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H L Fields

Publications and source records attributed to H L Fields.

At least 91 records · Page 5Linked to original sources
PubMed1986

Morphine microinjected into the periaqueductal gray has differential effects on 3 classes of medullary neurons.

The effects of microinjection of 5-10 micrograms of morphine into the midbrain periaqueductal gray (PAG) on the activity of neurons in the rostral ventral medulla (RVM) were studied in lightly anesthetized rats. Based on the relationship between changes in neuronal activity and the occurrence of the tail-flick reflex (TF), RVM neurons were divided into 3 groups: off-cells, on-cells and neutral cells. The off-cells exhibited an abrupt pause and the on-cells an acceleration beginning just prior to the occurrence of the TF. Neutral cell firing did not change at the time of the TF. Microinjections of morphine into the PAG which inhibited the TF had differential effects on the spontaneous activity of the 3 groups of neurons in RVM. Off-cells showed an increase and on-cells a decrease in spontaneous activity which preceded the inhibition of the TF. These microinjections also reduced the TF-related responses of off- and on-cells. The effects on cell activity were reversed by systemically administered naloxone and were not seen following microinjections which failed to block the TF. Neutral cell activity was unchanged following microinjection of morphine into the PAG. These results support the hypothesis that off- and on-cells in the RVM mediate the effects of microinjection of morphine into the PAG on spinal nociceptive reflexes.

Action Potentials↗
PubMed1986

The effect of analgesic doses of morphine on regional cerebral glucose metabolism in pain-related structures.

The effect of morphine on regional cerebral glucose metabolism was measured in rats using high resolution [14C]2-deoxyglucose autoradiography with concurrent confirmation of morphine-induced analgesia measured by tail-flick latency to noxious heat. Within the limits of resolution of this technique, doses of morphine sufficient to inhibit the tail-flick reflex had no significant effect on glucose metabolism in structures implicated in the modulation of pain.

Animals↗
PubMed1986

Putative pain modulating neurons in the rostral ventral medulla: reflex-related activity predicts effects of morphine.

Three physiologically-defined classes of neurons are found in the rostral ventromedial medulla (RVM), a region which contributes to the antinociceptive action of opiates. The off-cell exhibits an abrupt pause just prior to the occurrence of the tail flick reflex (TF). The on-cell shows a burst of activity beginning just prior to the occurrence of the TF. Neutral cell firing does not change in relation to the TF. Systemic administration of morphine has been shown to produce a consistent increase in the activity of off-cells. In the present studies, the effects of systemically-administered morphine on spontaneous and TF-related activity of on-cells and neutral cells were examined in lightly-anesthetized rats. Measures of spontaneous activity were obtained before and after morphine (1.25-2.5 mg/kg, i.v.). On-cells exhibited an irregular cyclic rate of spontaneous discharge similar to that previously reported for off-cells. In contrast, neutral cells had a nearly constant level of spontaneous activity. After administration of morphine, spontaneous activity ceased for 8 of 8 on-cells, and heat-related activity was eliminated. Administration of naloxone resulted in a return of the periodic firing pattern and the burst associated with the TF. Seven of 8 neutral cells showed no change in firing rate and one showed a decrease rate after morphine administration. These results show that the effect of systemic opiates on an RVM neuron can be predicted based on whether a cell increases or decreases its firing just prior to the occurrence of a nocifensive reflex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Action at the mu receptor is sufficient to explain the supraspinal analgesic effect of opiates.

Mu, delta and kappa opiate receptors have been implicated in the production of analgesia. In order to study the relative contributions of these receptor types to supraspinally mediated analgesia, apparent pA2 values and rank order potencies were determined for i.c.v. injected highly selective opioid agonists in the mouse using a thermal nociceptive test. Drugs used included the prototypical mu agonist morphine, putative mu agonists [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin and BAM 22P, putative delta agonists [D-Pen2, D-Pen5] enkephalin, [D-Thr2, Thr6, Leu5] enkephalin and [D-Ser2, Leu5, Thr6] enkephalin and the putative kappa agonists [trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methane sulfonate hydrate] and Dynorphin A (1-13). We were unable to demonstrate significant analgesic potencies for i.c.v. injected Dynorphin A (1-13) or BAM 22P in the absence of marked behavioral abnormalities. The rank order potency of the remaining compounds studied was found to be: [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin greater than [D-Thr2, Thr6, Leu5] enkephalin greater than [D-Ser2, Leu5, Thr6] enkephalin greater than Morphine greater than [D-Pen2, D-Pen5] enkephalin greater than [trans-3, 4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methane sulfonate hydrate]. Apparent pA2 values of morphine, [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin and [D-Pen2, D-Pen5] enkephalin in naloxone antagonism trials did not differ significantly. These results indicate that although both mu- and delta-selective ligands produce potent analgesia, a single receptor (mu) is sufficient to explain the supraspinal effects of opiate drugs.

Analgesia↗
PubMed1985

Effects of intrathecally administered methysergide and yohimbine on microstimulation-produced antinociception in the rat.

This study examined whether intrathecal (i.t.) administration of the serotonergic antagonist methysergide, of the alpha 2 noradrenergic antagonist yohimbine, or of both drugs antagonized stimulation-produced antinociception (SPA) evoked from the nucleus raphe magnus (NRM) and the nucleus reticularis paragigantocellularis (NRPG) of lightly anesthetized rats. The increase in tail flick latency (TFL), but not the increase in paw pinch withdrawal threshold (PWT), evoked from NRM sites was antagonized by i.t. administration of methysergide. Intrathecal administration of yohimbine antagonized both the increase in TFL and the increase in PWT produced by stimulation of NRM sites. Stimulation of sites in the NRPG also increased TFL and PWT; these increases were not antagonized by i.t. administration of methysergide. Although i.t. administration of yohimbine antagonized the increase in TFL evoked from the NRPG, the increase in PWT was not antagonized. When coadministered intrathecally, methysergide and yohimbine antagonized the increases in TFL and PWT produced by stimulation of NRM and of NRPG sites. In contrast, i.v. administration of the same doses of methysergide and yohimbine did not antagonize either the increase in TFL or the increase in PWT evoked from either set of sites. These results support the concept that activation of serotonergic and noradrenergic bulbospinal neurons mediates SPA and additionally suggest that the noradrenergic component involves an alpha 2 noradrenergic receptor.

Animals↗
PubMed1985

Anatomy and physiology of a nociceptive modulatory system.

Although efferent control of sensory transmission is a well-established concept, a specific network for nociceptive modulation has only recently been discovered. This network includes interconnected components at midbrain, medullary and spinal levels. At the midbrain level, electrical stimulation of the periaqueductal grey (p.a.g.) inhibits spinal neurons that respond to noxious stimuli as well as nociceptor-induced reflexes and escape behaviour in a variety of species. Midbrain stimulation also produces analgesia in patients with clinically significant pain. The rostral ventral medulla (r.v.m.) has similar behavioural and physiological effects and mediates midbrain antinociceptive actions at the level of the spinal cord. Endorphins are present at all levels of this nociceptive modulating network. Opiate microinjections at p.a.g., r.v.m. or spinal levels produce analgesia, presumably by mimicking the actions of the endorphins. The nociceptive modulatory system is diffusely organized, highly interconnected and appears to act as a unit whether activated by opiates or electrical stimulation. There are two classes of r.v.m. neurons the activity of which is correlated with the occurrence of reflexes induced by noxious stimulation. One class (the on-cell) accelerates, the other class (the off-cell) pauses just before tail flick. Both classes project to the spinal cord and are excited by electrical stimulation of the midbrain. However, when morphine is injected either systemically or into the p.a.g., the off-cell is excited and the on-cell stops firing. The off-cell is probably the r.v.m. output cell that inhibits nociceptive transmission at the level of the spinal cord. The function of the on-cell is not clear. The nociceptive modulatory system can be activated by a variety of stressful environmental factors, which are often, but not necessarily, noxious. The idea that the system acts as a simple negative feedback circuit is not consistent with its known properties.

Animals↗
PubMed1984

Midbrain stimulation inhibits tail-flick only at currents sufficient to excite rostral medullary neurons.

The effects of midbrain electrical stimulation on the activity of tail-flick (TF) related neurons in the rostral ventromedial medulla (RVM) were studied. Neurons whose activity either decreased (off-cells) or increased (on-cells) immediately prior to TF were examined. Of 31 off- and on-cells, 26 (84%) showed increased activity during midbrain stimulation sufficient to suppress the TF. Furthermore, in 21 of these cells, the threshold for activation was identical to the threshold for TF suppression, and in the other 5 cells the threshold difference was less than or equal to 5 microA. This study provides evidence that off-and on-cells in the RVM mediate the antinociceptive actions of midbrain stimulation.

Animals↗
PubMed1984

Tail-flick related activity in medullospinal neurons.

Using the classification system of Fields et al. 131 neurons in the rostral ventromedial medulla (RVM) of lightly anesthetized rats were divided into 3 groups according to their response during tail-flick (TF) testing: those with an abrupt increase in activity prior to TF (on-cells); those with a sudden pause in activity prior to TF (off-cells); those with no change in activity prior to TF (neutral cells). Collision testing was performed using a cervical spinal cord stimulating electrode to determine whether these neurons projected to the cord. Conduction velocities were determined for all cord-projecting neurons. All 3 cell types projected to the cord and approximately 38% of cord-projecting neurons were flick-related (off-or on-cells). All projecting neurons were within or immediately adjacent to the nucleus raphe magnus. The mean conduction velocity of on-cell axons (17.7 m/s) was significantly greater than that of off-cell axons (10.7 m/s) and neutral cell axons (12.4 m/s). Conduction velocities for all cells were within the range for myelinated axons. These findings support the hypothesis that off-and on-cells in the RVM play a significant role in pain modulation at the spinal cord level.

Animals↗
PubMed1984

Neurophysiology of pain and pain modulation.

An endogenous central nervous system pain-modulating network, with links in the mid brain, medulla, and spinal cord, has recently been discovered. This system produces analgesia by interfering with afferent transmission of neural messages produced by intense stimuli. Although other neurotransmitters are involved, the analgesia produced by this system depends on the release of endogenous opioid substances, generically referred to as endorphins. The system is set in motion by clinically significant pain--such as that resulting from bony fractures or postoperative pain. The analgesia network monitors the pain and controls it at the level of the spinal cord. Complex psychologic factors play an important role in the variability of perceived pain, partly because of their ability to trigger this pain-suppressing system. For example, this system contributes to the analgesic potency of placebo administration and is also activated by stress. Knowledge of this analgesia system has greatly expanded our understanding of the mechanisms underlying pain management. Opiates, like morphine and meperidine, produce analgesia by mimicking the action of endorphins in the pain. Tricyclic drugs may produce analgesia by enhancing the nonendorphin links of the same system. Future research on this system will provide new insights and, consequently, new approaches to the management of pain.

Brain↗
PubMed1984

Relations among threshold, spike height, electrode distance, and conduction velocity in electrical stimulation of certain medullospinal neurons.

This report describes how the threshold for extracellular, electrical stimulation of cell bodies in the rat's rostromedial medulla depends on the distance to the stimulating electrode. A monopolar microelectrode both delivered current pulses near medullospinal neurons and, after decay of the stimulus artifact, detected whether an orthodromic spike had occurred by collision of that spike with a suitably timed antidromic spike initiated at the thoracic spinal cord. The liminal current and the height of antidromic spikes were noted at a series of vertical electrode positions. Regression analysis was performed to determine whether threshold and the inverse of peak-to-peak spike height varied more as the radial distance or its square. The square relationship provided a much better fit for threshold and a marginally better fit for the inverse of spike height. The spatial decline in excitability (K2) averaged 859 microA/mm2, falling within the range of values found for fibers and cell bodies in other studies. The constant of spatial decline in spike height (C2) in millivolts per square millimeter was positively correlated with K2. Both C2 and K2 were negatively correlated with conduction velocity. From threshold distance curves fitted by regression analysis, the mean separation of sites of spike maxima and threshold minima along each electrode path was 16 micron; the estimated distance from these sites to, respectively, the loci of spike generation and spike excitation were positively correlated and similar. The variation of C2 and K2 with conduction velocity may be due either to an influence of the size and shape of the dendritic tree on the spatial decrement of excitability and spike height or to a confounding in the studied equations of the space-independent effect of the size of a cell body on spike height and excitability.

Action Potentials↗
PubMed1984

An estimate of minimum number of brain stem neurons required for inhibition of a flexion reflex.

The tail-flick reflex elicited by noxious heat in lightly anesthetized rats is known to be prevented by trains of low-amplitude current pulses passed through a monopolar microelectrode in the rostromedial medulla ( RMM ). The effect of the distance from such an electrode on the threshold of cell bodies was described in the preceding paper (11). This paper estimates the density of cell bodies in the RMM and, subsequently, estimates the number of cell bodies excited by the aforementioned pulses, a figure whose upper bound is between 30 and 75. The mean chronaxy for suppression of tail flick was found to be 162 microS. Correspondingly, for activation of spikes in somata of the RMM , it was found to be 170 microS. The axons belonging to these somata, located in the spinal lateral columns, had mean chronaxies of 360 microS. These comparisons favor the idea that cell bodies in the RMM , not axons, mediate the suppression of tail flick. Other evidence for this conclusion is given in the text. Resting activity in the RMM was found to average 6.33 Hz. Thus if the inhibitory process depends only on the instantaneous sum of activity in the many thousands of RMM neurons, all nocifensive reflexes should be continuously suppressed. But since this is not so, the relative timing of spikes in the population may also be critical. The synchronizing effect of electrical stimulation then explains the low number of cells needed to prevent the reflex.

Animals↗
PubMed1984

Pain--mechanics and management.

In the past two decades there has been remarkable progress in understanding the neural mechanisms of pain. However, chronic pain is poorly understood and, by definition, poorly managed. In addition to hyperactivity of the sympathetic nervous system and damage to normal inhibitory mechanisms, social and psychological factors play a major role in producing the disability of chronic pain. New approaches to manage chronic pain include nonopiate drugs, transcutaneous electral nerve stimulation and psychological and behavioral methods. A nervous system network has recently been described that suppresses pain. This analgesic action is mediated by endogenous opioid peptides (endorphins) and by biogenic amines. The analgesia network can be activated either by electral stimulation or by opiates such as morphine or methadone.

Analgesics, Opioid↗
PubMed1983

Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system.

Trycyclic antidepressants are often effective in the management of neuropathic pains. To elucidate the mechanism of tricyclic-induced analgesia, amitriptyline and other drugs were injected into lightly anesthetized rats either systemically or via lumbar intrathecal cannulas. Analgesia was assessed by measuring the latency of the tail flick reflex. Using this model, intrathecal amitriptyline (30 micrograms) significantly enhanced the analgesic effect of an intraperitoneal dose of morphine (0.5 mg/kg) that by itself produced no measurable effect. Given systemically, amitriptyline (30 or 100 micrograms intraperitoneally) was ineffective. Cocaine (30 micrograms) also potentiated morphine analgesia, but iprindole, a tricyclic antidepressant with a very weak inhibitory effect on monoamine uptake, was ineffective. This enhancement of analgesia by intrathecal amitriptyline was prevented by pretreating the rats with p-chlorophenylalanine (300 mg/kg). These results are consistent with the hypothesis that amitriptyline produces analgesia by blocking serotonin uptake and therefore enhancing the action of serotonin at the spinal terminals of an opioid-mediated intrinsic analgesia system.

Amitriptyline↗
PubMed1983

Actions of opiates, substance P, and serotonin on the excitability of primary afferent terminals and observations on interneuronal activity in the neonatal rat's dorsal horn in vitro.

Approximately 5 segments of lumbo-thoracic spinal cord together with connected dorsal root ganglia were removed from 1-11-day-old rats and maintained in vitro. Dorsal root afferents, recorded from the ganglion and stimulated at the root entry zone, had conduction velocities typical of unmyelinated fibers (less than 2 m/s). The spinal terminals of individual afferents showed increased excitability with bath application of substance P and serotonin and decreased excitability with morphine sulfate, [D-ala2]methionine-enkephalinamide, manganese ions and magnesium ions. Naloxone by itself elicited no change in excitability, although it appeared to reduce the ongoing effect of opiates. Neurons recorded extracellularly in the dorsal horn responded to afferent volleys with one or more of 3 distinct phases: an excitation roughly coincident with the volley's arrival, a 50-300 ms period of inhibition, and a late excitation of 150-300 ms latency. The excitability results are accounted for by a model in which substance P, gamma-aminobutyric acid and possibly other depolarizing agents are contained in interneurons which synapse on afferent terminals. These interneurons could receive inhibitory enkephalinergic input, and, in the neonate but not the adult, excitatory serotoninergic input. An alternate scheme would have enkephalin and serotonin acting directly on afferent terminals, although perhaps by non-synaptic diffusion since the appropriate synapses have not been seen in histochemical studies. Such an action for enkephalin might explain the existence of opiate receptor on afferent terminals. The interneuronal responses to afferent volleys are parallel in most aspects to those found in the dorsal horns of adult mammals in vivo.

Afferent Pathways↗
PubMed1983

The activity of neurons in the rostral medulla of the rat during withdrawal from noxious heat.

Neurons of the rostral ventromedial medulla (RVM) have been implicated in the modulation of nociceptive transmission. In order to further analyze their role in pain behavior, we studied their activity while eliciting the tail flick reflex with noxious heat. Recording sites were regions in the RVM from which microstimulation (less than or equal to 10 microA, 400 mu sec, 50 Hz continuous pulse trains) inhibited the tail flick reflex. Extracellular unit activity and tail temperature were recorded, stored, and plotted with reference to either the time of tail flick or the time when the stimulating temperature reached 45 degrees C. Neuronal discharges were found to be either increased (on-cells), decreased (off-cells), or unchanged around the time of the tail flick. The decreases in discharge were more closely correlated with the tail flick behavior than with the temperature of the stimulus. These off-cells were located at sites of lowest threshold for tail flick inhibition and tended to be ventral to on-cells. We propose that off-cells must pause if the tail flick is to occur, and that this pausing allows the transmission of nociceptive input through spinal reflex loops.

Action Potentials↗