Biomedical subjects

R L Hayes

Publications and source records attributed to R L Hayes.

At least 19 recordsLinked to original sources

PubMed1992

Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy.

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA receptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1992

Pain-related increases in spinal cord membrane-bound protein kinase C following peripheral nerve injury.

Neuropathic pain following nerve injury is thought to involve central nervous system Ca(2+)-mediated neuronal plastic changes. This study provides evidence that induction and/or maintenance of post-injury neuropathic pain behaviors in the rat is associated with increases in membrane-bound protein kinase C (PKC), a Ca(2+)-dependent process known to mediate central nervous system neuronal plasticity. In addition, spinal cord administration of GM1 ganglioside, an intracellular inhibitor of PKC translocation/activation, reverses both increased levels of membrane-bound PKC and pain-related behaviors. Thus, persistent post-injury neuropathic pain may be mediated by the initiation of excitatory neuropathological processes resulting from an increase in membrane-bound PKC.

Animals↗

PubMed1992

Enduring suppression of hippocampal long-term potentiation following traumatic brain injury in rat.

This study investigated changes in synaptic responses (population spike and population EPSP) of CA1 pyramidal cells of the rat hippocampus to stimulation of the Schaffer collateral/commissural pathways 2-3 h after traumatic brain injury (TBI). TBI was induced by a fluid percussion pulse delivered to the parietal epidural space resulting in loss of righting responses for 4.90-8.98 min. Prior to tetanic stimulation, changes observed after the injury included: (1) decreases in population spikes threshold but not EPSP thresholds; (2) decreases in maximal amplitude of population spikes as well as EPSPs. TBI also suppressed long-term potentiation (LTP), as evidenced by reductions in post-tetanic increases in population spikes as well as EPSPs. Since LTP may reflect processes involved in memory formation, the observed suppression of LTP may be an electrophysiological correlate of enduring memory deficits previously demonstrated in the same injury model.

Animals↗

PubMed1992

Post-injury treatment with GM1 ganglioside reduces nociceptive behaviors and spinal cord metabolic activity in rats with experimental peripheral mononeuropathy.

In a rat model of painful peripheral mononeuropathy, this study examined the effects of post-injury treatment with a monosialoganglioside, GM1, on abnormal nociceptive behaviors and spinal cord neural activity resulting from loose ligation of the rat common sciatic nerve (chronic constrictive injury, CCI). Thermal hyperalgesia and spontaneous pain behaviors of CCI rats were assessed by measuring foot-withdrawal latencies to radiant heat and by rating spontaneous hind paw guarding positions, respectively. Neural activity within different regions of the spinal cord was inferred in both CCI and sham-operated rats by employing the [14C]-2-deoxyglucose (2-DG) autoradiographic technique to measure spinal cord glucose metabolism. Intraperitoneal (i.p.) GM1 treatment (10 mg/kg) initiated 1 h or 24 h after injury and once daily for the first 9 post-injury days reduced thermal hyperalgesia of the hind paw ipsilateral to nerve ligation and lowered spontaneous pain behavior rating scores in CCI rats. Sciatic nerve ligation reliably increased basal 2-DG metabolic activity of CCI rats in all four sampled regions (laminae I-IV, V-VI, VII, VIII-IX) of spinal cord lumbar segments (L2-L5) both ipsilateral and contralateral to nerve ligation 10 days after injury. Consistent with the drug's effects on spontaneous pain behaviors, 10 daily GM1 treatments (10 mg/kg, i.p.) initiated 1 h after nerve ligation reduced spinal cord 2-DG metabolic activity in laminae V-VI and VII ipsilateral to nerve ligation and in all four sampled regions contralateral to nerve ligation. This attenuation of the increased spinal cord glucose utilization that occurs in the absence of overt peripheral stimulation may reflect an influence of GM1 on increased neural activity contributing to spontaneous pain. Since gangliosides are thought to protect neurons from excitotoxic effects of excitatory amino acids, these results suggest that ganglioside treatment may result in attenuation of excitatory neurotoxicity that may occur following peripheral nerve injury. Thus, ganglioside treatment could provide a new approach to the clinical management of neuropathic pain syndromes following peripheral nerve injury.

Animals↗

PubMed1992

Intrathecal GM1 ganglioside and local nerve anesthesia reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy.

Our previous experiments demonstrated that systemic treatment with GM1 ganglioside reduces nociceptive behaviors and spinal cord metabolic activity in a rat model of painful peripheral mononeuropathy produced by experimental sciatic nerve ligation (chronic constrictive injury, CCI). In the present study, we examined the effects of intrathecal (i.t.) GM1 treatment on thermal hyperalgesia and spontaneous pain behaviors resulting from nerve ligation in order to determine the locus of GM1 action. In addition, a local anesthetic agent, bupivacaine, given alone or combined with i.t. GM1, was applied to the injured sciatic nerve to determine if peripheral nerve anesthesia would influence post-injury nociceptive behaviors. Thermal hyperalgesia to radiant heat decreased in a dose-dependent manner when GM1 (10-80 nmol, i.t.) was administered once daily onto the lumbar segments of the spinal cord beginning 1 h after experimental nerve injury and continued for the first 9 days after nerve ligation. Moreover, this GM1 (80 nmol) treatment regimen reliably lowered spontaneous pain behavior rating scores in CCI rats suggesting the possible attenuation of spontaneous pain. The central site of i.t. GM1 action is located at the caudal (probably lumbar) spinal cord, since i.t. injection of 20 nmol GM1 onto the cervical spinal cord did not produce any protective effect. A single perinerve injection of a local anesthetic agent, bupivacaine (0.5%, 0.6 ml), on the 3rd day after nerve ligation reduced thermal hyperalgesia for at least 24 h following injection, a duration longer than that of the local anesthetic action of bupivacaine. Neither a single bupivacaine injection nor four daily i.t.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Local↗

PubMed1992

Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy.

The hyperalgesia and spontaneous pain that occur following peripheral nerve injury may be related to abnormal peripheral input or altered central activity, or both. The present experiments investigated these possibilities by examining the effects of MK-801 (a non-competitive N-methyl-D-aspartate, NMDA, receptor antagonist) and bupivacaine (a local anesthetic agent) on thermal hyperalgesia and spontaneous nociceptive behaviors in rats with painful peripheral mononeuropathy. Peripheral mononeuropathy was produced by loosely ligating the rat's common sciatic nerve, a procedure which causes chronic constrictive injury (CCI) of the ligated nerve. The resulting hyperalgesia to radiant heat and spontaneous nociceptive behaviors was assessed by using a foot-withdrawal test and a spontaneous pain behavior rating method, respectively. CCI rats receiving 4 daily intraperitoneal (i.p.) MK-801 injections (0.03, 0.1, 0.3 mg/kg) beginning 15 min prior to nerve ligation exhibited less hyperalgesia (i.e., longer foot-withdrawal latencies) on days 3, 5, 7, 10, and 15 after nerve ligation as compared to those receiving saline injections. Thermal hyperalgesia also was reduced when a single MK-801 injection was given intrathecally (i.t.) onto the spinal cord lumbar segments on Day 3 after nerve ligation. This effect of postinjury MK-801 treatment was dose-dependent (2.5-20 nmol) and lasted for at least 48 h after injection. Moreover, i.t. injection of MK-801 (10 nmol) reliably lowered spontaneous pain behavior rating scores in CCI rats compared to those in the saline group. The spinal site of MK-801 action is situated within the caudal (probably lumbar) spinal cord, since i.t. injection of MK-801 (10 nmol) onto the spinal cord thoracic segments did not affect thermal hyperalgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Local↗

PubMed1992

Postinjury scopolamine administration in experimental traumatic brain injury.

A single bolus dose of scopolamine (1.0 mg/kg) or saline (equal volume) was injected (i.p.) at 15, 30 or 60 min after fluid percussion traumatic brain injury in the rat. Scopolamine administered at 15 min postinjury significantly reduced beam walking deficits and body weight loss assessed for 5 days after injury. Scopolamine treatment at 30 or 60 min postinjury had no effect on behavioral outcome assessed for 5 days after injury. Plasma concentrations of scopolamine were measured with a radioreceptor assay. The plasma half-life for scopolamine was 21.6 min in injured rats and 17.3 min in normal rats (P less than 0.05). These results, along with evidence from previous studies, suggest that a brief period of excessive neuronal excitation can produce relatively long-lasting behavioral deficits. The temporal effectiveness of receptor antagonist intervention in this process appears to be brief.

Animals↗

PubMed1992

Cognitive deficits following traumatic brain injury produced by controlled cortical impact.

Traumatic brain injury produces significant cognitive deficits in humans. This experiment used a controlled cortical impact model of experimental brain injury to examine the effects of brain injury on spatial learning and memory using the Morris water maze task. Rats (n = 8) were injured at a moderate level of cortical impact injury (6 m/sec, 1.5-2.0 mm deformation). Eight additional rats served as a sham-injured control group. Morris water maze performance was assessed on days 11-15 and 30-34 following injury. Results revealed that brain-injured rats exhibited significant deficits (p less than 0.05) in maze performance at both testing intervals. Since the Morris water maze task is particularly sensitive to hippocampal dysfunction, the results of the present experiment support the hypothesis that the hippocampus is preferentially vulnerable to damage following traumatic brain injury. These results demonstrate that controlled cortical impact brain injury produces enduring cognitive deficits analogous to those observed after human brain injury.

Animals↗

PubMed1992

Microtubule-associated protein 2 levels decrease in hippocampus following traumatic brain injury.

We examined microtubule-associated protein 2 (MAP2) levels in hippocampal and cortical tissue 3 h following moderate traumatic brain injury (TBI) in the rat. MAP2 levels were assayed by quantitative immunoreactivity in tissue fractions obtained from naive, sham-injured, or fluid percussion-injured animals. Tissues were homogenized in the presence of protease inhibitors (0.3 mM phenylmethylsulfonyl fluoride, PMSF), a specific calpain inhibitors (0.1 mM leupeptin), and chelators (2 mM ethylene glycol-bis-tetraacetic acid, EGTA; 1 mM ethylenedinitrilo-tetraacetic acid, EDTA) to eliminate in vitro MAP2 proteolysis during tissue processing. Compared to naive rats, sham injury had no effect on soluble MAP2 levels in either cortex (105.0 +/- 4.4% of naive value) or hippocampus (106.6 +/- 5.2% of naive value). However, TBI caused a significant (p < 0.005) decrease in hippocampal MAP2 levels (55.7 +/- 5.9% of sham-injured controls). The effect appeared to be regionally selective, since the MAP2 decrease did not occur in cortex (89.1 +/- 1.4%). The degree of MAP2 decrease in hippocampus was similar in both membrane (57.8%) and cytosolic (55.7%) fractions, ruling out the possibility of partitioning artifacts. The data suggest that sublethal alterations of neuronal structure and function caused by MAP2 degradation may play an important role in the development of TBI-induced functional deficits. Since MAP2 is exclusively associated with the cytoskeleton in somal and dendritic compartments of neurons, the pathophysiology of sublethal magnitudes of TBI may also involve dendritic and somal dysfunction.

Animals↗

PubMed1992

Blood-brain barrier permeability changes after experimental subarachnoid hemorrhage.

Basic mechanisms underlying cerebrovascular permeability responses to subarachnoid hemorrhage (SAH) are still to be defined in detail. Previous investigations examining the occurrence of blood-brain barrier (BBB) breakdown after SAH in the experimental setting have yielded conflicting results. In a rat model of SAH, we assessed BBB changes by means of the quantitative [14C]-alpha-aminoisobutyric acid technique. Experiments were carried out on the second day post-SAH. In blood-injected rats [14C]-alpha-aminoisobutyric acid transport across the BBB increased significantly in cerebral cortices and cerebellar gray matter, averaging 1.3 to 1.5 times control values. The present data indicate that SAH induces well-defined changes in BBB function, possibly involved in the pathogenesis of post-SAH cerebral dysfunction in humans. Results reported here have also potential clinical implications for the management of aneurysm patients.

Aminoisobutyric Acids↗

PubMed1992

Outcome measures for clinical trials involving traumatically brain-injured patients: report of a conference.

A conference was held in Houston, Texas, on October 8-9, 1991, to develop recommendations for outcome measures for clinical trials in traumatic brain injury. Participants, all experts in this area, discussed and agreed on treatments for patients with severe brain injury (Glasgow Coma Score [GCS] < or = 8) and moderate brain injury (GCS, 9-12). A parallel trial design was recommended rather than a factorial, sequential, or crossover design. It was agreed that stratifying randomization based on motor score alone or on a combination of motor score and age would result in increased power. Acute stage measurements, such as cerebral blood flow, cerebrospinal fluid biochemistry, and evoked potentials, were recommended only when they satisfied a specific hypothesis. Functional outcome measures were recommended as the primary outcome measure for severe brain injury (GCS, 3-8). Either the Glasgow Outcome Scale or Disability Rating Scale, measured at 6 months after injury, were recommended as the primary outcome measure for severe brain injury (GCS, < or = 8). For patients with moderately severe brain injury (GCS, 9-12), the Disability Rating Scale at 3 months after injury was recommended as the primary outcome measure. The Neurobehavioral Rating Scale appears to be a satisfactory instrument for measuring behavioral changes. Specific neuropsychological measures were recommended as supplementary outcome measures for both severe and moderate brain injury, consistent with a 1.5-hour period available for testing.

Adolescent↗

PubMed1992

The effect of age on motor and cognitive deficits after traumatic brain injury in rats.

Age is one of the most important predictors of outcome after human traumatic brain injury. This study used fluid percussion brain injury to investigate the effects of aging on outcome after brain injury in rats. Three-month-old (n = 8) and 20-month-old (n = 11) rats were injured at a low level (1.7-1.8 atm) of fluid percussion brain injury or received a sham injury (n = 6 for both age groups). Body weight and motor function (beam balance and beam walking) were assessed before injury and for the first 5 days after injury. Cognitive outcome was assessed with the Morris water maze on Days 11 to 15 after injury. Injury did not produce significant weight loss in either age group. At the low level of brain injury used in this study, the 3-month-old rats did not demonstrate any significant motor deficits on the beam-balance or beam-walking tasks. However, the 20-month-old rats displayed significant beam-balance deficits on each of the 5 postinjury test days and significant beam-walking deficits for the first 3 postinjury days. Although Morris water maze performance was impaired in both age groups, the magnitude of impairment was greater in the aged animals. These data demonstrate that traumatic brain injury in the aged animal is marked by increased motor and cognitive deficits, in the absence of pronounced compromise of the animal's general health.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1992

Neurotransmitter-mediated mechanisms of traumatic brain injury: acetylcholine and excitatory amino acids.

Research into traumatic brain injury (TBI), focusing on changes in energy metabolism, cerebrovascular dysfunction, and brain parenchymal morphology, has not produced complete descriptions of mechanisms mediating the pathophysiology of TBI. New studies indicate that neurochemical alterations mediate important components of brain physiology associated with TBI, and these alterations may be responsive to pharmacologic therapy. We discuss rodent models of TBI, review current experimental evidence of muscarinic cholinergic and excitatory amino acid (EAA) receptor involvement in its pathophysiology, and address issues relevant to the interpretation of these data.

Acetylcholine↗

PubMed1992

Cholinergic and opioid mediation of traumatic brain injury.

There is considerable evidence for the involvement of cholinergic and opioid systems in the pathophysiological responses associated with traumatic brain injury (TBI). To some extent, interest in this area has been eclipsed by a strong focus on, and rapid progress in, studies of the role of excitatory amino acids in TBI. We present evidence that both cholinergic and opioid systems are important modulators of the pathophysiological response to TBI, potentially equally as important as excitatory amino acids. There is a relatively large body of experimental data documenting the involvement of these systems in TBI that has yielded important principles with general significance for laboratory studies of the neuropharmacology of TBI. In fact, the first demonstration of excitotoxic mechanisms of TBI involved studies of the role of acetylcholine in experimental TBI. There also are clinical data suggesting that modulation of opioid and cholinergic systems could benefit patients.

Acetylcholine↗

PubMed1992

The cellular immunotherapy of primary brain tumors.

The use of adjuvant immunotherapy for the treatment of primary malignant brain tumors dates to studies performed in the 1960's and 1970's using non-specific immune stimulators. Although the theoretical designs have remained similar, recent advances in molecular biotechnology have produced a new group of recombinant cytokines, spawning a new generation of immunotherapy-based clinical trials. In contrast to other published Phase I/II studies, we have had highly encouraging preliminary results using lymphokine-activated killer (LAK) cells and recombinant human Interleukin-2 (rIL-2; Cetus, Emeryville, CA), when the patients' use of corticosteroids could be restricted while on study. Patients with recurrent grade 3/3 glioma received multiple cycles of autologous LAK cells and rIL-2, post-operatively, via an Ommaya reservoir implanted into the tumor cavity following re-operation. The overall median survival for 13 patients with grade 3/3 glioma has not yet been reached at 55 weeks following second surgery, [mean +/- SEM, 64.7 +/- 10.5 weeks], with 5 patients still alive. Three patients have had partial responses (PR) demonstrated by CT scanning. In addition, one patient with grade 2/3 glioma has had a complete response (CR), with the disappearance of all residual CT-documented enhancement and mass effect.

Brain Neoplasms↗

PubMed1991

Regional changes in spinal cord glucose metabolism in a rat model of painful neuropathy.

Spinal cord patterns of metabolic activity in a model of neuropathic pain were assessed in unanesthetized rats by the [14C]-2-deoxyglucose (2-DG) technique. Rats used in this procedure had demonstrable thermal hyperalgesia ipsilateral to sciatic nerve ligation and ipsilateral hindpaws that were lifted in a guarded position. The latter indicated possible spontaneous pain. Sciatic nerve ligation produced significant increases in glucose utilization in the dorsal and ventral horns of both sides, with greater activity present on the ipsilateral as compared to the contralateral side. Peak activity was in laminae V-VI, a region involved in nociceptive processing. Thus, a chronic increase in neuronal activity in these regions may reflect spontaneous neuropathic pain.

Animals↗

PubMed1991

High-frequency septal stimulation suppresses long-term potentiation (LTP) in the CA1 region of rat hippocampus.

The effects of high-frequency stimulation (HFS) of the medial septum/diagonal band (MSDB) on long-term potentiation (LTP) of CA1 extracellular field potentials were assessed in anesthetized rats. Ten rats received HFS of the Schaffer collateral pathway alone, and 10 received MSDB HFS 10 min prior to hippocampal HFS. Septal HFS suppressed LTP development assessed by change in population spike (PS) amplitude 60 min after hippocampal HFS (ANOVA, P less than 0.03). Septal inhibition of LTP development was most prominent when septal HFS had little direct effect on the CA1 PS. These results provide a novel demonstration of the functional heterogeneity of septohippocampal pathways and in vivo modulation of hippocampal LTP by HFS of natural afferent inputs.

Animals↗

PubMed1991

A controlled cortical impact model of traumatic brain injury in the rat.

Controlled cortical impact models produce brain injury by using a pneumatic impactor to impact exposed brain. This study systematically examined the effects of varying magnitudes of controlled cortical impact to the rat brain on neurological, cardiovascular, and histopathological variables. As the magnitude of injury increased, the duration of suppression of somatomotor reflexes and the duration of chronic vestibular motor deficits increased. The blood pressure response was observed to depend on injury levels; a moderate injury level produced a hypotensive response while a high injury level produced an immediate brief hypertensive response followed by hypotension. Low injury levels produced no significant macroscopic or microscopic change, but higher injury levels produced cortical contusion and intraparenchymal hemorrhage which, with increasing survival time, evolved into necrotic changes and cavitation underlying the injury site. Also with high levels of injury, axonal injury was found throughout the brain-stem with the greatest concentration of injured axons occurring in the cerebellar peduncles and pontomedullary junction. These data demonstrate that controlled cortical impact in the rat reproduces many of the features observed in other experimental animal models. This model allows independent control of many mechanical loading parameters associated with traumatic brain injury. The controlled cortical impact rat model should be an effective experimental tool to investigators of traumatic brain injury.

Animals↗