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W D Willis

Publications and source records attributed to W D Willis.

At least 19 recordsLinked to original sources
PubMed1992

The non-NMDA antagonist CNQX prevents release of amino acids into the rat spinal cord dorsal horn evoked by sciatic nerve stimulation.

Basal extracellular concentrations of 9 amino acids (AAs: aspartate, Asp; glutamate, Glu; asparagine, Asn; serine, Ser; glycine, Gly; threonine, Thr; alanine, Ala; taurine, Tau; and glutamine, Gln) were determined in the spinal cord dorsal horn of anesthetized rats using microdialysis and HPLC techniques. The concentrations of all measured AAs but Gln increased significantly (P < 0.05) during sciatic nerve stimulation at C-fiber strength. The concentration of Tau remained elevated following stimulation, while the other AAs returned to prestimulation values. Addition of the specific non-NMDA antagonist, CNQX, to the perfusing solution prevented the nerve stimulation-evoked AA release. Since the measured increases in extracellular AA concentrations are probably mainly due to activation of interneurons, these results suggest that blockade of non-NMDA receptors prevented activation of interneurons in the dorsal horn and support a major role of non-NMDA receptors at the first synapse of primary afferent fibers in the dorsal horn. Complete block of AA release and decreased basal levels of Glu after infusion of TTX into the dorsal horn also implies increased neuronal activity as the main source of higher AA levels during nerve stimulation.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

Glutamate-immunoreactive terminals synapse on primate spinothalamic tract cells.

Glutamate has been shown to excite spinothalamic tract (STT) neurons and has been localized to primary afferent neurons, spinal cord projection neurons, and interneurons in the spinal cord dorsal horn. The likelihood that glutamate-immunoreactive (GLU-IR) terminals directly innervate STT neurons was investigated. For these studies three lamina IV or V STT cells in the lumbar spinal cords of three monkeys (Macaca fascicularis) were identified electrophysiologically and characterized. Two were identified as high threshold neurons and one as a wide dynamic range neuron. Following intracellular injection of the cells with HRP and reaction to give the cells a Golgi-like appearance, the tissues were processed for electron microscopy. Postembedding immunogold methods with antibodies specific for glutamate were used to identify GLU-IR terminals apposing the somata and dendrites of the STT neurons, including dendrites that extended into laminae IV and III. The GLU-IR terminals were numerous and constituted a mean of 46% of the population counted that appose the STT soma and 50% of the profiles apposing the dendrites. Fifty-four percent of the somatic and 50% of the dendritic surface length was contacted by GLU-IR terminals. Most terminals contained round clear vesicles and some contained a variable number of large dense core vesicles. For one of the three cells examined it was determined that 45% of the terminals apposing the soma were GLU-IR and 30% of the terminals were gamma aminobutyric acid-immunoreactive (GABA-IR). In an additional monkey, a lamina I cell retrogradely labeled from the ventral posterolateral nucleus of the thalamus was found to be ensheathed in glial processes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

GABA-immunoreactive terminals synapse on primate spinothalamic tract cells.

Gamma-aminobutyric acid (GABA) is a putative inhibitory neurotransmitter in the vertebrate nervous system. Several lines of evidence suggest that GABA plays an important role in the processing and modulation of sensory input in the spinal cord dorsal horn. In the present study, the relationship between GABA-immunoreactive (GABA-IR) terminals and spinothalamic tract (STT) cells in the monkey lumbar cord was investigated. Physiologically characterized STT cells, one located in lamina V and two located in lateral lamina IV, were intracellularly injected with horseradish peroxidase (HRP). A fourth STT cell, located in lamina I, was retrogradely labeled following injection of HRP into the contralateral thalamus. Immunogold labeling of ultrathin sections through the cell bodies and proximal dendrites of the STT neurons demonstrated that the percentage of the GABA-IR terminals in contact with these profiles was 24.7% and 36%, respectively. The average STT surface length contacted by GABA-IR terminals for cell bodies and proximal dendrites was 18.2% and 26.7%, respectively. For the lamina I cell, 7 out of 35 (20%) of the terminals were GABA-IR and they covered 9.6% of the surface analyzed. These data demonstrate that GABA-IR terminals synapse directly on STT cells, constituting a substantial proportion of the terminal population on these cells. Furthermore, compared to the cell bodies, a greater percentage of the input on the proximal dendrites is GABAergic. These anatomical data are consistent with the findings of a previously published iontophoretic study that demonstrated that GABA can exert a strong inhibitory influence on STT cells. These findings are discussed in relation to GABAergic involvement in tonic and phasic inhibition of STT neurons.

Animals↗
PubMed1992

Serotonin is found in myelinated axons of the dorsolateral funiculus in monkeys.

Physiological measurements suggest that the inhibition of primate spinothalamic tract cells by serotonin is mediated by myelinated axons. Previous morphologic studies emphasize that most serotonin-containing axons in the spinal cord are unmyelinated. Accordingly, the possibility that some serotonin-containing axons in the primate dorsolateral funiculus of the spinal cord are myelinated was investigated. Macaque monkeys were given L-tryptophan and the monoamine oxidase inhibitor, nialamide, intraperitoneally 1 h prior to sacrifice to increase axonal stores of serotonin. The animals were perfused (0.05 or 0.5% glutaraldehyde, 4% paraformaldehyde), and transverse sections of the thoracic cord were reacted with antibody against serotonin and then prepared for electron microscopy. Many of the immunostained axons in the dorsolateral funiculus included fine, myelinated fibers with diameters of 0.7-2.2 microns. Unmyelinated serotonin-containing axons were also observed. The observation of myelinated serotonin-containing axons in the white matter of the monkey dorsolateral funiculus contradicts the view that the descending serotoninergic projection consists entirely of unmyelinated fibers, particularly since the conduction velocity of the fine fibers would be too slow to account for the earliest latency of descending inhibition following stimulation in the brainstem. The presence of myelinated serotoninergic axons presumably accounts for the latencies reported for the inhibition of primate spinothalamic cells following stimulation of the periaqueductal gray, an inhibition that can be blocked with serotonin antagonists and that is associated with the release of serotonin in the dorsal horn.

Animals↗
PubMed1992

Stimulation in the ventral posterior lateral nucleus of the primate thalamus leads to release of serotonin in the lumbar spinal cord.

Stimulation in the ventrobasal complex of the thalamus relieves neuropathic pain and inhibits spinal cord transmission of nociceptive information. Electrical stimulation of the ventral posterior nucleus of the thalamus elicited increases in extracellular serotonin concentration in the spinal cords of anesthetized monkeys. These results suggest that thalamic stimulation activates the raphe-spinal tract and thus implicates serotonin as a mediator of thalamic stimulation induced analgesia.

Animals↗
PubMed1992

The segmental distribution of afferent fibers from the vaginal cervix and hypogastric nerve in rats.

Injections of horseradish peroxidase-wheat germ agglutinin (HRP-WGA) into the walls of the vagina and cervix (vaginocervical injections) of rats resulted in labeling of dorsal root ganglia (DRG) cells located at T11-L4 and L6-S2. In a second group of animals, exposure of the hypogastric nerve to HRP-WGA resulted in a similar bimodal distribution of labeled cells as compared to vaginocervical injections. In a third group, unilateral hypogastric nerve transection prior to injection of HRP-WGA into the vaginocervical walls resulted in a significant reduction in DRG cells labeled at T13, L1, L2, L6 and S1. Bilateral transection of the hypogastric nerves prior to vaginocervical injections eliminated labeled DRG cells at thoracolumbar levels but not at L6 and S1. Bilateral pelvic neurectomy reduced, but did not eliminate labeled DRG cells at L6 and S1 following vaginocervical injections. These results indicate that the hypogastric nerve constitutes a major sensory pathway from the vaginocervical walls to thoracic, lumbar and sacral levels of the spinal cord. The hypogastric nerve may subserve the transmission of noxious input from the vaginocervical walls as well as the activation of ascending spinal pathways involved in neuroendocrine reflexes during parturition.

Afferent Pathways↗
PubMed1992

Evidence that fine primary afferent axons innervate a wider territory in the superficial dorsal horn following peripheral axotomy.

Peripheral axotomy initiates changes in central primary afferent receiving areas of the dorsal horn of the spinal cord. Most of the presently known changes are degenerative in nature and consist of such things as cell and axon death or declines in peptides or enzymes. Other changes are regenerative in nature and because most of these occur in the superficial dorsal horn, which is where fine primary afferents end, we wished to ask whether peripheral axotomy results in a change in the distribution in these fine afferents. Using recently available markers for fine primary afferent axons and small dorsal root ganglion cells, we demonstrate that peripheral axotomy results in a considerable increase in the immunolabeled area for these compounds. Our interpretation is that there may be an extension of fine primary afferent fibers into lamina III and possibly lamina IV following peripheral axotomy. If further work bears out this conclusion, this would provide a possible explanation for the chronic pain states that sometimes follow peripheral nerve damage.

Afferent Pathways↗
PubMed1992

Changes in the response states of primate spinothalamic tract cells caused by mechanical damage of the skin or activation of descending controls.

1. The responses of a population of 318 spinothalamic tract (STT) cells to mechanical stimulation of the skin were recorded in anesthetized macaque monkeys by several teams of investigators. The responses were subjected to k-means cluster analysis, a multivariate statistical procedure. 2. For an analysis that pertained to the responsiveness of the neurons, the mean responses to four standard mechanical stimuli (Brush, Pressure, Pinch, and Squeeze) were used. Although no true clusters were found, the cells could be partitioned into four groups (called clusters a, b, c, and d) that responded progressively more vigorously to the stimuli. 3. For an analysis that pertained to the selectivity of the cells for various stimulus intensities, from innocuous to highly noxious, the data were normalized by taking the ratio of the mean response evoked by each stimulus to the sum of the responses and multiplying by 100. This procedure does not have a bias toward selection of any particular number of clusters and resulted in three clusters of STT cells. 4. Cluster 1 STT cells responded best to Brush. Cluster 2 cells responded weakly to Brush and Pressure and maximally to Pinch. Cluster 3 cells responded weakly to Brush, Pressure, and Pinch and maximally to Squeeze. 5. The response states of STT cells with respect to mechanical stimulation of the skin can be defined by their cluster assignments on the basis of the responsiveness (clusters a-d) and selectivity (clusters 1-3) of the cells. The response states of newly recorded STT cells can be determined by discriminant analysis from the nearest centroids of the two types of clusters in the reference population of STT cells. 6. No consistent changes in response state were detected when a second series of mechanical stimuli was applied 1 cm from the site stimulated initially or when the stimulus series was alternately repeated at the initial site and at progressively more proximal sites. However, when the stimulus series was applied five times to the initial site, the response state of five of eight cells tested showed a change. Although a change in response state required repetitive damage, even a single stimulus series increased background activity and responses to Brush at undamaged sites. 7. The background activity and responses to Brush and Pressure of all five STT cells recorded in the superficial laminae increased after repeated testing. The background activity of five STT cells recorded in the nucleus proprius also increased, but the responses of only three of the cells to Brush and Pressure increased.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Responses of spinothalamic tract cells to mechanical and thermal stimulation of skin in rats with experimental peripheral neuropathy.

1. Responses of spinothalamic tract (STT) neurons to mechanical and thermal stimulation of skin were recorded under urethane and pentobarbital anesthesia in 12 control rats and in 20 rats with experimental neuropathy. Activity of the STT cells in neuropathic rats was recorded 7, 14, and 28 days after inducing the neuropathy by placing four loose ligatures on the sciatic nerve. 2. All neuropathic animals showed guarding of the injured hindpaw and a shorter withdrawal latency from a radiant heat source of the neuropathic hindpaw than that of the sham-operated paw. 3. STT neurons in neuropathic animals showed the most profound changes 7 and 14 days after the nerve ligation. When compared with STT cells in unoperated animals, approximately half of the neurons had high background activity, responses to innocuous stimuli represented a larger percentage of the total evoked activity in wide dynamic range neurons, and the occurrence and magnitude of afterdischarges to mechanical and thermal stimuli were increased. 4. The mean threshold temperatures of heat-evoked responses of the STT cells in neuropathic animals were not different than those of cells from control animals. However, in neuropathic rats, cells reacting to small heat stimuli usually already had afterdischarges. 5. The increase in the background activity of STT cells is consistent with behavioral observations of spontaneous pain in this model of experimental neuropathy. Furthermore, the afterdischarges of STT cells may parallel the prolonged paw withdrawal in response to noxious stimuli that is seen in these animals and that is evidence for hyperalgesia. However, there was no indication of a lowered threshold for thermal stimuli as might be expected if the animals have thermal allodynia. Mechanical allodynia may have resulted from a relative increase in responsiveness to innocuous mechanical stimuli. However, responses to noxious mechanical stimuli were reduced compared with control, at least at 28 days after the ligation. Peripheral and central mechanisms responsible for the changes in responses of STT cells in neuropathic animals are suggested.

Animals↗
PubMed1992

Responses of neurons in the gracile nucleus of cats to innocuous and noxious stimuli: basic characterization and antidromic activation from the thalamus.

1. Responses to innocuous and noxious mechanical and thermal stimuli were recorded from 90 neurons in the gracile nucleus of anesthetized cats. Cells were tested by antidromic activation for projections to the contralateral ventrobasal thalamus. 2. Cells were characterized broadly by their responses to mechanical stimuli as 1) responding only to tapping (16%), 2) fast-adapting to low-intensity mechanical stimuli (33%), or 3) slowly adapting (51%; most with a fast-adapting component to their responses). All fast-adapting cells and those slowly adapting cells that were tested with noxious heat were further categorized on the basis of their patterns of firing and responses to stimuli. These plus the tap-responsive cells comprised a more restricted sample of 76 categorized cells. 3. Many (22) slowly adapting cells responded to noxious heat (69% of tested slowly adapting cells; 29% of all categorized cells), either on the first application (9 cells) or after sensitization (13 cells), indicating input originating in nociceptors. Nearly all of these (21) responded more to intense pressure than to innocuous pressure. The majority of slowly adapting cells not responsive to noxious heat (5 of 8) or not tested with it (8 of 12) also responded more to intense than to innocuous pressure, suggesting possible input originating in nociceptors. Most cells that responded to noxious heat also had both rapidly and slowly adapting responses with low thresholds. Many were recorded in the range of the cluster region of the gracile nucleus. 4. Cells antidromically activated from the thalamus projected to the rostral part of the ventral posterior lateral nucleus, regardless of their physiological category, and included many with nociceptive input. Latencies of antidromic activation were shorter at more caudal locations in the gracile nucleus, indicating higher conduction velocities to the thalamus. Responses of antidromically activated cells to low-intensity phasic stimuli tended to be greater than those of cells not antidromically activated. 5. Background activity of the neurons was low, most firing at less than one spike/s. Antidromically activated cells had higher background activity than cells not antidromically activated. 6. The results indicate a greater proportion and more widespread distribution of cells with nociceptive input in the cat gracile nucleus than has been previously recognized. Many of these projected to the ventrobasal thalamus, showing that information originating in nociceptors can reach the thalamus through a dorsal column-medial lemniscal pathway in cats.

Adaptation, Physiological↗
PubMed1992

Responses of spinothalamic tract neurons to mechanical and thermal stimuli in an experimental model of peripheral neuropathy in primates.

1. An experimental peripheral neuropathy (EPN) was induced in three monkeys (Macaca fascicularis) by ligation of spinal nerve L7. Behavioral responses to innocuous mechanical stimuli were tested before and after the surgery. Two weeks after the nerve ligation, the activity of spinothalamic tract (STT) neurons was recorded on both sides of the spinal cord with the animal under general anesthesia. Responses of the STT neurons to the following stimuli applied to the skin were recorded: graded mechanical stimuli (brush, press, pinch and squeeze), von Frey filaments of different bending forces (0.077-19.05 g), 5-s heat stimuli ranging from 39 to 53 degrees C, and 15 s cold stimuli (32-8 degrees C). 2. Innocuous mechanical stimulation of the foot did not evoke hindlimb withdrawal in the animals before surgery. Within 24-48 h after nerve ligation, the animals showed hindlimb withdrawal to the same innocuous stimuli. This behavior was more pronounced on the side of the ligation than on the sham-operated side and more frequent during the second week after the surgery. 3. Responses of 51 STT neurons recorded on the side of the ligation (EPN all group) were compared with responses of 33 STT cells recorded on the sham-operated side (control group) and with records from STT neurons in unoperated animals obtained earlier (reference group). Neurons from the EPN all group were divided into two sets according to their rostrocaudal location (EPN R, rostral to L6/7 border, n = 40; EPN C, caudal to L6/7 border, n = 11). 4. Neurons from the EPN all and EPN R groups had significantly higher background frequencies than those from the control and reference groups. Innocuous brush stimuli evoked mean discharge frequencies of approximately 35 Hz in EPN R neurons and only approximately 15 Hz in both control and reference groups. Increased responsiveness of EPN R neurons to innocuous stimuli was also demonstrated by lower thresholds and higher discharge frequencies to von Frey filament stimulation and by discriminative analysis of the responses evoked by graded mechanical stimuli. 5. The responses of the EPN R neurons to heat stimulation of the skin showed decreased thresholds and increased responses to suprathreshold stimuli, resulting in a significant leftward shift of the stimulus-response curve compared with both reference and control groups. The neurons from the control group showed responses comparable to reference group values. 6. Neurons from the reference group tested with the cooling stimuli showed no evoked response above background.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, chemical, thermal, and electrical stimuli.

The role of excitatory amino acids (EAAs) in the excitation of monkey spinothalamic tract (STT) neurons following activation of cutaneous primary afferent fibers by noxious and non-noxious stimuli was investigated. The responses of STT neurons to either NMDA or non-NMDA EAA ligands were blocked by infusion of specific antagonists through a microdialysis fiber into the region surrounding the cells. Our results show that blockade of non-NMDA receptors results in a nearly complete elimination of the responses of STT neurons to all stimuli. Blockade of NMDA receptors results in an attenuation of the responses to noxious stimuli but, in addition, prevents the development of the sensitization of STT neurons that is often observed after intradermal injection of capsaicin. These observations further support a role of EAAs in the transmission of sensory information from primary afferent fibers to dorsal horn neurons and a role for NMDA receptors in the generation of hyperalgesia.

2-Amino-5-phosphonovalerate↗
PubMed1992

Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey.

Sensitization of the responses of dorsal horn neurons to mechanical stimulation may play a role in the generation of hyperalgesia. Intradermal injection of capsaicin (CAP) provides a model of experimental hyperalgesia that possesses a component of allodynia. This hyperalgesia is produced by chemical stimulation of C-fibers, leading to sensitization of dorsal horn neurons, including spinothalamic tract (STT) cells. The changes in the physiological responses of STT neurons following intradermal CAP in monkeys parallel the acute pain and hyperalgesia produced by intradermal CAP in humans. The present study addresses the role that excitatory amino acids (EAAs) may play in the sensitization of STT neurons by intradermal CAP. Our results show that the background discharge rate and the responses of STT cells to mechanical stimulation increase following intradermal CAP. In addition, the responses of the sensitized cells to one or more iontophoretically released EAA agonists, including NMDA, glutamate, aspartate, kainate, DL-alpha-amino-3-hydroxy-5-methyl-isoxazoleproprionic acid, and/or quisqualate, increase following intradermal CAP. It is proposed that an increase in the responses of STT neurons to EAAs contributes to the hyperalgesia produced by this noxious chemical stimulus.

Amino Acids↗
PubMed1991

Changes in lectin, GAP-43 and neuropeptide staining in the rat superficial dorsal horn following experimental peripheral neuropathy.

The density and distribution of reactivity for two lectins (soybean agglutinin (SBA) and RL-29), growth associated protein-43 (GAP-43) and the neuropeptides substance P and calcitonin gene-related peptide were analyzed in the spinal cord dorsal horn of rats with an experimental peripheral neuropathy. Twenty-eight days postsurgery, the density of label for RL-29 and GAP-43 was increased in laminae I and II on the experimental compared to the control side. In contrast, the density of neuropeptide label was decreased in the same region. Furthermore, on the experimental side, the distribution of both SBA and RL-29 reactivity was increased, extending into lamina III. We hypothesize that the increases in density and distribution of reactivity for the lectins and GAP-43, as well as the decreases in neuropeptide reactivity, reflect injury-induced regenerative changes in primary afferent terminals.

Animals↗
PubMed1991

Descending adrenergic input to the primate spinal cord and its possible role in modulation of spinothalamic cells.

The present study focuses on 3 different aspects of the descending adrenergic system in the primate: (1) the distribution of adrenergic fibers and terminals in the spinal cord, (2) the source of this input and (3) the possible physiological effects of this system on spinal nociceptive processing. Antibodies to the enzyme phenylethanolamine-N-methyltransferase (PNMT) were employed to map the distribution of epinephrine-containing axonal profiles in the primate spinal cord. Smooth longitudinally oriented fibers were localized to the outer edge of the lateral funiculus. PNMT-containing axonal enlargements were distributed to the superficial dorsal horn, intermediate gray matter and the region surrounding the central canal at all spinal cord levels. PNMT-immunostained profiles were also observed in the intermediolateral cell column. A double labeling study employing retrograde transport of HRP from the spinal cord and PNMT immunohistochemistry identified a small population of HRP-PNMT-labeled neurons in the 'C1' region at the levels of the medulla and ponto-medullary junction. Thus, these cells are a probable source of adrenergic input to the spinal cord. Electrophysiological studies demonstrated that iontophoresis of epinephrine onto identified primate spinothalamic tract neurons in the lumbar dorsal horn resulted in inhibition of the glutamate-induced firing of these cells. The data from these studies support the hypothesis that adrenergic (PNMT-containing) cells in the caudal brainstem project to all levels of the cord and may contribute to descending modulation of nociceptive processing at these levels.

Animals↗
PubMed1991

Modification of the responses of primate spinothalamic neurons to mechanical stimulation by excitatory amino acids and an N-methyl-D-aspartate antagonist.

Excitatory amino acids (EAAs) are likely to play a key role in sensory transmission in the spinal cord. In the present study, the microiontophoresis technique was used to investigate the effects of L-glutamate (GLUT), N-methyl-D-aspartate (NMDA), and quisqualate (QUIS), as well as an NMDA receptor antagonist, AP-7, on the discharges evoked in nociceptive primate spinothalamic tract (STT) neurons by mechanical stimulation of the skin. Responses to innocuous brushing of the skin were facilitated by GLUT and NMDA (and in some neurons by QUIS) and sometimes reduced by AP-7. GLUT also facilitated the responses to noxious mechanical stimuli. The results are consistent with anatomical evidence for the presence of synapses that contain EAAs on primate STT cells and with the proposal that the co-release of EAAs and neuropeptides may contribute to hyperalgesia.

2-Amino-5-phosphonovalerate↗
PubMed1991

Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of N-methyl-D-aspartic acid and substance P.

A role for sensitization of nociceptors in the generation of primary hyperalgesia is well documented. More recent work has begun to define a role of an increased excitability of neurons within the spinal cord in the generation of secondary hyperalgesia. The present study demonstrates increased responses of primate spinothalamic neurons following co-administration of N-methyl-D-aspartic acid (NMDA) and substance P (SP) by micro-iontophoresis. Wide dynamic range and high threshold STT neurons in laminae I-VI showed an increased frequency of discharges following application of NMDA which was characterized by a slow onset to peak discharge rate and a slow return to background levels of discharge. Combined application of NMDA with SP resulted in an enhancement of responses to NMDA that often long outlasted the administration of SP. This increase in response of the cells to NMDA was not produced by repeated application of NMDA alone or following combined application of NMDA with an SP analog. NMDA responses were reduced or prevented in all cases by co-application of an NMDA-receptor antagonist. Finally, long-lasting potentiation of NMDA responses by SP was paralleled by enhanced responses to mechanical stimulation of skin. It is proposed that a mechanism involving the combined synaptic release of excitatory amino acids and peptides leads to secondary hyperalgesia.

Animals↗