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Biomedical subjects

H L Fields

Publications and source records attributed to H L Fields.

At least 37 records · Page 2Linked to original sources
PubMed1998

Mu and kappa opioid receptors in periaqueductal gray and rostral ventromedial medulla.

The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are important brain stem pain modulating regions. Recent evidence suggests that kappa opioids antagonize the effects of mu opioids in the RVM. However, the anatomical relationship between mu and kappa opioid receptors in PAG and RVM is not well characterized. This study examined relationships between mu and kappa opioid receptor immunoreactivity (IR) and mRNA in PAG and RVM. Brain slices were processed for either immunocytochemistry or in situ hybridization. We found considerable anatomical overlap of mu and kappa opioid IR and mRNA in the RVM and PAG. These results provide an anatomical basis for recent behavioral and electrophysiological findings in RVM, and suggest modulatory interactions between mu and kappa opioids in PAG.

Animals↗
PubMed1998

Postherpetic neuralgia: irritable nociceptors and deafferentation.

Postherpetic neuralgia (PHN) is a common and often devastatingly painful condition. It is also one of the most extensively investigated of the neuropathic pains. Patients with PHN have been studied using quantitative testing of primary afferent function, skin biopsies, and controlled treatment trials. Together with insights drawn from an extensive and growing literature on experimental models of neuropathic pain these patient studies have provided a preliminary glimpse of the pain-generating mechanisms in PHN. It is clear that both peripheral and central pathophysiological mechanisms contribute to PHN pain. Some PHN patients have abnormal sensitization of unmyelinated cutaneous nociceptors (irritable nociceptors). Such patients characteristically have minimal sensory loss. Other patients have pain associated with small fiber deafferentation. In such patients pain and temperature sensation are profoundly impaired but light moving mechanical stimuli can often produce severe pain (allodynia). In these patients, allodynia may be due to the formation of new connections between nonnociceptive large diameter primary afferents and central pain transmission neurons. Other deafferentation patients have severe spontaneous pain without hyperalgesia or allodynia and presumably have lost both large and small diameter fibers. In this group the pain is likely due to increased spontaneous activity in deafferented central neurons and/or reorganization of central connections. These three types of mechanism may coexist in individual patients and each offers the possibility for developing new therapeutic interventions.

Afferent Pathways↗
PubMed1998

Tetrodotoxin: anesthetic activity in the de-epithelialized cornea.

BACKGROUND: Tetrodotoxin (TTX) binds with high affinity to sodium channels and produces local anesthesia. We investigated whether TTX is an effective, long-acting corneal anesthetic in rabbits. METHODS: After mechanical debridement of the central corneal epithelium, topical TTX (1 mM, 0.1 mM, or 0.01 mM) was applied to one eye each of 18 New Zealand White rabbits. The fellow eye of each rabbit was treated with control vehicle. Blink response to a mechanical stimulus was assessed. Blink response was also assessed every 3 h for 30 h in 6 rabbits treated with 1 mM TTX administered every 6 h. In a separate group of 12 rabbits with central epithelial debridement, the rate of epithelial healing was compared between animals treated with topical 1.0 mM TTX and animals receiving no treatment. RESULTS: After 4 h, eyes treated with 1.0 mM and 0.1 mM TTX were anesthetic. At 6 h, five of six rabbit eyes treated with 1.0 mM TTX were still partially anesthetic. By 8 h, the mean anesthesia score for 1.0 mM TTX was approaching normal. With multiple dosing, all six rabbit eyes remained anesthetic for the duration of the experiment. There was no significant difference in the rate of re-epithelialization between eyes treated with TTX and untreated controls. There was no evidence of systemic or local toxicity from topical TTX. CONCLUSION: In a rabbit model, TTX is a long-acting topical anesthetic that retains its effectiveness when administered repeatedly over 24 h and does not inhibit epithelial healing. It may have application in management of pain after photorefractive keratectomy.

Administration, Topical↗
PubMed1998

Experimental study of tetrodotoxin, a long-acting topical anesthetic.

PURPOSE: To determine the effectiveness and toxicity of tetrodotoxin for use as a long-acting topical anesthetic. METHODS: Four groups of six rabbits each received a 40-microl aliquot of either tetrodotoxin in one of three concentrations (10 mM, 1 mM, or 0.1 mM) or proparacaine 0.5% into the inferior conjunctival cul-de-sac of one eye, with the fellow eye of each rabbit receiving 40 microl of a 60-mM, pH 4.3 sodium citrate vehicle as a control. Corneal sensation was tested for up to 8 hours after administration of drugs, and response was noted by no blink, partial blink without full eyelid closure, and full blink. Slit-lamp examination at 12 and 24 hours after administration and pachymetry before and 24 hours after administration were performed to detect corneal toxicity. RESULTS: Rabbits receiving all three concentrations of tetrodotoxin did not demonstrate any ocular irritation, corneal thickening, or signs of systemic toxicity. At a dose of 10 mM, tetrodotoxin produced an anesthetic effect lasting up to 8 hours. At 1 mM, tetrodotoxin was an effective but shorter-acting anesthetic. At 0.1 mM, tetrodotoxin had no significant anesthetic effect. Proparacaine-treated rabbits initially were anesthetic, but this effect was largely gone by 1 hour and completely gone by 3 hours. CONCLUSIONS: Tetrodotoxin is a long-acting topical anesthetic in the rabbit cornea. Although additional toxicity studies are required, tetrodotoxin may provide an effective, long-lasting topical anesthetic for use in pain control after corneal procedures such as photorefractive keratectomy.

Anesthesia, Local↗
PubMed1998

The contribution of the rostral ventromedial medulla to the antinociceptive effects of systemic morphine in restrained and unrestrained rats.

Although there are numerous opioid-sensitive structures in the central nervous system, the contribution of each to the analgesic effect of systemically administered morphine is controversial. One such structure is the rostral ventromedial medulla. In the present study, we tested the hypothesis that the rostral ventromedial medulla is necessary for the full expression of systemic morphine-induced antinociception. Additionally, we examined whether the modulatory effect of the rostral ventromedial medulla on tail-flick latency is dependent on the behavioral state of the animal. In unrestrained rats, inactivation of the rostral ventromedial medulla with either lidocaine (0.5 microl of 4%) or muscimol (50 ng) had no effect on tail-flick latency. In contrast, in restrained rats, inactivation of the rostral ventromedial medulla with either lidocaine (0.5 microl of 4%) or muscimol (50 ng) significantly decreased tail-flick latency. In both conditions, microinjection of morphine (5 microg) into this region significantly increased tail-flick latency. Additionally, in unrestrained rats, muscimol (50 ng) and cholecystokinin tetrapeptide (0.5 ng) infusion into the rostral ventromedial medulla completely reversed systemic morphine-induced analgesia, while lidocaine (0.5 microl of 4%) and cholecystokinin octapeptide (0.25 ng) infusion partially reversed systemic morphine-induced analgesia. These findings demonstrate that the rostral ventromedial medulla does not tonically modulate tail-flick latency in unrestrained rats, but does modulate tail-flick latency when animals are stressed via restraint. These findings also strongly support the hypothesis that the rostral ventromedial medulla is necessary for the full analgesic effects of systemically administered morphine.

Analgesics, Opioid↗
PubMed1998

Treatment of intractable pain with topical large-dose capsaicin: preliminary report.

UNLABELLED: Complex regional pain syndromes (CRPS) and neuropathic pain are often poorly controlled by conventional pharmacologic interventions. We administered 8-methyl-N-vanillyl-noneamide (capsaicin) at doses of 5%-10% to individuals with such disorders in this trial. Previous limitations to trials with larger-dose, topical concentrations of capsaicin included intense burning sensations experienced after application. To enable patients to tolerate the high concentrations, we first performed regional anesthesia. All patients reported at least some relief. Of 10 patients, 9 obtained substantial analgesia that lasted 1-18 wk. At Week 1 after therapy, the mean verbal analog scale (VAS) scores decreased from 8.0 to 3.0. At Week 4 after therapy, mean VAS score was 4.5. Analgesia lasted from < 1 wk (1 patient) to more than 50 wk (1 patient). Patients received one to eight treatments. With one exception, patients receiving more than one treatment obtained additional relief with subsequent treatment. Pain responsive to opioids was the only side effect of treatment. Large-dose capsaicin administered with regional anesthesia may effectively minimize refractory CRPS and neuropathic pain. A double-blind, placebo-controlled study in patients with bilateral peripheral neuropathy using epidural anesthesia with and without large-dose topical capsaicin is in progress. IMPLICATIONS: Sensory neuropathies are associated with many diseases. Pain from these disorders can produce greater disability than the primary disease processes themselves. Currently available therapies are limited. However, the intermittent application of large-dose topical capsaicin may provide significant pain relief, decrease chronic analgesic dependence, and decrease aggregate health care expenditures.

Administration, Topical↗
PubMed1998

Endogenous opioid peptides acting at mu-opioid receptors in the dorsal horn contribute to midbrain modulation of spinal nociceptive neurons.

Activation of neurons in the midbrain periaqueductal gray (PAG) inhibits spinal dorsal horn neurons and produces behavioral antinociception in animals and analgesia in humans. Although dorsal horn regions modulated by PAG activation contain all three opioid receptor classes (mu, delta, and kappa), as well as enkephalinergic interneurons and terminal fields, descending opioid-mediated inhibition of dorsal horn neurons has not been demonstrated. We examined the contribution of dorsal horn mu-opioid receptors to the PAG-elicited descending modulation of nociceptive transmission. Single-unit extracellular recordings were made from rat sacral dorsal horn neurons activated by noxious heating of the tail. Microinjections of bicuculline (BIC) in the ventrolateral PAG led to a 60-80% decrease in the neuronal responses to heat. At the same time, the responses of the same neurons to iontophoretically applied NMDA or kainic acid were not consistently inhibited. The inhibition of heat-evoked responses by PAG BIC was reversed by iontophoretic application of the selective mu-opioid receptor antagonists, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP). A similar effect was produced by naloxone; however, naloxone had an excitatory influence on dorsal horn neurons in the absence of PAG-evoked descending inhibition. This is the first demonstration that endogenous opioids acting via spinal mu-opioid receptors contribute to brain stem control of nociceptive spinal dorsal horn neurons. The inhibition appears to result in part from presynaptic inhibition of afferents to dorsal horn neurons.

Adrenergic alpha-Agonists↗
PubMed1998

Midbrain periaqueductal gray (PAG) inhibits nociceptive inputs to sacral dorsal horn nociceptive neurons through alpha2-adrenergic receptors.

Modulation of sacral spinal dorsal horn neurons by the ventrolateral PAG was studied by extracellular recording combined with microiontophoretic applications of alpha-adrenergic agonists or antagonists. Bicuculline (BIC, 15 ng) microinjected into the ventrolateral PAG produced a consistent inhibition of the responses of nociceptive dorsal horn neurons. After PAG-BIC applications, the total number of spikes per heat stimulation period was significantly decreased to a mean of 37 +/- 19% (n = 8) of the pre-BIC control. Local iontophoresis of the selective alpha2-adrenoceptor antagonists idazoxan or yohimbine but not the selective alpha1 antagonist benoxathian significantly reversed PAG-BIC-evoked inhibition. At low ejection currents, clonidine, an alpha2-adrenoceptor agonist, markedly reduced noxious heat-evoked responses but had no consistent action on the responses to iontophoresed excitatory amino acids [EAA; N-methyl--aspartate (NMDA) or kainic acid]. At ejection currents higher than required to block descending inhibition, idazoxan potentiated responses to both heat and EAA iontophoresis. At higher ejection currents, EAA responses were inhibited by clonidine. This indicates that both presynaptic and postsynaptic alpha2 receptors are capable of inhibiting the recorded neurons. Activation of the alpha1 adrenoceptors by iontophoresis of methoxamine often led to a marked increase in the responses to kainic acid and, to a lesser extent, to NMDA iontophoresis or noxious heat. Together with previously reported work, the current experiments demonstrate that PAG neurons inhibit nociceptive dorsal horn neurons primarily through an indirect alpha2 adrenoceptor mechanism. In this same population of dorsal horn neurons, norepinephrine has a direct alpha1-mediated excitatory effect.

Adrenergic alpha-Agonists↗
PubMed1997

Cholecystokinin and enkephalin in brain stem pain modulating circuits.

Neurons in rostral ventromedial medulla and the periaqueductal gray modulate dorsal horn nociceptive transmission. Endogenous peptides implicated in this modulation include enkephalin (ENK), which is antinociceptive, and cholecystokinin (CCK), which has anti-opioid effects. In this study double-label fluorescence immunocytochemistry demonstrated somata and terminals with ENK- or CCK-like immunoreactivity in these regions. Although the distribution of CCK- and ENK-immunoreactive terminal fields overlapped significantly, co-localization was rare. Furthermore, CCK- and ENK-immunoreactive somata had different morphologies and distinct distributions. The overlap of CCK- and ENK- immunoreactive terminals arbors provides a morphological substrate for an antagonistic interaction of CCK and ENK within brainstem pain modulating circuits, as has been demonstrated in the spinal cord.

Animals↗
PubMed1997

Cellular mechanism for anti-analgesic action of agonists of the kappa-opioid receptor.

The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primarily through mu-opioid receptors, but the function of the kappa-receptor in opioid analgesia is unclear. Although kappa-receptor agonists can produce analgesia, behavioural studies indicate that kappa agonists applied intravenously or locally into the spinal cord antagonize morphine analgesia. As morphine, a primary mu agonist, also binds to kappa-receptors and the analgesic effectiveness of morphine decreases with repeated use (tolerance), it is important to understand the mechanism for the functional interaction between kappa- and mu-opioid receptors in the central nervous system. Here we present in vitro electrophysiological and in vivo behavioural evidence that activation of the kappa-receptor specifically antagonizes mu-receptor-mediated analgesia. We show that in slice preparations of a rat brainstem nucleus, which is critical for the action of opioids in controlling pain, functional kappa- and mu-receptors are each localized on physiologically different types of neuron. Activation of the kappa-receptor hyperpolarizes neurons that are activated indirectly by the mu-receptor. In rats, kappa-receptor activation in this brainstem nucleus significantly attenuates local mu-receptor-mediated analgesia. Our findings suggest a new cellular mechanism for the potentially ubiquitous opposing interaction between mu- and kappa-opioid receptors and may help in the design of treatments for pain.

Analgesics↗
PubMed1997

GABA-immunoreactive boutons contact identified OFF and ON cells in the nucleus raphe magnus.

The pontomedullary raphe magnus (RM) contains two physiologically defined types of neurons that participate in the opioid-induced modulation of dorsal horn nociceptive messages: OFF cells, which decrease, and ON cells, which increase their discharge rates when reflex behavior is evoked by noxious pinch or heat. Because both types of neuron have inhibitory inputs and because there is evidence that gamma-aminobutyric acid (GABA) inhibitory mechanisms within RM contribute to the antinociceptive action of opioids, we have sought anatomical evidence for a direct GABAergic input to OFF and ON cells. In this study, cells of each type located in the RM were electrophysiologically defined and intracellularly filled with horseradish peroxidase or Neurobiotin. One cell of each type was labeled in the cat, and 2-3 cells of each type were labeled in the rat. Thin sections were labeled by a postembedding immunogold procedure by using an antibody directed against glutaraldehyde-conjugated GABA. GABA-immunoreactive (GABA-ir) boutons contained small, round, clear vesicles and made symmetrical synapses with identified dendrites. GABA-ir boutons were apposed to soma and to proximal and distal dendrites of both cell types in both species. These findings demonstrate direct GABAergic input to identified OFF and ON cells in the RM. J. Comp. Neurol. 378:196-204, 1997.

Animals↗
PubMed1997

Noradrenergic input to nociceptive modulatory neurons in the rat rostral ventromedial medulla.

Within the rostral ventromedial medulla (RVM), there are two classes of putative pain modulation neurons: ON cells and OFF cells, which respectively burst or pause prior to withdrawal reflexes elicited by noxious stimulation. Alpha-adrenergic agonists injected into the RVM produce changes in the latency of spinal nocifensive reflexes and, when iontophoretically applied, alter the firing of RVM ON but not OFF cells. To provide further information about the contribution of norepinephrine to RVM neuron function, we analyzed the distribution of tyrosine hydroxylase immunoreactive (TH-ir) appositions upon RVM ON and OFF cells. In the lightly anesthetized rat, seven ON and five OFF cells were identified by changes in their discharge rate in relation to nociceptive withdrawal reflexes and were labeled by intracellular injection of neurobiotin. Sections containing labeled cells were visualized by using avidin conjugated to a Texas Red fluorophore. Tissue with labeled cells was subsequently processed for TH-ir by using a Bodipy fluorophore conjugated secondary antibody. The distribution of the Bodipy-labeled fibers and terminals upon the Texas Red-labeled neurons was mapped using a confocal laser-scanning microscope. All the labeled neurons exhibited close TH-ir appositions. Appositions were of two types: swellings and fibers. Although the numbers and density of appositions varied among the cells, there were no consistent differences that correlated with physiological properties. Thus the overall density of appositions for ON cells (29.0 +/- 22.2 x 10(4) microns2) did not differ significantly from that for OFF cells (25.4 +/- 22.2 x 10(4) microns2). Tyrosine hydroxylase immunoreactive (TH-ir) appositions upon ON and OFF cells varied with their location along the dorso-ventral axis with more ventral neurons having a greater density of TH-ir swelling-type appositions. In a separate study, TH-ir and dopamine-beta-hydroxylase-like immunoreactivity (DBH-ir) were mapped in the same sections by using confocal microscopy. Nearly 97% of the TH-ir profiles co-localized with DBH-ir. These observations provide evidence that both ON and OFF cells in the RVM are targeted by noradrenergic inputs.

Adrenergic Fibers↗
PubMed1997

Intrinsic membrane characteristics distinguish two subsets of nociceptive modulatory neurons in rat RVM.

Pain modulating neurons of the rostral ventromedial medulla (RVM) include three physiologically distinct classes of neurons in intact, anesthetized animals: and cells that change their activity before the onset of withdrawal reflexes and cells, which have activity unrelated to withdrawal reflexes. A previous in vitro intracellular study demonstrated that the RVM contains two types of neurons that are distinguished by their action-potential characteristics. The present in vivo intracellular study examined whether these intracellularly recorded action-potential characteristics are correlated with the physiological response properties of RVM neurons recorded. RVM neurons exhibited two distinct types of action potentials in vivo. Fast-spike (FS) neurons (n = 30) had short-duration action potentials (0.27 +/- 0.02 (SE) ms at half amplitude) and biphasic afterhyperpolarizations with a characteristic rapid overshooting spike repolarization. Slow-spike (SS) neurons (n = 25) had longer duration action potentials (0.44 +/- 0.02 ms at half-amplitude) due to a slower-spike repolarization rate and monophasic afterhyperpolarization. and cell classes included both FS and SS neurons. FS and neurons had an early onset response to noxious heat stimulation. SS and cells showed a delayed onset response to noxious heat. cells (n = 13) were all SS cells. Among the SS neurons, only cells had action potentials longer than 0. 45 ms (n = 9). FS and SS neurons were intermingled throughout the RVM. The majority of intracellularly labeled cells (n = 15) had fusiform somata with two to five fine caliber primary dendrites and a predominantly mediolateral orientation of the long axis of their dendritic tree. All labeled FS cells (n = 5) had large, multipolar somata with four to nine large caliber primary dendrites. The present study defines in vivo membrane and morphological characteristics of RVM neurons that correlate with physiological differences and may be used for identification of nociceptive modulatory RVM neurons in slice preparations.

Action Potentials↗
PubMed1996

Cutaneous innervation density in the allodynic form of postherpetic neuralgia.

The relationship between deafferentation, sensory function, and pain was explored in 18 subjects with chronic postherpetic neuralgia (PHN). Subjective thresholds for warmth, cooling, and heat pain were measured quantitatively in painful skin areas and compared with normal contralateral skin. The severity of allodynia was graded in the affected area. Two 3-mm punch biopsies were taken from the most painful skin area and one from unaffected contralateral mirror-image skin. Immunofluorescence with the axonal marker PGP 9.5 revealed a reduction in density of innervation of the epidermis, the dermal-epidermal junction, and the eccrine sweat glands in PHN skin. In painful PHN skin, the reduction in innervation density was positively correlated with the magnitude of the thermal sensory deficits. However, loss of cutaneous innervation was inversely correlated with allodynia, indicating that surviving cutaneous primary afferent nociceptors that are spontaneously active and/or sensitized contribute to PHN pain and allodynia.

Aged↗
PubMed1996

Endogenous opioid-mediated inhibition of putative pain-modulating neurons in rat rostral ventromedial medulla.

The rostral ventromedial medulla is a critical relay for midbrain regions, including the periaqueductal gray and nucleus cuneiformis, that control nociception at the spinal cord. Opioid-containing neurons and terminals are concentrated in both the periaqueductal gray and the rostral ventromedial medulla in the rat. However, the function of endogenous opioid peptides within the medulla in pain modulation is unclear. In this study, bicuculline (30-50 ng) or morphine (5 micrograms) microinjected into the periaqueductal gray inhibited the tail-flick reflex and the firing of on-cells (cells that increase firing just before tail flick) in the medulla. Iontophoretically applied naloxone (20 or 30 nA), which blocked the inhibition of on-cell firing induced by iontophoresis of morphine (20 or 30 nA), consistently reduced the on-cell inhibition produced by bicuculline or morphine microinjected into the periaqueductal gray. Naloxone did not reduce the inhibition of on-cell firing induced by iontophoretically applied clonidine (10 or 20 nA), an alpha 2 adrenoceptor agonist. The firing of off-cells (cells that pause in firing just prior to tail-flick) in the medulla was increased by bicuculline applied in the periaqueductal gray and was not affected by naloxone. The present results suggest that when activation of neurons in the periaqueductal gray produces antinociception, endogenous opioid peptides are released in the rostral ventromedial medulla and selectively inhibit on-cells, which presumably have a facilitating action on spinal nociceptive transmission. This action is proposed to be critical for the behavioral antinociception induced by bicuculline or morphine in the periaqueductal gray.

Animals↗