Biomedical subjects

H L Fields

Publications and source records attributed to H L Fields.

At least 55 records · Page 3Linked to original sources

PubMed1996

Endogenous opioids acting at a medullary mu-opioid receptor contribute to the behavioral antinociception produced by GABA antagonism in the midbrain periaqueductal gray.

This study examined the contribution of endogenous opioids to the antinociception produced by microinjection of the GABAA receptor antagonist, bicuculline, into the rat midbrain ventrolateral periaqueductal gray region. Microinjection of bicuculline (40 ng/0.4 microliter) into the periaqueductal gray produced robust antinociception as measured by the tail-flick latency to noxious heat. This antinociception was partially reversed by intravenous administration of the non-selective opioid antagonist naloxone hydrochloride (1 and 5 mg/kg), indicating that endogenous opioid release is necessary for this effect. To determine whether opioid release in the rostral ventromedial medulla, a major projection target of the periaqueductal gray, contributes to this effect, we microinjected another opioid antagonist, naltrexone, into the rostral ventromedial medulla. Naltrexone in the rostral ventromedial medulla (5 and 10 micrograms/microliter) significantly attenuated bicuculline antinociception elicited from the periaqueductal gray. Cys2, tyr3, orn5, pen7-amide (26.5 nmol), a selective mu-opioid receptor antagonist, also reversed the antinociception when microinjected into the rostral ventromedial medulla. Microinjections of naltrexone (10 micrograms/microliter) or cys2, tyr3, orn5, pen7-amide at sites in the medulla dorsal to the rostral ventromedial medulla were ineffective. None of the antagonists altered baseline tail-flick latencies. These results support the hypothesis that a population of periaqueductal gray neurons produces antinociception through a mu-opioid receptor-mediated action of endogenous opioids in the rostral ventromedial medulla. Thus, two opioid-sensitive pain-modulating brainstem sites are linked by an endogenous opioid synapse in the rostral ventromedial medulla.

Animals↗

PubMed1996

The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia.

In the syndrome of post-herpetic neuralgia (PHN), the nature of the sensory disturbance and its relationship both to the severity and cause of the pain is controversial. To address these issues, sensory mapping and quantitative thermal sensory testing was carried out four times in separate sessions on 35 subjects with established PHN. All subjects had pain affecting the torso or extremities and brush-evoked allodynia. Each session included rating of ongoing pain, mapping of the area of any sensory disturbance and the area of greatest pain, grading of allodynia severity within the area of greatest ongoing pain, and quantitative testing of thermal sensation in both the painful and the contralateral unaffected mirror-image skin. The severity of allodynia was positively correlated with reported ongoing pain severity. As a group, subjects had a sensory deficit to thermal stimuli in PHN skin compared with unaffected mirror-image skin. However, the magnitude of the heat pain sensory deficit was inversely correlated with both pain intensity and severity of allodynia. In fact, 12 subjects had heat hyperalgesia in their region of maximum pain. Compared with the 23 subjects with heat hypoalgesia, the group of 12 heat hyperalgesic subjects had significantly higher pain ratings and allodynia severity. Sensory loss was less strongly, but still inversely related to pain severity for the thermal modalities of innocuous warming, cooling and cold pain. This implies that there is no simple relationship between loss of peripheral nerve function and spontaneous or evoked pain. Rather, the preservation of several sensory modalities in their area of maximal pain suggests that in some PHN patients, activity in primary afferent nociceptors that remain connected to both their peripheral and central targets contributes significantly to ongoing pain. Although other mechanisms are likely to contribute to the pain, the demonstrated responsivity of PHN to topical agents including local anaesthetics, capsaicin, and non-steroidal anti-inflammatory drugs, supports this proposed mechanism of pain generation.

Aged↗

PubMed1995

Topical lidocaine gel relieves postherpetic neuralgia.

Postherpetic neuralgia (PHN) following herpes zoster is a common and disabling neuropathic pain syndrome. In a double-blind, three-session study, 5% lidocaine gel or vehicle was applied simultaneously to both the area of pain and to the contralateral mirror-image unaffected skin. In the local session, lidocaine gel was applied to the painful skin area. In the remote session, lidocaine gel was applied to mirror-image skin. In the placebo session, vehicle was applied bilaterally. For cranial PHN, gel was applied without occlusion for 8 hours. For limb or torso PHN, gel was applied under occlusion for 24 hours. The 16 subjects with cranial PHN reported pain relief significantly favoring local drug application at 30 minutes, 2, 4, and 8 hours. The 23 subjects with torso or limb PHN reported significantly lower pain intensity with local drug application at 8 hours and both pain relief and reduced pain intensity at 24 hours. Remote lidocaine application to mirror-image skin was no different from placebo. No systemic adverse effects were reported and blood levels did not exceed 0.6 microgram/ml. Topical application of 5% lidocaine gel relieves PHN pain by a direct drug action on painful skin.

Administration, Cutaneous↗

PubMed1995

Dorsal horn projection targets of ON and OFF cells in the rostral ventromedial medulla.

1. The rostral ventromedial medulla (RVM) participates in the modulation of nociceptive transmission by spinal cord neurons. Previous anatomic studies have demonstrated that RVM neurons project to laminae I, II, and V of the dorsal horn; laminae VII and VIII of the intermediate and ventral horns; the intermediolateral column; and lamina X. The RVM contains at least three physiologically defined classes of neurons, two of which, the ON and the OFF cells, have been implicated in nociceptive modulation. Because these cells classes are intermingled in the RVM, it has not been possible to determine the spinal laminar projection targets of ON and OFF cells by anatomic methods. Therefore in the current study we employed antidromic microstimulation methods to determine the laminar projections of two of the three classes of RVM neurons, the ON and the OFF cells. 2. In lightly anesthetized (with methohexital sodium) rats, single-unit extracellular recordings were made from 48 RVM neurons that were physiologically characterized as ON (30) or OFF (18) cells. The recording locations of 45 of these neurons were recovered. Thirty-seven were found in the nucleus raphe magnus and eight were located near its dorsal and lateral borders. 3. Thirty-two physiologically identified RVM neurons (18 ON and 14 OFF cells) were antidromically activated from the cervical spinal cord using a monopolar stimulating electrode. The stimulating electrode was moved systematically in the white matter until antidromic activation could be produced with currents of < or = 20 microA (6.1 +/- 0.7 microA, mean +/- SE). The points from which minimum currents were required to antidromically activate the neurons were located mainly in the ipsilateral dorsolateral funiculus (DLF) (27 of 32). In a few cases, lowest antidromic threshold currents were found near the border between the DLF and ventrolateral funiculus (VLF) or, rarely, in the VLF itself. In these cases, the cell recordings were found to be near the dorsal boundary of the RVM. 4. While one electrode was used to stimulate the parent axon in the lateral funiculus, a second was used to explore the gray matter for the presence of collateral branches. The identification of a branch was initially determined by an increase in antidromic latency. At the same rostrocaudal plane of the spinal cord, stimulation of the DLF induced an antidromic spike that invaded the neuron earlier than the antidromic spike elicited by stimulation in the gray matter. Collateral branches were confirmed by establishing that the location of the minimum threshold point for antidromic activation of the neurons from the second electrode was in the gray matter, that the minimum current required to antidromically activate the neuron from that point was too low to activate the parent axon in the DLF, and that a collision occurred between the spikes induced by the two stimulating electrodes. 5. In 17 cases, physiologically identified RVM neurons (10 ON and 7 OFF cells) were antidromically activated from the gray matter of the cervical spinal cord using a current of 8.4 +/- 2.1 (SE) microA. Minimum threshold points for antidromic activation were found in laminae I-II (3 ON and 4 OFF cells), lamina V (5 ON and 6 OFF cells), and regions ventral to the lateral reticulated area (3 ON and 2 OFF cells) of the gray matter. As indicated by these numbers, some neurons were antidromically activated from more than one gray matter region. In general, all OFF cells and 9 of 10 ON cells were antidromically activated from low threshold points in either laminae I-II or lamina V. 6. In six cases, neurons were activated from separate points located in two or three different laminae of the gray matter. Three OFF cells were activated from laminae I-II and V, one OFF cell and one ON cell were activated from lamina V and from more ventral points, and one ON cell was activated from laminae I-II and from points ventral to lamina V.

Animals↗

PubMed1995

The density and distribution of serotonergic appositions onto identified neurons in the rat rostral ventromedial medulla.

Neurons in the rostral ventromedial medulla (RVM) contribute to the modulation of nociceptive transmission and to the analgesic effects of opioids. The RVM contains serotonergic terminal arbors, serotonergic neurons and several types of serotonin (5-HT) receptors. Limited evidence suggests that 5-HT acting within RVM decreases nociceptive responsiveness and contributes to opioid analgesia. The present study examines the density and distribution of serotonergic afferents onto physiologically identified neurons in the RVM. In anesthetized rats, RVM neurons were characterized by their response to noxious stimulation as either on (excited), off (inhibited) or neutral (unaffected) cells. Tissue containing intracellularly labeled RVM neurons was processed for 5-HT immunocytochemistry. Five off, five on, and three serotonergic neutral cells were examined with the confocal microscope for appositions between 5-HT immunoreactive (5-HT-IR) processes and intracellularly labeled processes. Serotonergic neutral cells had the highest density of 5-HT-IR appositions. The density of 5-HT-IR appositions onto off cells was slightly lower. On cells demonstrated the lowest density of 5-HT-IR appositions. These results indicate that 5-HT contributes to nociceptive modulation by direct actions on the activity of RVM cells. Because the RVM has several sources of serotonergic input and a number of different 5-HT receptor subtypes, further understanding of the role of RVM 5-HT afferents will require pharmacological studies to determine the action of 5-HT on each cell class and anatomical studies to determine the brainstem origin of serotonergic input to each cell class.

Analysis of Variance↗

PubMed1994

Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla.

Activation of neurons in the rostral ventral medulla, by electrical stimulation or microinjection of glutamate, produces antinociception. Microinjection of opioid compounds in this region also has an antinociceptive effect, indicating that opioids activate a medullary output neuron that exerts a net inhibitory effect on nociception. When given systemically in doses sufficient to produce antinociception, morphine produces distinct, opposing responses in two physiologically identifiable classes of rostral medullary neurons. "Off-cells" are activated, and have been proposed to inhibit nociceptive transmission. "On-cells" are invariably depressed, and may have a pro-nociceptive role. Although on-cell firing is also depressed by iontophoretically applied morphine, off-cells do not respond to morphine applied in this manner. The present study used local infusion of the mu-selective opioid peptide Tyr-D-Ala-Gly-MePhe-Gly-ol-enkephalin (DAMGO) within the rostral medulla to determine whether off-cells are activated by an opioid action within this region that is sufficient to produce a behaviorally measurable antinociception. Activity of on- and off-cells was recorded before and after local infusion of DAMGO noxious heat-evoked tail flick reflex was inhibited in 17 of 28 cases. On-cell firing was profoundly depressed, and this occurred irrespective of the antinociceptive effectiveness of the injection. Off-cells were activated following DAMGO microinjections, but only in experiments in which the tail flick reflex was inhibited. Both reflex inhibition and neuronal effects were reversed following systemic administration of naloxone. These observations thus confirm the role of the on-cell as the focus of direct opioid action within the rostral medulla, and strongly support the proposal that disinhibition of off-cells is central to the antinociception actions of opioids within this region.

Amino Acid Sequence↗

PubMed1994

The interpretation of pain relief and sensory changes following sympathetic blockade.

A comparative study of the effects of sympathetic blockade by stellate ganglion block (SGB) and intravenous phentolamine infusion (PhI) was carried out in 24 patients with presumed sympathetically maintained pain of an upper extremity. A total of 15 SGBs and 16 PhIs were performed, with seven patients undergoing both procedures. All patients developed a Horner's syndrome with SGB and nasal stuffiness and cardiovascular changes with PhI. Similar pain relief was obtained with SGB and PhI in six of the seven who underwent both procedures. Pre-procedure patient characteristics including age, sex, duration of pain, historical and physical examination features suggestive of the reflex sympathetic dystrophy syndrome, and sensory disturbances such as allodynia and hyperpathia did not predict pain relief from either procedure. Changes in skin temperature following the sympatholytic procedure did not correlate with pain relief. For PhI, pain relief correlated with the magnitude of decrease in systolic blood pressure. After SGB, changes in quantitative thermal sensory testing (QST) suggestive of a partial deficit in thermal sensation correlated with pain relief. In 20 normal controls, water bath immersion to cool the hand passively by 7 degrees C and warm the hand passively by 4 degrees C had small and selective effects on thermal QST thresholds, but did not produce a general impairment in thermal sensation. In conclusion, the diagnosis of sympathetically maintained pain based on the history and physical examination alone cannot be made with confidence and therefore a sympatholytic procedure is necessary. When SGB produces pain relief but PhI does not, systemic absorption of local anaesthetic and/or sensory blockade by spread to somatic nerves may be the reason. Thus, PhI appears to be a less sensitive but more specific test than SGB. These two procedures provide complementary information and both may be needed to establish the diagnosis of sympathetically maintained pain.

Adult↗

PubMed1994

Inhibition and facilitation of different nocifensor reflexes by spatially remote noxious stimuli.

1. Noxious stimuli have been shown to produce a diffuse inhibition of nociresponsive neurons in the spinal and trigeminal dorsal horns. The present study sought to extend these electrophysiological studies of diffuse noxious inhibitory controls (DNIC) by determining the effect of a spatially remote noxious stimulus on behavioral measures of nociception. Changes in latency for hindpaw withdrawal and tail flick reflexes were measured in lightly halothane-anesthetized or awake, spinally transected rats before, during, and after application of a spatially remote noxious stimulus. 2. Surprisingly, in no case did application of a spatially remote noxious stimulus inhibit the hindpaw withdrawal reflex. The latency for this reflex was either reduced or did not change when the tail or contralateral hindpaw was placed in hot water (50 degrees C) or when a noxious pinch was applied to the ear. In contrast, the latency for the tail flick reflex was consistently increased when the hindpaw was placed in hot water. Both the hindpaw reflex facilitation and the tail flick reflex inhibition produced by a noxious conditioning stimulus were attenuated in spinally transected rats indicating supraspinal modulation of both reflexes. 3. In addition, and consistent with the work of others, placing the tail in hot water reduced the evoked activity of convergent neurons in both the trigeminal and lumbar spinal dorsal horns. Thus inhibition of the activity of nociresponsive neurons in the dorsal horn is consistent with inhibition of the tail flick reflex, but not with facilitation of the hindpaw withdrawal reflex.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗

PubMed1994

Pronounced changes in the activity of nociceptive modulatory neurons in the rostral ventromedial medulla in response to prolonged thermal noxious stimuli.

1. Brain regions that inhibit nociception can be activated by various environmental stimuli, including prolonged noxious stimuli. The present study tested the effect of such a prolonged noxious stimulus on the activity of nociceptive modulatory neurons in the rostral ventromedial medulla (RVM). These neurons, called ON- and OFF-cells because of their respective burst and pause in activity associated with nocifensor reflexes, have been shown to facilitate and inhibit nociception, respectively. 2. Single-unit activity of ON- and OFF-cells was assessed in lightly halothane- or barbiturate-anesthetized rats exposed to prolonged noxious heat (50 degrees C water). This prolonged noxious stimulus caused an increase in ON-cell and a decrease in OFF-cell activity regardless of anesthetic (halothane or barbiturate) or stimulus location (hindpaw or tail). 3. Surprisingly, and despite the consistent changes in RVM cell activity, the prolonged noxious stimulus caused different effects depending on the reflex used to assess nociception. The hindpaw withdrawal reflex was facilitated when the tail was immersed in hot water, whereas the tail flick reflex was inhibited when the hindpaw was immersed in hot water (see preceding manuscript). Lidocaine inactivation of the RVM shortened the latency for both reflexes but had no effect on tail flick inhibition produced by the noxious conditioning stimulus. In contrast, lidocaine inactivation of the RVM completely reversed the hindpaw reflex facilitation produced by tail heat, indicating the involvement of RVM ON-cells in facilitation of this reflex. 4. These data demonstrate that RVM neurons respond in a consistent manner to noxious stimuli whether applied for a brief or prolonged time: ON-cell activity increases and OFF-cell activity decreases. Moreover, the activation of RVM ON-cells produced by a noxious stimulus is sufficient to enhance some nocifensor reflexes, whereas neural structures other than the RVM appear to mediate the antinociceptive effects produced by a prolonged noxious stimulus.

Afferent Pathways↗

PubMed1994

Serotonin immunoreactivity is contained in one physiological cell class in the rat rostral ventromedial medulla.

Neurons in the rostral ventromedial medulla (RVM) are the major source of serotonergic projections to the dorsal horn. A large body of evidence implicates RVM serotonergic neurons in the modulation of spinal nociceptive transmission. Three physiological classes of RVM neurons, on, off, and neutral cells, are postulated to have different nociceptive modulatory effects on spinal nocifensor reflexes. This study was undertaken to determine which RVM cell class(es) contains 5-HT. In anesthetized rats, RVM neurons were identified by their responses to noxious cutaneous stimuli, intracellularly labeled, and processed for 5-HT immunocytochemistry. Labeled neurons were examined with epifluorescence and imaged using a confocal laser microscope. A total of 25 RVM neurons were intracellularly labeled. No off (n = 9) or on (n = 8) cells were serotonergic. Half of the neutral cells (4 of 8) demonstrated 5-HT immunoreactivity. These results call for a reevaluation of the mechanisms of RVM modulatory influence on spinal cord nociceptive transmission. The finding that some neutral cells are serotonergic strongly suggests that serotonergic neutral cells are involved in the modulation of spinal nociceptive transmission. Additionally, inhibition of spinal nociceptive transmission by off cells is unlikely to involve 5-HT release. Finally, since opioid administration does not alter the firing of RVM neutral cells, the results of the present study indicate that serotonergic RVM neurons do not directly mediate the effects of supraspinal opioids in the rat.

Animals↗

PubMed1993

Peptides and the primary afferent nociceptor.

An expanding knowledge of neuropeptides and their function has led to a profound change in our view of how the PAN contributes to pain. In addition to their expected direct action on postsynaptic cells in the dorsal horn, neuropeptides can modify transmitter release from nearby terminals of other PANs and/or diffuse to act on dorsal horn neurons at a considerable distance from their site of release (Fig. 2). Contrary to early expectations and despite the evidence that several neuropeptides excite central nociceptive neurons, there is no clear correspondence between neuropeptide content and physiologically defined classes of small-diameter primary afferents. There is, however, a tendency for populations of afferents innervating different organs to differ consistently in their peptide content. In fact, the peptide content of primary afferents is, in part, determined by specific factors in the tissues that they innervate. Furthermore, peptide content can change dramatically in response to certain prolonged stimuli or nerve damage. The lack of correspondence of peptide content and physiological response pattern, the plasticity of peptide content, its tissue specificity, and the possibility for action at a distance from the site of their release from central PAN terminals strongly suggest that PAN peptides have functions that are fundamentally different from those of the short-range actions of amino acid neurotransmitters that are also found in the PAN. Finally, nowhere is the plasticity of function of the PAN more evident than at its peripheral terminals. Long-term changes are produced in these terminals by a host of peptides that derive from a variety of cell types. The complexity of this transduction process is augmented by the activity-induced release of peripherally active neuropeptides from the PAN itself. In addition to the variety of fundamental neurobiological issues that recent studies of PANs have raised, they have also generated a great deal of clinical interest, in view of the role of the PAN in inflammation and its accessibility for study and for therapeutic intervention.

Animals↗

PubMed1992

Circuitry linking opioid-sensitive nociceptive modulatory systems in periaqueductal gray and spinal cord with rostral ventromedial medulla.

The interactions among opioid-sensitive nociceptive modulatory systems, which include the midbrain periaqueductal gray, rostral ventromedial medulla and spinal cord, are likely to play a central role in the potent antinociception that results when morphine is administered systemically. The aim of the present study was to investigate the mechanisms through which local application of morphine, either in the periaqueductal gray or at the lumbar spinal cord in the rat, influences the activity of one population of putative nociceptive modulatory neurons in rostral ventromedial medulla, i.e. "on-cells". Previous studies have shown that the spontaneous and tail-flick-related firing of on-cells is invariably depressed when morphine is given systemically in doses demonstrated to inhibit the tail-flick reflex, and that a similar depression of this activity is produced when morphine is applied directly in the periaqueductal gray or intrathecal space. In the present experiments, on-cells were activated pharmacologically using iontophoretically applied glutamate to provide an indication of whether morphine-induced suppression of on-cell firing reflected a postsynaptic inhibition or a disfacilitation resulting from blockade of an excitatory input to the on-cell. Microinjection of morphine into the periaqueductal gray blocked glutamate-evoked activity of on-cells in parallel with its suppression of the tail-flick reflex, suggesting activation of an inhibitory input to these cells. No change in glutamate-evoked activity occurred in rats in which morphine did not produce antinociception. Intrathecal administration of morphine did not alter the glutamate-evoked activity of these neurons despite blocking the tail-flick reflex, suggesting that morphine acting in the spinal cord removes an excitatory input to on-cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Direct and indirect actions of morphine on medullary neurons that modulate nociception.

The rostral ventromedial medulla is part of a neural network through which systemically administered morphine produces antinociception. Two physiologically characterized classes of presumed nociceptive modulating neurons that respond differentially to systemically administered morphine have been identified in this region: the firing of "on-cells" is depressed, whereas "off-cells" become continuously active. On-cells have been proposed to permit or facilitate, and off-cells to inhibit, nociceptive transmission. Because local application of morphine in the rostral ventromedial medulla itself is sufficient to produce antinociception, it is important to determine whether systemically administered morphine exerts its effects on neurons in this region by a direct action. Thus, activity of physiologically characterized neurons was studied before, during and after ionotophoretic administration of morphine. As with systemic administration, iontophoretic application of morphine depresses the activity of on-cells, an effect that is reversed by iontophoretic as well as by systemic administration of naloxone. In contrast, no reliable changes in the firing of off-cells are produced by iontophoretic administration of morphine. Cells of a third class, "neutral cells", are not affected by systemic morphine administration, nor do they respond to iontophoretic application of the drug. The present experiments demonstrate that direct opioid responsiveness in the rostral ventromedial medulla is limited to a single physiologically characterized class of presumed nociceptive modulatory neuron, the on-cell. This implies that the antinociceptive effect exerted by systemically administered morphine involves at least two components within the rostral ventromedial medulla: a direct inhibition of on-cells, and an indirect activation of off-cells. Each of these actions is likely to have a net hypoalgesic effect.

Animals↗

PubMed1992

A confocal laser microscopic study of enkephalin-immunoreactive appositions onto physiologically identified neurons in the rostral ventromedial medulla.

Neurons in the rostral ventromedial medulla (RVM) are important in the opioid modulation of dorsal horn nociceptive transmission. Systemically administered morphine inhibits one class of RVM cells, the on-cells; excites a second class of RVM cells, the off-cells; and has no effect on a third class, neutral cells. In contrast, iontophoretic application of morphine inhibits on-cells but does not alter the activity of either off- or neutral cells. The present study addresses whether the differential sensitivity to exogenous opioids is correlated with a differential termination pattern onto the three classes of RVM neurons by afferents containing endogenous opioids. Intracellular recordings were made from RVM neurons in rats under light halothane anesthesia. Physiologically characterized neurons were injected with Neurobiotin and then subsequently visualized with a Texas red fluorophore. Thick (50 microns) sections containing labeled RVM cells were processed for enkephalin immunoreactivity (ENK-IR) using an FITC fluorophore and then optically sectioned at 1.5 micron intervals using a dual-channel confocal laser scanning microscope. ENK-IR appositions were found on the somata and dendrites of all on-cells. Although ENK-IR varicosities were also apparently apposed to off- and neutral cells, the density of such appositions was significantly less than the density of ENK-IR appositions onto on-cells. The greater overall density of ENK-IR appositions onto on-cells was apparently due to a concentration of appositions on the soma and proximal dendrites of these neurons. These results support a model of RVM function in which endogenous opioid peptides produce an antinociceptive action by a direct inhibitory action on on-cells that facilitate nociceptive transmission. This on-cell inhibition may produce an additional antinociceptive effect by removing a possible on-cell inhibition of off-cells, which are thought to inhibit nociceptive transmission.

Animals↗

PubMed1991

Spatial and temporal variation of microstimulation thresholds for inhibiting the tail-flick reflex from the rat's rostral medial medulla.

Suppression of the tail-flick reflex by microstimulation of the rostral medial medulla in rats lightly anesthetized with barbiturates was studied with regard to spatial and temporal variations in electrical threshold. Trains of constant-current pulses with linearly descending amplitudes (called 'ramps') were passed through the extracellular brain microelectrode during noxious heating of the tail. The pulse amplitude at the time of the reflex, after allowance for conduction and reaction latencies, was taken as the threshold reading. This new method revealed a range of vertical electrode positions corresponding roughly to the nucleus raphe magnus, where the thresholds tended to be lowest (a mean of 4.1 microA for 0.4-ms pulses delivered at 50 Hz). In confirmation of the technique's validity neither the duration of the ramp nor its starting amplitude, within their useful range, significantly affected the measured threshold. Pronounced temporal fluctuation was seen in thresholds measured every 2 min. Spatial variability within the low-threshold region and differences between preparations were statistically much smaller sources of variation. The temporal fluctuation appeared to have a stationary mean for at least 20 min under constant conditions of anesthesia. In some experiments, action potentials from single neurons were recorded through the stimulating electrode, and classified into those inhibited during the tail-flick (off-cells), those excited (on-cells), and those unaffected (neutral cells). The thresholds where off-cells exhibited their maximum action potential were on average significantly lower than corresponding thresholds for on-cells. Short-range (less than 0.2 mm) spatial variations in the threshold appeared however to be uncorrelated with the distance to an individual recorded off-cell or on-cell.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Evidence that inhibition of a nociceptive flexion reflex by stimulation in the rostroventromedial medulla in rats occurs at a premotoneuronal level.

The amplitude of the hamstring monosynaptic reflex was measured before and during stimulation of the rostroventromedial medulla (RVM) in the lightly anaesthetized rat. The RVM was stimulated at currents sufficient to completely inhibit a paw withdrawal reflex evoked by noxious heat. At these currents, RVM stimulation produced no significant change in monosynaptic reflex amplitude, evidence that inhibition occurs at a premotoneuronal level.

Anesthesia↗

PubMed1991

Neurotransmitters in nociceptive modulatory circuits.

Significant advances have been made in our understanding of nociceptive modulation from RVM. Among the most useful conceptually has been the discovery that there are two classes of modulatory neurons in the RVM that are likely to have opposing actions on nociception: on-cells, which may facilitate nociceptive transmission, and off-cells, which probably have a net inhibitory effect on nociception. The similarity in response properties among the members of each class, their large, somatic "receptive fields," and the wide distribution of the terminal fields of axons of individual neurons to the trigeminal sensory complex and to multiple spinal segments indicate that these neurons exert a global influence over nociceptive responsiveness. Drug microinjections into the RVM presumably shift the balance between states of on- or off-cell firing and also produce measurable changes in the threshold for nocifensor reflexes. The meaningful unit of function in the RVM nociceptive modulatory system therefore probably consists of large ensembles of physiologically and pharmacologically similar neurons. The strong coordination of activity of the two classes of RVM neuron may depend largely upon intranuclear projections from RVM off-cells that excite other off-cells and inhibit on-cells. The off-cell pause is GABA-mediated, and it is likely that there is a subset of GABA-containing RVM on-cells that directly inhibit off-cells. Furthermore, the available evidence indicates that exogenous opiates activate off-cells by inhibiting GABAergic release. Presumably, enkephalinergic cells in the RVM disinhibit off-cells in a similar way. Although non-serotonin-containing off-cells certainly exist, we propose that some off-cells contain serotonin. Other possible connections are based on more limited data; however, ACh, neurotensin, NE, and EAAs are present in neurons that project to the RVM, and each of these compounds, when microinjected into the RVM, has a modulating effect on nociceptive transmission. The local circuits in the RVM that underlie these actions remain to be elucidated. At the level of the dorsal horn, there is good evidence for each of three inhibitory mechanisms: direct inhibition of nociceptive projection neurons, inhibition of excitatory relay interneurons, and excitation of an inhibitory interneuron. The relative contribution made by each of these circuits is unknown.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1991

Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia.

We studied the analgesic efficacy of an intravenous infusion of lidocaine and morphine in 19 adults with well-established postherpetic neuralgia in a three-session, randomized, double-blind, placebo-controlled trial. Compared with saline placebo, both lidocaine and morphine reduced pain intensity. Reductions in pain did not correlate with side effects produced by the infusions. For morphine, there was a significant correlation between reductions in pain intensity and blood level achieved. In the majority of subjects who reported definite pain relief, allodynia also disappeared. The results show that neuropathic pain can respond to opioids and to systemically administered local anesthetic drugs.

Aged↗