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H L Fields

Publications and source records attributed to H L Fields.

At least 73 records · Page 4Linked to original sources
PubMed1991

Evidence for GABA-mediated control of putative nociceptive modulating neurons in the rostral ventromedial medulla: iontophoresis of bicuculline eliminates the off-cell pause.

This study was undertaken to test the hypothesis that gamma-aminobutyric acid (GABA) is an endogeneous neurotransmitter regulating the activity of a class of putative nociceptive modulatory neurons (termed "off-cells") in the rostral ventromedial medulla (RVM) of the barbiturate-anesthetized rat. Off-cells, which are believed to correspond to the RVM output neuron that inhibits nociceptive processing at the level of the spinal cord, exhibit an abrupt pause in firing that begins immediately prior to the occurrence of the tail flick response (TF), a nocifensive reflex evoked by application of noxious heat to the tail. Single-unit recording and iontophoretic techniques were used to examine the ability of the GABAA receptor antagonist bicuculline methiodide (BIC) to antagonize selectively the characteristic off-cell pause. Iontophoretic application of BIC (5-30 nA) blocked the TF-related pause in each of the off-cells tested. This effect of BIC was generally slow in onset, and outlasted the period of application by several minutes. BIC iontophoresis also eliminated the cyclic alternation between active and silent periods that is often displayed by off-cells in lightly anesthetized rats. BIC application did not have a consistent effect on the firing of two other classes of RVM neurons ("on-cells" and "neutral cells"). Iontophoretically applied BIC antagonized the inhibitory effect of iontophoretically applied GABA, but not that produced by glycine. The glycine receptor antagonist strychnine did not mimic the action of BIC on off-cell activity. These data demonstrate antagonism of a synaptically evoked response using iontophoretic application of BIC, and provide strong evidence that the inhibitory neurotransmitter GABA mediates the TF-related off-cell pause. Taken together with behavioral experiments demonstrating that a GABA-mediated inhibitory process within RVM is crucial in permitting execution of the TF response, the present observations point to the significant functional relevance of GABA transmission within RVM in modulation of nociception.

Afferent Pathways↗
PubMed1991

Hyperalgesia during acute opioid abstinence: evidence for a nociceptive facilitating function of the rostral ventromedial medulla.

Naloxone-precipitated opioid abstinence is associated with enhancement of reflex responses to noxious stimulation (hyperalgesia). The present experiments in lightly anesthetized rats were designed to determine (1) whether neurons in the rostral ventromedial medulla (RVM) contribute to this enhancement, and (2) whether this enhancement is due to removal of an inhibitory modulatory influence or to activation of a facilitatory influence. In the first experiment, 10 micrograms of morphine was microinjected into the RVM; subsequent administration of naloxone (1 mg/kg, i.v.) shortened tail-flick latency. This is evidence that a synaptic action of opioids within the RVM can contribute to hyperalgesia. In the second experiment, systemic administration of morphine (2 mg/kg, i.v.) was followed by systemic administration of naloxone (1 mg/kg, i.v.), which produced a significant hyperalgesia that could be markedly attenuated by microinjection of 10 micrograms lidocaine into the RVM. That inactivation of RVM reduces the hyperalgesia indicates that the CNS is capable of generating a facilitating action on nociceptive transmission. Previous studies from this laboratory have indicated that a population of RVM neurons, on-cells, shows increased activity during opioid abstinence. The present experiments support the hypothesis that RVM on-cells exert a facilitating influence on nociceptive transmission.

Animals↗
PubMed1990

Alpha-adrenergic receptor agonists, but not antagonists, alter the tail-flick latency when microinjected into the rostral ventromedial medulla of the lightly anesthetized rat.

The present experiments, part of an ongoing study designed to characterise the role of norepinephrine (NE) in regulating the activity of putative nociceptive modulatory neurons in the rostral ventromedial medulla (RVM), assessed the effects of alpha-adrenergic receptor-selective agents on the nociceptive threshold (as measured by the tail-flick withdrawal response on noxious heat). These microinjection studies were carried out in the barbiturate-anesthetized rat, a preparation which is favourable for acute neurophysiological studies. The data obtained demonstrate that, as observed by others in the awake animal, activation of alpha 2-adrenergic receptors in the RVM produces hypoalgesia. However, unlike in the awake animal, when antagonists selective for either the alpha 1- or alpha 2-adrenergic receptor are microinjected alone into the RVM there is no change in the nociceptive threshold. These data suggest that the alpha 2-adrenergic receptor has a postsynaptic location and that barbiturate anaesthesia suppresses a tonically active or noxious stimulus-activated noradrenergic input to the RVM that is present in the awake animal.

Adrenergic alpha-Agonists↗
PubMed1990

Somatodendritic morphology of on- and off-cells in the rostral ventromedial medulla.

The rostral ventromedial medulla (RVM) contains two classes of physiologically defined neurons, on-cells and off-cells, that are implicated in nociceptive modulation. In a continuing effort to detail the neural circuitry that underlies the activity of these two distinct neuronal types, the somatodendritic morphology of on- and off-cells was studied in the cat, rat, and ferret. In lightly anesthetized animals, on-cells increased and off-cells decreased their discharge rate during a withdrawal reflex evoked by noxious stimuli. Following their physiological characterization by using intracellular recording, on- and off-cells were injected with either horseradish peroxidase or biocytin and their somatodendritic arborizations were examined. Labeled on- and off-cells included fusiform and stellate cells of all sizes as well as large multipolar neurons. Although the somatic shape of both on- and off-cells in RVM was heterogeneous, off-cells tended to be fusiform neurons whose long axis was oriented mediolaterally. The dendritic domains of both on- and off-cells extended bilaterally past the lateral edge of the trapezoid body or pyramid and ventrally to, and sometimes including, the trapezoid body or pyramid. In contrast to their extensive mediolateral spread, the dendritic domains of both cell types were limited to the ventral half of the reticular formation and were compressed along the rostrocaudal axis. The dendritic arbor of individual on- and off-cells extended well beyond the cytoarchitectonic boundaries of any single nuclear region, within the domain delineated as the RVM. The spatial domains of the dendritic arbors of on- and off-cells are further evidence that the on- and off-cells throughout the RVM constitute an integrated unit in the modulation of nociceptive transmission.

Animals↗
PubMed1990

Morphine analgesia and acute physical dependence: rapid onset of two opposing, dose-related processes.

Enhanced responsiveness to noxious stimulation is a reliable sign of opioid withdrawal and is therefore a measure of physical dependence. In lightly anesthetized rats, naloxone, given i.v. 15 min following i.v. morphine, caused a significant shortening of tail flick latency (hyperalgesia). At each dose of naloxone (0.1, 1.0 or 2.0 mg/kg), the magnitude of the observed hyperalgesia was a function of the preceding dose of morphine (0.5, 1.0 or 2.0 mg/kg). Thus morphine rapidly induces two dose-related opposing processes: one results in antinociception and the other in the potential for hyperalgesia.

Analgesics↗
PubMed1990

Hyperalgesia during naloxone-precipitated withdrawal from morphine is associated with increased on-cell activity in the rostral ventromedial medulla.

Hyperresponsiveness to noxious stimulation (hyperalgesia) is observed with naloxone-precipitated morphine withdrawal in several experimental models, and may be due to changes in central nervous system neurons. Previous studies have demonstrated that certain neurons in the rostral ventromedial medulla (on-cells) discharge just prior to nocifensive withdrawal reflexes and are inhibited by morphine. Because the tail flick latency (TFL) is shorter when on-cells are active, it has been proposed that on-cells facilitate nocifensive reflexes. The present study examined the hypothesis that the hyperalgesia observed following naloxone-precipitated withdrawal from morphine is caused by increased on-cell discharge. Rats were maintained in a lightly anesthetized state with chloral hydrate. Administration of saline (1.25 cc, i.v.) or morphine sulfate (1.25 mg/kg, i.v.) was followed by naloxone (1.0 mg/kg, i.v.). On- and off-cell activity was continuously recorded and was correlated with TFL and paw withdrawal threshold (PWT). As previously reported, morphine increased off-cell activity, blocked on-cell activity, and suppressed the tail flick and paw withdrawal reflexes. When naloxone was given after morphine, TFL and PWT were reduced to values significantly below baseline (hyperalgesia). Both spontaneous and reflex-related on-cell activity increased to levels greater than the premorphine baseline. Spontaneous off-cell activity decreased abruptly to near zero when morphine was followed by naloxone. Linear regression analysis during the hyperresponsive state revealed a significant correlation between increased on-cell activity and reduced TFL, but not between decreased off-cell activity and TFL. These findings are consistent with the hypothesis that on-cells facilitate spinal nocifensive reflexes, and that the naloxone-precipitated hyperalgesia is at least in part accounted for by increased on-cell activity. A neural model of opiate dependence, tolerance, and withdrawal is proposed.

Afferent Pathways↗
PubMed1989

Opioid peptides (DAGO-enkephalin, dynorphin A(1-13), BAM 22P) microinjected into the rat brainstem: comparison of their antinociceptive effect and their effect on neuronal firing in the rostral ventromedial medulla.

The highly mu-selective agonist Tyr-D-Ala-Gly-MePhe-Gly-ol-enkephalin (DAGO) produces potent, dose-dependent naloxone-reversible antinociception when microinjected into the ventrolateral periaqueductal gray (PAG) (ED50 = 0.72 nmol) or rostral ventromedial medulla (RVM) (ED50 = 0.05 nmol) as measured on the rat tail flick (TF) assay. In single-unit recording experiments, DAGO microinjected into the PAG also affected On- and Off-Cell firing in the RVM in the same way as previously demonstrated by our group for morphine. PAG-microinjected DAGO inhibits spontaneous and noxious-evoked On-Cell firing (attenuating the characteristic On-Cell burst) (n = 19), and excites spontaneous Off-Cell firing, preventing the characteristic Off-Cell pause (n = 12) at doses which suppress the TF. These results support a major role for the mu receptor in PAG and RVM mechanisms of opiate antinociception. In our experiments using BAM22P, an endogenous weakly mu-selective opioid peptide, we could not demonstrate a dose-dependent antinociceptive effect, whether the peptide was microinjected supraspinally into the PAG (n = 9) or RVM (n = 11), or intrathecally at the lumbar cord (n = 4). In two animals, a naloxone-reversible antinociceptive effect was observed following the microinjection of 10 nmol BAM 22P into the RVM; however, no effect was seen in 3 animals microinjected with 20 nmol. Dyn A(1-13), a putative endogenous ligand for the kappa receptor, had no antinociceptive effect when microinjected into the ventrolateral PAG, and no effect on the firing (spontaneous or noxious-evoked) of RVM On (n = 3)- or Off (n = 2)-Cells.

Action Potentials↗
PubMed1989

Axonal trajectories and terminations of on- and off-cells in the cat lower brainstem.

Two physiologically defined classes of pontomedullary raphe neurons were intracellularly labeled in order to determine the target nuclei of their axonal projections. In the lightly anesthetized cat, cells either increased (on-cells) or decreased (off-cells) their discharge rate during the paw withdrawal reflex evoked by noxious pinch or heat. On- and off-cells were injected with horseradish peroxidase and the initial course of labeled axons through the lower brainstem was reconstructed. On-cell projections to the pontomedullary raphe and medial reticular nuclei were sparse. On-cells projected densely to regions of the lateral reticular formation and the ventrolateral medulla at both rostral and caudal medullary levels. In general, on-cells had few collaterals and spare axonal swellings. In contrast to on-cells, most off-cells had axons that collateralized densely within the brainstem raphe and adjacent reticular formation. Such collaterals were either local, within the neuron's dendritic field, or distant, involving a projection of 1-8 mm. One off-cell had a dense terminal field within the sensory trigeminal complex, a projection that may subserve the inhibition of trigeminal sensory neurons produced by raphe magnus stimulation. Well-labeled off-cells had numerous collaterals and dense regions of axonal swellings. In summary, off-cells terminated densely in the raphe magnus and adjacent reticular formation whereas on-cells projected predominantly to the ventrolateral medulla, a region implicated in autonomic control. Local off-cell collaterals provide an anatomical substrate that would enable off-cells to coordinate the activity of on- and off-cells through synaptic contacts.

Action Potentials↗
PubMed1989

Putative nociceptive modulatory neurons in the dorsolateral pontomesencephalic reticular formation.

The present study was undertaken to confirm the dorsolateral pontomesencephalic reticular formation (an area that includes the nucleus cuneiformis (NCF) and nucleus parabrachialis (NPB)) as a sensitive site for stimulation-produced antinociception and to investigate the possibility that there are cells in this region that show a change in activity that can be correlated with the occurrence of a nocifensive reflex (the tail-flick withdrawal response from noxious heat (TF)). Such cells have been previously demonstrated in the rostral ventromedial medulla (RVM). Extracellular single unit recording studies were made at sites from which it was possible to inhibit the TF with currents of 10 microA or less. Cellular response to 3 TF trials at 5 min intervals, and spontaneous activity over a 10 min period, were monitored for each unit. Of the cells encountered, 17% displayed an increase (on-cells) and 4% a decrease (off-cells) in activity that preceded the TF. The remaining cells were unaffected by the TF (neutral cells). On- and off-cells were found throughout the region from which TF suppression was observed but were most concentrated in the areas of the NCF and NPB. The presence of on- and off-cells in the NCF/NPB region as well as the RVM suggests that the input to RVM from NCF/NPB may be important in descending nociceptive modulation.

Action Potentials↗
PubMed1989

Putative nociceptive modulatory neurons in the rostral ventromedial medulla of the rat display highly correlated firing patterns.

Recent work in this laboratory has identified two classes of putative nociceptive modulating neurons in the rostral ventromedial medulla (RVM) of the rat: "off-cells," which pause beginning just prior to the tail flick response (TF) evoked by noxious heat, and "on-cells," which accelerate shortly before the occurrence of the TF. In the unstimulated, lightly anesthetized rat, the spontaneous firing pattern of individual on- and off-cells consists of alternating periods of silence and activity lasting from several seconds to a few minutes. In the present study, simultaneous recordings were made from pairs of TF-related neurons, and the relationships among the firing patterns of cells within a class and between cells of different classes were determined. All cells of a given class showed fluctuations in spontaneous discharge that were in phase. On the other hand, there was a striking reciprocity of firing between the two cell classes, such that a decrease in activity of cells of one class was accompanied by an increase in activity of cells of the other class. These observations point to the existence of integrating mechanisms that coordinate the activity of all members of each class of TF-related neurons. Thus, the pattern of activity of any single on- or off-cell provides a useful index of the excitability of all cells of that class. Moreover, because of the highly reciprocal nature of the firing of the two classes, it is possible to infer the current state of both cell populations from the pattern of activity of any single TF-related neuron.

Afferent Pathways↗
PubMed1989

Putative nociceptive modulating neurons in the rostral ventromedial medulla of the rat: firing of on- and off-cells is related to nociceptive responsiveness.

In the unstimulated, lightly anesthetized rat, both on- and off-cells exhibit alternating periods of silence and activity lasting from several seconds to a few minutes. In the preceding paper, we showed that the active periods of all cells of the same class are always in phase, whereas the firing of cells of different classes is invariably out of phase. Thus, the pattern of firing of any single on- or off-cell provides a useful indication of the excitability of all on- and off-cells in the rostral ventromedial medulla (RVM). In this study, we measured the latency of the tail flick response (TF) at set intervals while recording from TF-related neurons in RVM, and were able to demonstrate a significant relationship between the spontaneous firing of both on- and off-cells and the latency of the TF response. If noxious heat is applied at a time when an off-cell is spontaneously active (or an on-cell is silent), the TF latency is longer than if the TF trial falls during a period in which the off-cell is silent (or the on-cell is active). This correlation between on- and off-cell firing and changes in TF latency is consistent with a nociceptive modulatory role for either or both cell classes. These findings support the hypothesis that off-cells inhibit and on-cells facilitate spinal nociceptive transmission and reflexes.

Afferent Pathways↗
PubMed1988

How two sites in the rat's nucleus raphe magnus interact to inhibit the tail-flick reflex.

Two stimulating microelectrodes were inserted 0.5 mm apart in the rat's nucleus raphe magnus (NRM), giving a joint electrical threshold for suppression of the heat-evoked tail-flick reflex. Synchronous stimulation often required more current than predicted by consideration of each site's solitary threshold. Asynchronous stimulation required yet more current. We postulate that some NRM cells, perhaps corresponding to the 'on-cells' found previously by microelectrode recording, facilitate flexion and become relatively more influential at higher stimulus currents. We also postulate that the dominating cells that suppress flexion, possibly 'off-cells', operate optimally when firing simultaneously.

Afferent Pathways↗
PubMed1987

Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray.

The midbrain periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM) are important links in a neuronal network that modulates nociceptive transmission. In the RVM, 2 classes of cells have been identified that show changes in activity at the time of the tail-flick response (TF) elicited by noxious heat (Fields et al., 1983a). We now report that neurons in the PAG region also show changes in activity related to TF. Extracellular recordings were made from the PAG and the ventrally adjacent tegmentum at sites from which it was possible to inhibit TF using stimulating currents of 10 microA or less. Cell activity, time of TF occurrence, and tail temperature were recorded during 5 repetitions of the heat stimulus. Periresponse and peristimulus histograms were plotted with reference to the TF and tail temperature, respectively. A significant number of neurons in the PAG region showed changes in activity that preceded the TF. "Midbrain On-cells" (13.6% of the sample) displayed an abrupt increase in firing just prior to the TF. "Midbrain Off-cells" (4.4%) paused just prior to the TF. The remaining neurons (241 of 294, or 82%) did not exhibit changes in firing prior to the TF. Thus, cells with changes in activity related to the TF are present in the PAG region as well as in the RVM. The PAG has a large projection to the RVM, and microinjection of morphine in the PAG increases activity of RVM Off-cells and decreases that of RVM On-cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1986

Evidence for GABA involvement in midbrain control of medullary neurons that modulate nociceptive transmission.

The effects of GABA-related compounds microinjected into the midbrain periaqueductal gray (PAG) on the tail-flick reflex (TF) and on the activity of tail-flick related neurons in the rostral ventromedial medulla (RVM), were studied in barbiturate anesthesized rats. Neurons whose activity either decreased (off-cells) or increased (on-cells) immediately prior to TF were examined. Bicuculline and picrotoxin microinjected into the ventrolateral aspect of the caudal PAG inhibited the TF, increased the spontaneous activity of the off-cells and decreased that of the on-cells. Concomitant with the increase in TF latency, the TF-related deceleration of the off-cells and acceleration of the on-cells were reduced. These effects were reversed by a microinjection of muscimol (MUS) into the PAG. The analgesic effect of morphine microinjected into the PAG was also reversed by a MUS microinjection at the same site. These results support the hypothesis that a GABAergic synapse inhibits cells in the PAG which modulate nociceptive transmission at the spinal level through actions on neurons in the RVM.

Action Potentials↗