduces a new experimental paradigm for the study of temporal lobe epilepsy. This approach utilizes the isolated guinea pig brain in vitro preparation, which generates a pattern of hypersynchronous neuronal activity similar to the peculiar 8-30 Hz rhythm characterizing stereoelectroencephalographic hippocampal recordings in human temporal lobe epilepsy. The present report describes an attempt to identify the functional events underlying the epileptiform activities observed in this preparation. Rhythmic epileptiform discharges (EDs), here defined as population spikes (PSs) recorded from somata or dendritic layers, were induced in the hippocampal formation of the isolated guinea pig brain maintained in vitro by tetanic stimulation of the entorhinal cortex (EC). Two patterns of EDs were distinguished by performing simultaneous field potential recordings along the dentate gyrus (DG), EC, CA1, and CA3. During stage 1, the first self-sustained EDs were isolated PSs occurring at a frequency of 2-3 Hz at all levels of the entorhinal-hippocampal loop, the only exception being the DG, where no signs of synchronized neuronal discharge could be found. Over the next 30-50 sec, the temporal organization of these EDs changed dramatically. During stage 2, at all levels of the entorhinal-hippocampal loop, EDs occurred in 0.3-0.5 sec trains of 16-25 Hz population spikes interrupted by 0.7-1.3 sec silent periods. The transition between stages 1 and 2 coincided with the occurrence of population spikes in the DG. Laminar analyses and multiple simultaneous field potential recordings revealed that the trains of EDs observed in stage 2 resulted from the repetitive, sequential activation of the hippocampal-entorhinal loop. In the transverse axis, the earliest event usually occurred in the CA3 region. Thereafter, population spikes occurred sequentially in the CA1 region, EC, DG, and back to the CA3 region. Intracellular recordings confirmed that the EDs recorded extracellularly resulted from the synchronous activation of the cells in phase with the locally recorded field potentials. Dentate granule cells, layer II entorhinal cells, as well as CA1 pyramids displayed large-amplitude EPSPs crowned by an isolated action potential phase locked to the locally recorded field potential. In contrast, the activity of CA3 pyramids consisted of typical paroxysmal depolarization shifts on which bursts of action potentials of decreasing amplitude were observed. These results suggest that reentrant loop activity in the hippocampal-entorhinal circuit represents the central event in the functional organization of hippocampal epileptic discharges.

Locomotor stepping elicited by electrical stimulation of the hypothalamus persists after lesion of descending fibers of passage

Locomotion initiated by electrical stimulation of the lateral hypothalamus could be due to activation of local neurons or of fibers of passage descending from locomotor regions in the basal forebrain. This study mapped hypothalamic sites for electrically elicited locomotion in six rats with electrolytic lesions of the ipsilateral basal forebrain sources of descending fibers of passage. For mapping, anesthetized rats were held in a stereotaxic apparatus supported by a sling so that stepping movements rotated a wheel. Anesthesia was maintained by periodic injections of Nembutal (7 mg/kg) supplemented by lidocaine injections. Stimulation (25 and 50 μA, 50 Hz, 0.5 msec cathodal pulses, 10 sec trains) was applied through 50–80 μm diameter pipettes filled with 2 M saline. In all cases, locomotor stepping could be elicited by stimulation in sites ipsilateral to the lesion at currents of 50 μA or less. In the one case in which 25 μA sites were not found in the lateral hypothalamus, the lesion extended caudally to within 1 mm of the stimulation sites. These findings do not exclude a locomotor role for fibers of passage but they suggest that activation of lateral hypothalamic neurons is sufficient to initiate locomotion.

Pharmacological characteristics of the postsynaptically mediated contractile responses of guinea-pig ileum to long-lasting electrical field stimulation

The contractile responses of the longitudinal smooth muscle layer of the isolated guinea-pig ileum which were elicited by long-lasting (40 sec train duration) electrical field stimulation (0.8 msec, 20 V), applied at a frequency of either 5 or 30 Hz, comprised an initial phasic component followed by a secondary tonic contraction, were studied against the background of postsynaptically-acting receptor antagonists. Atropine and apamin reduced both components of the responses while prazosin produced no change. Propranolol induced a slight reduction, decreasing mainly the responses evoked by stimulation at a frequency of 5 Hz. The simultaneous application of cholinoceptor and adrenoceptor Mockers revealed a non-cholinergic, non-adrenergic component of the responses. The putative prostaglandin antagonist, SC 19220 was found to reduce mainly the tonic component of the non-cholinergic, non-adrenergic contractions evoked by stimulation at both frequencies used. These results demonstrated that the two-component contractile responses of the guinea pig ileum to long-lasting electrical stimulation were due to the release of more than one neurotransmitter and/or spasmogenic substance. It is concluded that the initial phasic component was evoked by acetylcholine and by a non-cholinergic, non-adrenergic neurotransmitter, while the tonic component was maintained predominantly by prostaglandins released during stimulation.

The efficacy of hypnosis- and relaxation-induced analgesia on two dimensions of pain for cold pressor and electrical tooth pulp stimulation

This study evaluated the efficacy of hypnosis- and relaxation-induced suggestions for analgesia for reducing the strength and unpleasantness dimensions of pain evoked by noxious tooth pulp stimulation and by cold pressor stimulation. The Tellegen Absorption Questionnaire was used to assess hypnotic susceptibility for 28 subjects in order to match treatment groups according to sex and susceptibility scores. Tooth pulp stimulation consisted of a 1 sec train of 1 msec pulses at a frequency of 100 Hz, applied at 20 sec intervals to the central incisor. Six stimuli, selected between subject's pain and tolerance thresholds, were presented 3 times each in random order. Cold pressor stimulation consisted of forearm immersion in a circulating water bath maintained at 0–1°C. Subjects made threshold determinations of pain and tolerance and used Visual Analogue Scales to rate the strength and the unpleasantness of both noxious stimuli before and after receiving either hypnosis- or relaxation-induced analgesia. There were no significant differences in pain reductions between hypnosis- and relaxation-induced interventions. However, the percent reduction in both strength and unpleasantness varied significantly as a function of the type of pain. Both hypnosis and relaxation significantly reduced the strength and the unpleasantness of tooth pulp stimulation, but only the unpleasantness dimension of cold pressor pain. The pain reductions were not correlated with subjects' hypnotic susceptibility levels. The results indicate that the extent and the quality of the analgesia produced by these cognitive-based therapies vary not only according to subjects' characteristics and the efficacy of the intervention, but also according to the nature of the noxious stimuli. Tooth pulp and cold pressor stimulation represent qualitatively different stimuli with respect to both the type of nerves activated and the mode of stimulus application. Discrete, randomly presented levels of noxious electrical stimulation to the teeth activate predominantly small fibers and produce brief pain sensations that vary unpredictably in intensity. In contrast, continuous cold stimulation to the forearm activates a variety of nociceptive and non-nociceptive fibers and produces progressive cold and pain sensations with a predictable increase in intensity from cold sensations to paresthesia and severe pain.

Cardiovascular and respiratory changes elicited by stimulation of rat superior colliculus

Stimulation of the rat superior colliculus can produce either orienting or defensive movements, which if elicited by natural stimuli would be accompanied by cardiovascular changes. To assess whether cardiovascular changes might also be mediated by the superior colliculus, blood pressure and heart rate were measured in Saffan-anaesthetised rats while the dorsal midbrain was systematically explored with electrical and chemical stimulation. Electrical stimulation (10 sec trains of 0.3 msec 100 Hz cathodal pulses, 50 μA) within the superficial and intermediate layers of the rostral superior colliculus transiently lowered blood pressure without affecting heart rate. In contrast sites within the deep layers, and in adjacent periaqueductal grey and midbrain tegmentum, gave pressor responses accompanied by a variety of heart-rate changes, that usually included a period of bradycardia. A roughly similar distribution was obtained with the cell-stimulant bicuculline (200 or 500 nl, 490 μM), though sodium L-glutamate (200 nl, 0.05 or 1.0 M) was ineffective. These results suggest that (a) cardiovascular responses can be produced by stimulation of the rat superior colliculus ; (b) their nature depends on the location of the stimulation ; and (c) they may be mediated in part by cells differentially sensitive to glutamate and to bicuculline. In addition, in some animals respiratory responses were measured stethographically. Short-latency increases in thoracic girth, often accompanied by increases in respiratory rate and depth, were elicited by electrical stimulation from 61% of the collicular sites examined, and by microinjection of glutamate from 56% of collicular sites. These data suggest that (a) cells within the superior colliculus are capable of influencing respiration; (b) given the widespread distribution of responsive sites within the superior colliculus, the respiratory changes may be preparatory for both approach and defensive movements; (c) the collicular cells that affect respiration may be different from those that influence blood pressure, because the latter are relatively insensitive to microinjection of glutamate.

Brown adipose tissue thermogenesis induced by low level electrical stimulation of hypothalamus in rats

Brown adipose tissue (BAT) is an energy dissipating form of adipose tissue implicated in non-shivering thermogenesis as well as diet-induced thermogenesis. In the present study, in vivo interscapular BAT (IBAT) temperature was recorded prior to and following low level electrical stimulation (a 30 sec train of 60 Hz, 100 μA 0.5 msec isolated pulses) of various hypothalamic regions in rats. Significant increases in IBAT temperature were observed after stimulation of the anterior, medial preoptic, paraventricular and dorsomedial hypothalamus but not after stimulation of either ventromedial or caudal hypothalamus. For positive sites, IBAT temperature typically increased at 3–4 minutes following stimulation, peaked at 7–8 minutes after stimulation and declined at 20 minutes after stimulation. Although alterations in diet-induced thermogenesis have been reported after ventromedial hypothalamic lesions, the increases in BAT temperature noted in the present study suggest that inhibitory fibers that course through the paraventricular hypothalamus may form part of the central nervous system control of brown adipose tissue thermogenesis induced by overfeeding.

Hippocampal stimulation limits performance but does not retard acquisition of food-reinforced learning

Facilitation of the usually very slow acquisition of hippocampal (HPC) self-stimulation (SS) by prior, non-contingent HPC stimulation may be due to the progressive attenuation of a disruptive effect of the stimulation on learning. We attempted to answer two questions: (1) Does HPC stimulation disrupt food-reinforced learning when it follows each lever-press as in SS experiments? (2) Does prior exposure to the stimulation attenuate any such disruptive effect? We observed no significant differences in the rate of acquisition when each food-reinforced response was paired contingently with a 0.5 sec train of dorsal HPC stimulation (CS group), or when 0.5 sec trains were administered randomly throughout the session (RS), compared with an implanted control group (IC). Although acquisition was rapid in all groups, performance on the second day was significantly lower in the CS group than in the IC animals. These same electrode placements later supported SS. The same results were obtained with 3 similarly-treated groups that had previously received a program of daily HPC stimulation (kindling). The results imply that kindling does not produce its facilitating effect on acquisition of HPC SS by removing a disruptive effect of the stimulation.

The effect of naloxone on vasopressin release from rat neurohypophysis incubated in vitro.

Rat posterior pituitaries were superfused in vitro and stimulated electrically. The concentrations of vasopressin in the superfusion medium were determined by radioimmunoassay. When the pulses were applied in 10 sec trains with 10 sec intervals, vasopressin release per pulse increased progressively over the frequency range of 3-12 pulses/sec applied within the trains. The release was blocked by addition of tetrodotoxin or by removal of calcium ions from the superfusion medium. The opiate antagonist naloxone 1 or 10 microM was introduced into the superfusion medium before a second period of stimulation and enhanced vasopressin release from neurointermediate lobes after phasic stimulation at 9 pulses/sec within the trains, when compared to controls. However, naloxone 10 microM had not effect on vasopressin release from isolated neural lobes (intermediate lobes removed), although the addition of camel beta-endorphin 2 microM inhibited vasopressin release in a naloxone-reversible manner. After continuous stimulation at a frequency of 13 Hz naloxone 10 microM did not influence the release of vasopressin from neurointermediate lobes. We conclude that the evoked release of vasopressin from the neurointermediate lobe is reduced by an endogenous opiate of intermediate lobe origin, possibly beta-endorphin. Appropriate stimulation conditions are necessary for this mechanism to function.