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Biomedical subjects

R L Hayes

Publications and source records attributed to R L Hayes.

At least 145 records · Page 8Linked to original sources
PubMed1987

The frontal eye field and prefrontal cortex project to the paramedian pontine reticular formation in the cat.

Transcannular microinjections of horseradish peroxidase were made into the paramedian pontine reticular formation (PPRF) in adult cats to identify regions of the cerebral cortex having direct influence on this important center for the production of saccadic eye movements. The majority of retrogradely labeled cortico-(ponto)reticular neurons were located in lamina V of the dorsomedial precruciate shoulder cortex and presylvian sulcal cortex, the medial and lateral frontal eye fields of the cat respectively. In most cases, labeled cells also extended into the gyrus proreus, the cat prefrontal cortex.

Animals↗
PubMed1987

Endogenous opioids may mediate secondary damage after experimental brain injury.

Although endogenous opioids have been implicated in the pathophysiology of spinal cord injury and brain ischemia, the role of specific opioid peptides and opiate receptors in the pathophysiology of traumatic brain injury remains unexplored. This study examined regional changes in brain opioid immunoreactivity and cerebral blood flow (CBF) after fluid-percussion brain injury in the cat and compared the effect of an opiate antagonist (Win 44,441-3 [Win-(-)]) with its dextroisomer Win 44,441-2 [Win-(+)] (which is inactive at opiate receptors) in the treatment of brain injury. Dynorphin A immunoreactivity (Dyn A-IR) but not leucine-enkephalin-like immunoreactivity accumulated in injury regions after traumatic injury; Dyn-IR increases also occurred predominantly in those areas showing significant decreases in regional CBF. Administration of Win-(-) but not Win-(+) or saline at 15 min after injury significantly improved mean arterial pressure, electroencephalographic amplitude, and regional CBF and reduced the severity and incidence of hemorrhage. Win-(-) also significantly improved survival after brain injury. Taken together, these findings suggest that dynorphin, through actions at opiate receptors, may contribute to the pathophysiology of secondary brain injury after head trauma and indicate that selective opiate-receptor antagonists may be useful in treatment of traumatic brain injury.

Animals↗
PubMed1987

Transient suppression of event-related evoked potentials produced by mild head injury in the cat.

Studies in humans have shown that sensory stimuli, presented in the context of certain tasks, can elicit a late positive component (LPC), namely P300, in the scalp-recorded evoked potential believed to reflect neural activity related to attentional processes. A similar LPC has been reported in cats and monkeys. In this study, the LPC of the auditory evoked potential (AEP) in the cat was used to detect impairment in attention to a relevant stimulus after low levels of cerebral concussion produced by a fluid percussion device. A hollow screw (for fluid percussion) and stainless steel screws (for AEP recording) were surgically placed in the skull. After recovery from surgery, animals were trained in the paradigm to obtain an LPC. Pupillary dilation was conditioned to tones. A random sequence of two discriminable tones was presented. The lower tone had a probability of 0.1 and was followed by a tail shock (tone-shock). After 400 to 1000 tone-shock presentations, animals attended to the lower tone stimulus as inferred by selective pupillary dilation. In the AEP an early positive component at 50 to 120 msec related to an alerting response was enhanced, and an LPC at 250 to 450 msec appeared in response to the paired tone-shock. Animals were then subjected to cerebral concussion. Complete recovery of normal reflexes, motor coordination, and orienting response was seen within 2 hours after injury. The LPC was suppressed for a period of at least 3 days, suggesting that low magnitudes of brain injury can disrupt higher-order neural activities. This disruption can persist despite recovery of other neurological functions.

Animals↗
PubMed1987

A fluid percussion model of experimental brain injury in the rat.

Fluid percussion models produce brain injury by rapidly injecting fluid volumes into the cranial cavity. The authors have systematically examined the effects of varying magnitudes of fluid percussion injury in the rat on neurological, systemic physiological, and histopathological changes. Acute neurological experiments showed that fluid percussion injury in 53 rats produced either irreversible apnea and death or transient apnea (lasting 54 seconds or less) and reversible suppression of postural and nonpostural function (lasting 60 minutes or less). As the magnitude if injury increased, the mortality rate and the duration of suppression of somatomotor reflexes increased. Unlike other rat models in which concussive brain injury is produced by impact, convulsions were observed in only 13% of survivors. Transient apnea was probably not associated with a significant hypoxic insult to animals that survived. Ten rats that sustained a moderate magnitude of injury (2.9 atm) exhibited chronic locomotor deficits that persisted for 4 to 8 days. Systemic physiological experiments in 20 rats demonstrated that all levels of injury studied produced acute systemic hypertension, bradycardia, and increased plasma glucose levels. Hypertension with subsequent hypotension resulted from higher magnitudes of injury. The durations of hypertension and suppression of amplitude on electroencephalography were related to the magnitudes of injury. While low levels of injury produced no significant histopathological alterations, higher magnitudes produced subarachnoid and intraparenchymal hemorrhage and, with increasing survival, necrotic change and cavitation. These data demonstrate that fluid percussion injury in the rat reproduces many of the features of head injury observed in other models and species. Thus, this animal model could represent a useful experimental approach to studies of pathological changes similar to those seen in human head injury.

Animals↗
PubMed1986

Examination of the blood-to-brain transfer of alpha-aminoisobutyric acid and horseradish peroxidase: regional alterations in blood-brain barrier function following acute hypertension.

Blood-brain barrier (BBB) alterations following acute hypertension were studied in rats, employing as tracers in each animal both horseradish peroxidase (HRP) (MW 40,000) and [14C]alpha-aminoisobutyric acid ([14C]AIB) (MW 104). Eighteen animals were subjected to acute hypertension induced by the intravenous infusion of norepinephrine bitartrate (NE) (Levophed). Five animals injected with both tracers but not infused with NE served as controls. The brain of each animal was serially sectioned with adjacent sections processed either for macroautoradiography or for light microscopic visualization of HRP reaction product via histochemical reaction with tetramethylbenzidine. Quantitative blood-to-brain transfer constants for AIB were determined in each of 14 brain regions. Qualitative comparisons were also made between the AIB and HRP blood-to-brain extravasation patterns in each group. Acute hypertension increased cerebrovascular permeability to both AIB and HRP in most animals. Topographically, the sites of the most highly elevated AIB transfer corresponded with sites of HRP extravasation. Conversely, all sites of protein passage corresponded spatially to sites of elevated AIB transfer. Brain regions commonly showing increased permeability to both tracers included the cerebral cortices, corpus callosum, and thalamus. Importantly, some brain regions showed elevated AIB transfer constants where protein extravasation was absent. These regions included the caudate-putamen, hippocampus, basal forebrain, and cerebellum. These observations suggest that following acute hypertension, alterations in BBB permeability are not limited to vascular segments allowing protein extravasation.

Acute Disease↗
PubMed1986

Metabolic and neurophysiologic sequelae of brain injury: a cholinergic hypothesis.

This paper reviews a number of lines of evidence developed in our laboratories indicating that at least some components of neurologic disturbances following concussion may be attributable to increased functional activity of cholinergic systems located within specific brain regions. These lines of evidence include EEG studies indicating that disruption of the reticular activating system is not necessary for production of a reversible, flaccid, comatose state following low levels of concussion, systematic transection studies indicating that regions bounded by collicular and midpontine transections may contribute to at least motor components of the behavioral suppression associated with concussion, local rates of glucose utilization following fluid percussion injury increase in restricted areas bounded by collicular and midpontine transections; microinjection of carbachol (but not tetracaine) into these hypermetabolic regions produced behavioral suppression and electroencephalographic changes resembling those following concussion, systemic administration or microinjections of atropine, but not mecamylamine, antagonized the behavioral effects of carbachol, and data indicating that pharmacologic blockage of muscarinic cholinergic systems can attenuate neurologic deficits. Taken in conjunction with data from earlier clinical and laboratory studies, our research also indicates that anticholinergic therapy may potentially benefit head-injured patients.

Animals↗
PubMed1986

Range of environmental stimuli producing nociceptive suppression: implications for neural mechanisms.

Initial studies of environmentally induced analgesia in the rat established several important characteristics of this phenomenon. We demonstrated that stressful environmental stimuli were not sufficient to produce nociceptive suppression. However, emphasis by many researchers on stress-related analgesia has limited studies of the range of environmental contexts producing nociceptive suppression and handicapped efforts to describe neural mechanisms mediating EIA. Another feature of EIA was the observation that the nervous system might contain multiple opiate and non-opiate systems capable of modulating nociceptive responses. Although previous research had recognized the possibility of endogenous opiate analgesic systems, little attention had been given to non-opiate analgesic mechanisms. Since it seems unlikely that multiple systems would serve purely redundant roles, it seemed reasonable to speculate that at least some of these systems may mediate other modulatory functions in addition to regulating sensory information on noxious stimuli. The observation that some environmental conditions could increase nociceptive responses certainly indicated that environmentally induced nociceptive modulation was not restricted to analgesia. These and other observations lead us to suspect that neural mechanisms mediating at least some forms of EIA could be related to mechanisms mediating more general modulating processes associated with selective attention, orienting, or arousal. Subsequent studies in the primate established that changes in vigilance demands, stimulus relevance, and stimulus predictability could modulate responses of medullary dorsal horn nociceptors coding sensory-discriminative information on noxious thermal stimuli. However, these studies provided no information on the neural mechanisms mediating this modulation. Later studies in cats described an endogenous, non-narcotic analgesic system representing a subcomponent of a larger cholinergic system principally involved in regulating animals' responsiveness to external stimuli. Research also indicated that this cholinergic analgesic system could function physiologically to modulate nociceptive responsiveness in the presence of certain environmental stimuli but not others. Considered together, data from these studies indicate that, while stress is not sufficient to produce analgesia, a variety of environmental conditions can modulate nociceptive input. A number of different neural systems could contribute EIA associated with various stimuli. It is possible that the regulation of nociceptive input is not the exclusive, or even principal, consequence of normal activity within certain of these systems.

Analgesia↗
PubMed1985

Depression of afferent-induced primary afferent depolarization at the lumbar spinal cord following concussive head injury.

Afferent-induced primary afferent depolarization (PAD) was depressed for 2-5 min following concussive head injury in the cat, as assessed by dorsal root potentials and augmentation of antidromic dorsal root potentials, both evoked by stimulation of adjacent dorsal roots. These changes in PAD were abolished by spinal cord transection but not affected by midpontine transection. Spontaneous dorsal root potentials, resting amplitudes of antidromic dorsal root potentials and reductions of antidromic dorsal root potentials following tetanic root stimulation were not substantially altered by injury. These findings suggest that concussive head injury depresses spinal interneuronal transmission by neurally mediated processes involving the bulbar brainstem.

Animals↗
PubMed1985

Dissociation of endogenous components of auditory evoked potentials following carbachol microinjection into the cholinoceptive pontine inhibitory area.

Microinjections of the cholinergic agonist, carbachol, into an area ventromedial to the principal nucleus of the locus coeruleus produce pronounced suppression of postural somatomotor and sympathetic visceromotor functions, and profound unresponsiveness to external stimuli. In order to clarify whether this unresponsiveness is due exclusively to disruption of motor components of various behavioral responses, we examined changes in the endogenous components of auditory evoked potentials recorded in conjunction with a tone discrimination task. Concomitant with carbachol-induced behavioral unresponsiveness, the late positive component (LPC) at 250-350 ms disappeared, while the early positive component at 80-150 ms was enhanced. This result suggests that, after the onset of carbachol-induced behavioral unresponsiveness, external stimuli enter the brain but are not integrated in neural processes reflected in LPC which has previously been implicated in processes mediating orienting responses, selective attention, and/or cognitive evaluation.

Animals↗
PubMed1985

Pain suppression induced by electrical stimulation of the pontine parabrachial region. Experimental study in cats.

Cholinergic stimulation by microinjection of drugs into a region surrounding the lateral half of the brachium conjunctivum selectively produces a non-opiate form of pain suppression in the cat. Since this suppression does not appear to involve neural systems that mediate morphine analgesia, stimulation of this pontine parabrachial region (PBR) may potentially be useful for control of human pain resistant or tolerant to opiate treatment. Because of technical problems associated with the clinical use of microinjection techniques in the human brain, we investigated whether electrical stimulation of the PBR can produce pain suppression similar to pain suppression produced by cholinergic stimulation. The results indicate that electrical stimulation of an area generally corresponding to the PBR can also produce significant pain suppression. Although the PBR is a region previously implicated in a variety of behavioral and physiological functions, the stimulation parameters that produce maximal pain suppressive effects (namely, low frequency and relatively low intensity) were not associated with noticeable changes in such functions. The prolonged onset period and persistent analgesic effects outlasting the period of stimulation--features that have been reported in other studies of brain stimulation-produced pain suppression--were observed in the present study. The time course of pain suppression did not parallel other changes in behavioral and physiological functions. These data indicate that electrical stimulation of the PBR, under certain stimulation parameters, can activate previously demonstrated neural populations related to pain suppression without affecting neural elements contributing to other behavioral or physiological functions. The authors suggest that electrical stimulation of the PBR may be clinically applicable for treatment of human pain.

Acetylcholine↗
PubMed1985

Concussive head injury producing suppression of sensory transmission within the lumbar spinal cord in cats.

This study examines the effects of concussive levels of a fluid-percussion head injury on sensory transmission within the lumbar spinal cord of the cat. Primary afferent depolarization (PAD) was suppressed for 2 to 5 minutes following injury, as assessed by dorsal root potentials and augmentation of antidromic dorsal root potentials, both evoked by stimulation of adjacent dorsal roots. Polysynaptic reflex discharges in ventral root potentials evoked by dorsal root stimulation were also profoundly suppressed during this same period, even when spontaneous and monosynaptic reflex discharges were facilitated. Changes in PAD produced by injury were abolished by spinal cord transection, but were not affected by midpontine transection. These findings suggest that concussive head injury can produce suppression of segmental sensory transmission by neurally mediated processes involving the bulbar brain stem. Recordings of dorsal root resting potentials, antidromic dorsal root potentials, and reductions of antidromic dorsal root potentials induced by tetanic root stimulation indicated that depressed segmental sensory function produced by injury was due to suppression of postsynaptic interneuronal transmission rather than to excitability changes in primary afferent fibers. Somatosensory cortical potentials evoked by dorsal root stimulation were profoundly depressed at the same time as segmental sensory transmission was suppressed, suggesting that suppressed segmental sensory transmission may also contribute to suppression of ascending sensory transmission. It is hypothesized that transmission failure of interneuronal systems in the initial period following insult may be a general response occurring in wide areas of the central nervous system, and not restricted to areas to which mechanical stress is directly applied. This response pattern may result from indiscriminate activation of interconnected excitatory and inhibitory elements of interneuronal systems.

Animals↗
PubMed1985

Regional brain metabolite levels following mild experimental head injury in the cat.

Glucose, adenosine triphosphate, phosphocreatine, and lactate levels in the cortex, striatum, diencephalon, hippocampus, cerebellum, and brain stem were measured in cats 1 hour after they were subjected to low-level (2 atm) fluid-percussion injury. Following injury, there was a mild but significant increase in lactate levels in the majority of regions studied. The hippocampus exhibited the highest percentage increase in lactate (fourfold). The cortical area directly under the trauma device showed a threefold lactate increase, while there was a twofold increase in other brain regions studied. Although there were consistent decreases in phosphocreatine levels, these decreases were significant only in the hippocampus (p less than 0.05). Glucose levels in all brain regions studied were no different from control levels at the time of study. The unchanged glucose levels, together with previous studies of identically injured cats showing that cerebral blood flow was unimpaired, suggest that excess lactate was not a consequence of cerebral ischemia. Rather, the increase in lactate levels may indicate that concussive injury can produce a mild derangement of brain energy metabolism in the absence of substrate limitations. This derangement may reflect altered mitochondrial function.

Adenosine Triphosphate↗
PubMed1984

Bilateral lesions of the dorsolateral funiculus of the cat spinal cord: effects on basal nociceptive reflexes and nociceptive suppression produced by cholinergic activation of the pontine parabrachial region.

In cats, bilateral microinjections of the cholinergic agonist, carbachol (0.6 micrograms in 0.2 microliter), into an area surrounding the lateral half of the brachium conjunctivum (BC) produces a non-narcotic suppression of nociceptive responses, as assessed by flexion reflexes (tail-flick and calibrated pinch tests). Bilateral lesions of the dorsolateral funiculi (DLF) of the thoracic spina cord (T2) significantly reduced the magnitude of this nociceptive suppression. Nociceptive suppression following carbachol microinjections into sites along the dorsal aspect of BC was reduced by DLF lesions to a greater degree than nociceptive suppression following injections into sites within or ventral to BC. Relatively superficial DLF lesions produced reductions in nociceptive suppression which were equivalent to reductions induced by deeper lesions. DLF lesions, either superficial or deep, produced equivalent, reliable decreases in tail-flick test assessments of baseline nociceptive thresholds. The magnitude of decreases in baseline nociceptive thresholds produced by DLF lesions was not correlated with the magnitude of reduction of carbachol-induced suppression of nociceptive responses, indicating that DLF lesions suppress anti-nociception independent of baseline alterations. These data suggest that non-narcotic analgesia produced by cholinergic activation of cells along the dorsal aspect of BC may be predominantly mediated by fibers descending within the DLF. However, results of the retrograde horseradish peroxidase (HRP) tracing studies reported in the present investigation indicate that this pain suppression is probably mediated by polysynaptic pathways since this region dorsal to BC projects neither through DLF nor extra-DLF pathways. Retrograde HRP data show that areas ventral to and including BC projects to the cord via both DLF and extra-DLF pathways. Since DLF lesions were less effective in reducing analgesia attained from ventral compared to dorsal sites, spinal pathways other than DLF may mediate reflex suppression following carbachol microinjection into these more ventral sites. Possible cholinergic contributions to endogenous, non-opiate forms of analgesia are discussed.

Acetylcholine↗
PubMed1984

Muscarinic cholinergic mediation of opiate and non-opiate environmentally induced analgesias.

Previous studies have demonstrated that brief front paw shock and brief hind paw shock produce prolonged opiate and non-opiate analgesia, respectively. Additionally, opiate analgesia can be classically conditioned by using either front paw shock or hind paw shock as the unconditioned stimulus. However, beyond this point little is known regarding the neurochemistry of these phenomena. The present series of studies examined the potential involvement of nicotinic and muscarinic cholinergic systems in these 3 forms of environmentally induced analgesia. These experiments demonstrate that muscarinic cholinergic sites within the central nervous system are critically involved in the mediation of both hind paw (non-opiate) foot shock-induced analgesia ( FSIA ) and classically conditioned (opiate) analgesia since scopolamine, but not equimolar methylscopolamine, significantly attenuated analgesia. Furthermore, the primary muscarinic site(s) appears to exist at a supraspinal, rather than spinal, level since delivery of scopolamine directly to the lumbosacral cord produced, at most, only a slight decrease in analgesia. Nicotinic systems do not appear to be importantly involved in any of these forms of environmentally induced analgesias since mecamylamine had no effect on either front paw FSIA or hind paw FSIA and, at most, produced only a slight reduction in classically conditioned analgesia. These data and a review of the literature suggest that the critical cholinergic sites involved in hind paw FSIA exist within the caudal brainstem whereas cholinergic sites within more rostral brain levels probably mediate classically conditioned analgesia.

Analgesia↗
PubMed1984

Evidence for involvement of cholinoceptive cells of the parabrachial region in environmentally induced nociceptive suppression in the cat.

We have previously observed that activation of muscarinic receptors within the pontine parabrachial region (PBR) of cats produces potent analgesia. This study demonstrated that bilateral microinjections of the muscarinic antagonist atropine (each 4.0 micrograms in 1.0 microliter) into PBR attenuated nociceptive suppression elicited by exposure of cats to novel environmental changes without affecting general responsiveness to environmental stimulation. This observation suggests that muscarinic cholinoceptive cells in PBR function physiologically to modulate nociceptive responsiveness in response to certain environmental stimuli.

Animals↗
PubMed1984

Behavioral evidence for a cholinoceptive pontine inhibitory area: descending control of spinal motor output and sensory input.

Earlier studies have shown that microinjection of the cholinergic agonist carbamylcholine (carbachol) into the rostral pontine tegmentum of the cat elicits postural atonia. However, conflicting reports exist regarding other concomitant behavioral changes. The present study has demonstrated that a variety of functions supporting animals' responsiveness to external stimuli including postural somatomotor, sympathetic visceromotor and nociceptive somatosensory functions are differentially affected depending upon the injection sites. Sites associated with maximal effects on each of these functions are clustered in the dorsal pontine tegmentum, i.e. cholinoceptive pontine inhibitory area (CPIA). In a medial area of CPIA, which corresponds to an area caudal to the ventral tegmental nucleus of Gudden and ventromedial to the principal nucleus of locus coeruleus, postural somatomotor and sympathetic visceromotor functions were maximally suppressed. In a laterally adjacent area ventral to the principal nucleus of locus coeruleus, somatomotor function was predominantly suppressed. Nociceptive somatosensory function was primarily suppressed following microinjections into a more lateral area surrounding the lateral half of the brachium conjunctivum. Several lines of evidence suggest that each of these phenomena ultimately involves descending influences on the spinal motor output and/or sensory input. There was no correlation between maximal suppression of these spinal cord functions and signs of desynchronized sleep such as rapid eye movement. Carbachol microinjection into wide areas of CPIA also suppressed orienting behaviors. Taken together, these data suggest that CPIA is a system which primarily regulates animals' responsiveness to external stimuli, in part by influencing segmentally organized behaviors.

Animals↗
PubMed1984

Non-opiate analgesia induced by carbachol microinjection into the pontine parabrachial region of the cat.

These studies investigated the effect of microinjection of the cholinergic agonist carbamylcholine (carbachol) into various sites of the dorsolateral pontine tegmentum of the cat. Carbachol microinjection into an area surrounding the lateral half of the brachium conjunctivum (parabrachial region, PBR) produced profound suppression of nociceptive responses. In the dorsal part of PBR, carbachol microinjection produced no generalized sensory, emotional or motor deficits, indicating that nociceptive transmission was primarily affected. Carbachol microinjection into the ventral part of PBR resulted in slight suppression of motor responses in addition to profound nociceptive suppression. Carbachol-produced analgesia (CPA) observed within PBR blocked supraspinally as well as spinally integrated responses normally elicited by either phasic or tonic noxious stimuli. Atropine sulfate, but not mecamylamine hydrochloride, significantly antagonized CPA, indicating that muscarinic receptors mediate this phenomenon. The opiate antagonist naloxone, systemically administered either prior to or after carbachol microinjection, did not reliably attenuate CPA. Microinjection of morphine into the sites from which CPA had previously been obtained did not produce significant effects on nociceptive responses. Thus, opiate mechanisms appear not to be necessary either for the activation of this system or for the production of the resultant analgesia. These findings indicate that the neural population examined in the present study is anatomically and pharmacologically distinct from previously identified opiate-mediated pain inhibitory systems. Results are discussed in light of other recent evidence indicating the existence of endogenous non-opiate pain inhibitory systems.

Animals↗