Supraspinal modulation of neuronal synchronization by nociceptive stimulation induces an enduring reorganization of dorsal horn neuronal connectivity.

KEY POINTS: The state of central sensitization induced by the intradermic injection of capsaicin leads to structured (non-random) changes in functional connectivity between dorsal horn neuronal populations distributed along the spinal lumbar segments in anaesthetized cats. The capsaicin-induced changes in neuronal connectivity and the concurrent increase in secondary hyperalgesia are transiently reversed by the systemic administration of small doses of lidocaine, a clinically effective procedure to treat neuropathic pain. The effects of both capsaicin and lidocaine are greatly attenuated in spinalized preparations, showing that supraspinal influences play a significant role in the shaping of nociceptive-induced changes in dorsal horn functional neuronal connectivity. We conclude that changes in functional connectivity between segmental populations of dorsal horn neurones induced by capsaicin and lidocaine result from a cooperative adaptive interaction between supraspinal and spinal neuronal networks, a process that may have a relevant role in the pathogenesis of chronic pain and analgesia. ABSTRACT: Despite a profusion of information on the molecular and cellular mechanisms involved in the central sensitization produced by intense nociceptive stimulation, the changes in the patterns of functional connectivity between spinal neurones associated with the development of secondary hyperalgesia and allodynia remain largely unknown. Here we show that the state of central sensitization produced by the intradermal injection of capsaicin is associated with structured transformations in neuronal synchronization that lead to an enduring reorganization of the functional connectivity within a segmentally distributed ensemble of dorsal horn neurones. These changes are transiently reversed by the systemic administration of small doses of lidocaine, a clinically effective procedure to treat neuropathic pain. Lidocaine also reduces the capsaicin-induced facilitation of the spinal responses evoked by weak mechanical stimulation of the skin in the region of secondary but not primary hyperalgesia. The effects of both intradermic capsaicin and systemic lidocaine on the segmental correlation and coherence between ongoing cord dorsum potentials and on the responses evoked by tactile stimulation in the region of secondary hyperalgesia are greatly attenuated in spinalized preparations, showing that supraspinal influences are involved in the reorganization of the nociceptive-induced structured patterns of dorsal horn neuronal connectivity. We conclude that the structured reorganization of the functional connectivity between the dorsal horn neurones induced by capsaicin nociceptive stimulation results from cooperative interactions between supraspinal and spinal networks, a process that may have a relevant role in the shaping of the spinal state in the pathogenesis of chronic pain and analgesia.

Painless electrodiagnostic current perception threshold and pain tolerance threshold values in CRPS subjects and healthy controls: a multicenter study.

The purpose of this study is to evaluate both painless and painful sensory transmission in patients with Complex Regional Pain Syndrome (CRPS) using the automated electrodiagnostic sensory Nerve Conduction Threshold (sNCT) test. This test generates reliable, painless Current Perception Threshold (CPT) and atraumatic Pain Tolerance Threshold (PTT) measures. Standardized CPT and PTT measures using constant alternating current sinusoid waveform stimulus at 3 different frequencies 5 Hz, 250 Hz, and 2 kHz (Neurometer CPT/C Neurotron, Inc. Baltimore, MD) were obtained from CRPS subjects at a distal phalange of the affected extremity and at an ipsilateral asymptomatic control site. Matched sites were tested on healthy subjects. Detection sensitivities for an abnormal PTT and CPT test were calculated based on specificity of 90% as determined from data obtained from healthy controls. A Spearman rank correlation was used to test for a significant association between presence of allodynia and an abnormal PTT or CPT at any frequency tested. Thirty-six CRPS subjects and 57 healthy controls were tested. The highest detection sensitivity of the PTT test from symptomatic test sites was 63% for the finger and 71% for the toe. PTT abnormalities were also detected, to a lesser degree, at the asymptomatic control site (41% finger control site, 16% toe control site). The highest CPT detection sensitivity at the symptomatic site was 37% for the finger site and 53% for the toe site. CPT abnormalities were also detected at the asymptomatic control site (29% finger control site, 37% toe control site). Eighty-six percent of the CRPS subjects had either a PTT or CPT abnormality at any frequency at the symptomatic site. There was a significant correlation between presence of allodynia and presence of an abnormal CPT and PTT, respectively (P < .01). The correlation coefficient was lower for CPT than for PTT, ie, 0.34 versus 0.6 for the finger and 0.48 versus 0.67 for the toe, respectively. In studied CRPS patients an abnormal PTT was detected with higher sensitivity than an abnormal CPT. Assessing PTT may become a useful electrodiagnostic quantitative sensory test for diagnosing and following the course of neuropathic pain conditions.

Acute lower extremity paralysis following radiation therapy for cervical cancer.

BACKGROUND: Acute lower extremity paralysis secondary to lumbosacral plexopathy is a rare but severe complication that may follow pelvic radiotherapy for cervical cancer. CASE: A 49-year-old female with newly diagnosed stage IIIB cervical cancer developed progressive bilateral lower extremity paralysis and pelvic pain only 10 weeks following completion of radiation therapy for cervical cancer with no evidence of metastasis or progression of disease. Her bladder and bowel function were not affected. Following extensive workup, the most likely etiology was presumed radiation-induced lumbosacral plexopathy. CONCLUSION: Although metastatic carcinoma is more commonly the reason for progressive lower extremity weakness with pelvic pain in women with advanced cervical cancer, radiation-induced lumbosacral plexopathy, a rare but devastating complication, may be the cause. Diagnosis is by exclusion.

Halothane myocardial depression: interactions with the adenylate cyclase system.

The involvement of the adenylate cyclase system in myocardial depression by halothane was investigated in an isolated, electrically stimulated, rat left atrial preparation. The twitch tension dose-response curve to the muscarinic agent, carbachol, was unaltered by 0.27 mM (0.8%) halothane. Pertussis toxin irreversibly blocks the inhibition of adenylate cyclase by muscarinic agonists. Atria from animals pretreated with pertussis toxin were insensitive to the negative inotropic effect of carbachol, but the depression in twitch tension by halothane was unaltered. Halothane shifted the dose-response curve to isoproterenol downward and to the right. However, the depression in twitch tension by 0.27 mM halothane was similar in preparations incubated with the nonhydrolyzable cAMP analogue, dibutyryl-cAMP, compared to control atria stimulated with isoproterenol. We conclude that halothane attenuates the response to beta-adrenergic stimulation in myocardial tissue, and alterations in adenylate cyclase activity do not contribute significantly to this process.

Changes in Müller cell plasma membrane specializations during subretinal scar formation in the rabbit.

The aim of this study was to identify changes in Müller cell plasma membrane specializations during experimentally induced subretinal gliosis in rabbits. When rabbits are dosed with sodium iodate, large expanses of retinal pigment epithelium and photoreceptors are destroyed. They are replaced by a subretinal scar consisting mainly of the ascending processes of Müller cells. These processes transform from the slender, highly polarized structures seen in normal animals into irregular processes that form a glia limitans along the basement membrane of the pigment epithelium, left bare following its degeneration. As the scar processes extend through the subretinal space and contract this basement membrane, they undergo dramatic changes in shape that are especially apparent in three-dimensional computer reconstructions of serial thick sections examined by high-voltage electron microscopy. Other changes involve the intercellular junctions and apical microvilli normally associated with the external limiting membrane. These structures become scattered over the surfaces of the ascending processes and are eventually lost. Loss of microvilli is associated with disappearance of immunostaining for a specific glycoconjugate normally associated with the microvillar plasma membrane. The observations document profound changes in Müller cell structural and functional polarity during subretinal scar formation.

Electrophysiology of ganglionic transmission in the sympathetic nervous system.

The sympathetic nervous system contributes to the regulation and control of a great number of body functions. A considerable fraction of preganglionic fibers are constantly discharging nerve impulses, and this tonic activity is responsible for a number of sustained bodily conditions. These tonic sympathetic discharges are of central origin and may be decreased by inhibition or augmented by excitation of the central neural mechanisms in control of the relevant preganglionic neurons. Certain other sympathetic paths become active only when special conditions lead to excitation of their central connections. The effect of the activity of preganglionic fibers on the different target organs, however, does not depend entirely on central regulatory influences. The sympathetic ganglia play a significant role processing and integrating the information arriving from the central nervous system and controlling the output to the target organs. In this context, the different potentials described above constitute the basis for the integrative process to occur. We now have substantial information about the basic biophysical events associated with different electrical events in the sympathetic ganglia. Very little is known, however, about how they operate in an integrative manner to control specific functions. The control of sympathetic responses during surgical stimulation is an important goal of general anesthesia. General anesthetics may operate to produce this effect at both central and peripheral levels. The sympathetic ganglion as a peripheral synapse, with basic integrative properties similar to the complex central nervous system, is a model still not sufficiently exploited to understand mechanisms by which general anesthetics control sympathetic response. The relevance of the findings described above in a variety of clinical situations, such as stress, hypertension, exercise, and anesthesia, remains to be studied.

Subacute sensory neuronopathy secondary to dorsal root ganglionitis in primary Sjögren's syndrome.

Sensory neuropathies, particularly trigeminal neuropathy, have been recognized as neurological complications of Sjögren's syndrome, but the pathogenesis has not been established. We describe a woman with primary Sjögren's syndrome who developed a progressive debilitating subacute sensory neuronopathy. Results of electrophysiological studies were consistent with involvement of the trigeminal and dorsal root ganglia. A thoracic dorsal root ganglion biopsy showed lymphocytic infiltration and degeneration of ganglion cells. We believe that this is the first description of biopsy-documented dorsal root ganglionitis in a subacute sensory neuronopathy associated with Sjögren's syndrome and that the finding suggests an immunopathogenic basis.

Multicentric reticulohistiocytosis and Sjögren's syndrome.

A 66-year-old man with an 18-year history of cutaneous multicentric reticulohistiocytosis (MRH) developed a chronic destructive symmetrical arthritis and xerostomia. Biopsies of synovium and minor salivary glands established a diagnosis of MRH polyarthritis and lymphocytic infiltrative Sjögren's syndrome, respectively. Anti-Ro(SSA) antibody was present. Hypothyroidism was also identified. This report of Sjögren's syndrome in MRH may enlarge the spectrum of autoimmune diseases associated with MRH.

The action of serotonin on excitatory nerve terminals in lobster nerve-muscle preparations.

1. The action of serotonin on excitatory transmission in the opener muscle of the dactyl of the lobster walking leg was examined by intracellular recording techniques. 2. Serotonin, at concentrations as low as 5 x 10(-9) M, caused a sustained increase in the size of the excitatory junctional (synaptic) potential (e.j.p.). When serotonin was washed out of the bath the e.j.p. declined in two steps (T 1/2 approximately equal to 1-2 min; T 1/2 approximately equal to 30 min) to the control size. The increased e.j.p. size was predominantly due to a serotonin-induced increase in the release of quanta of excitatory transmitter with nerve stimulation. 3. The increase in transmitter release did not require nerve stimulation or the presence of Na+ or Ca2+ ions in the bathing medium during the period of serotonin treatment. 4. Three types of experiments suggested that a part of the action of serotonin on excitatory nerve terminals might involve a long-term metabolic change within terminals, possibly involving the buffering or storage of Ca2+ ions. First, serotonin increased the frequency of spontaneous release of transmitter in both normal saline (26 mM-Ca2+) and saline with very low levels of Ca2+ (less than 10(-8) M). Secondly, serotonin greatly potentiated increases in miniature excitatory junctional potential frequency induced by the loading of the nerve terminal with Na+ either by veratridine or by inhibition of the Na+ pump or by the addition of the Na-ionophore monensin in low-Ca2+ salines. Thirdly, in some experiments, serotonin treatment produced a partial restoration of the nerve-evoked release of transmitter in the low-Ca2+ medium (less than 10(-8) M).

Noradrenaline augments tetanic potentiation of transmitter release by a calcium dependent process.

Noradrenaline (25 microM-50 microM) causes an increase in tetanic potentiation and in the augmentation phase of posttetanic potentiation of miniature and plate potential frequency. These effects were observed at both the frog and the rat neuromuscular junctions. The action of noradrenaline on quantal transmitter release depends on the presence of calcium ions in the extracellular medium.

The filum terminale of the frog spinal cord, a nontransformed glial preparation: II. Uptake of serotonin.

The uptake of 5-HT was measured in the frog filum terminale (FT), a preparation composed almost exclusively of normal glia. [3H]5-HT was taken up by the FT via a high-affinity, sodium-dependent, temperature-sensitive transport system having a Km of 0.7 microM. In addition, a variety of drugs and aromatic amines known to selectively inhibit 5-HT uptake by synaptosomes and brain slices affected the uptake of 5-HT by the FT in qualitatively similar manner. The FT was shown to accumulate [3H]5-HT at rates significantly greater than the lumbar enlargement which contains both neurons and glia. The glial accumulation of 5-HT by the FT was verified by autoradiography. These findings strongly support the suggestion that glia may modulate aminergic transmission by competing with neurons for the reuptake of neuronally released amines.

Amines and a peptide as neurohormones in lobsters: actions on neuromuscular preparations and preliminary behavioural studies.

In this communication we report that four substances, thought to function as neurohormones in Crustacea, all produce long-term changes in the physiological properties of lobster opener muscle preparations. The substances are the amines, octopamine, serotonin and dopamine, and the peptide, proctolin. The actions of these substances are superimposed on the normal synaptic apparatus that utilizes the amino acids GABA and glutamate (probably) as the inhibitory and excitatory neurotransmitter compounds. Serotonin acts on excitatory and inhibitory nerve endings to facilitate transmitter release and directly on muscle fibres to produce a contracture and to induce the appearance of Ca2+ action potentials. The latter two actions of serotonin are shared by proctolin and octopamine as well. Dopamine, on the other hand, relaxes muscle baseline tension. The mechanism of action of these substances at their target site (or sites) has been explored with electrophysiological and biochemical techniques and the results will be presented. In addition preliminary behavioural experiments have been carried out with serotonin and octopamine. These substances produce opposite postures when injected into lobsters. The amines act on central ganglia to produce these effects where they cause a programmed readout of firing of neurones that will produce either a flexed posture (serotonin) or an extended posture (octopamine).

A peptide action in a lobster neuromuscular preparation.

The neuropeptide proctolin causes a sustained contraction of the opener muscle of the dactyl of the lobster walking leg. This substance acts directly on the muscle at concentrations as low as 10(-10)M. The contraction is dependent on extracellular calcium. Neither a significant depolarization nor a detectable change in the input resistance accompanies the response. No presynaptic action of proctolin is indicated; excitatory and inhibitory junctional potential sizes and the frequency of spontaneous miniature excitatory junctional potentials are unaffected.

Primary afferent depolarization. Distribution of the gamma-aminobutyric acid system in frog spinal cord.

In the frog spinal cord primary afferent depolarization (PAD) constitutes a powerful inhibitory control mechanism. It has been suggested that gamma-aminobutyric acid (GABA) is the transmitter substance involved in the genesis of PAD. In these studies we show that maximal glutamic acid decarboxylase activity is localized roughly 400-600 micrometers from the dorsal surface, and that correlates well with the intraspinal distribution of field potentials associated with PAD. Measurements of GABA in serial spinal cord sections cut in a dorsal--ventral direction shows that high levels of GABA are seen at 400--600 micrometers, with a peak at 800 micrometers from the dorsal surface. Stimulation at frequencies shown to produce PAD augments the release of endogenous GABA from a superfused frog hemicord preparation.

The filum terminale of the frog spinal cord, a non transformed preparation: I. Morphology and uptake of gamma-aminobutyric acid.

The filum terminale of the frog spinal cord is a rather pure glial cell preparation, largely devoid of neuronal elements. gamma-Aminobutyric acid (GABA) is taken up by the frog filum terminale (FT) via a Na+-dependent, ouabain-inhibited, saturable high affinity transport system with a Km of 2.7 x 10(5) M. The rate of the FT GABA uptake is significantly greater than the velocities observed in the spinal cord. In fact, the Vmax increases caudally beyond the level of the last root, and is maximal in the FT per se. beta-Alanine is a competitive inhibitor of the FT high affinity transport system for GABA (Ki 11.1 x 10(-5) M). In addition to GABA, the FT also takes up beta-alanine, glycine, glutamate and aspartate at rates significantly higher than those shown by the spinal cord of the frog. Light and electron microscope level radioautography clearly shows that GABA uptake occurs primarily in the glial cells and also in ependymal cells present in the FT. In that the FT contains few ependymal cells and a large number of glia, it is fair to state that most of the GABA accumulated by the FT reflects the glial transport of this amino acid. Unlike the adult frog, the spinal cord of the tadpole does not show any regional differences in the rate of GABA transport during early development. However, during later developmental stages, the rates of GABA transport increase in the caudal portion of the tadpole cord as compared to the more rostral areas. Close to metamorphosis, the terminal portion of the tadpole cord, which is destined to become the filum terminals of the frog, accumulates GABA at rates not greatly different from those observed in the FT of the adult frog. Therefore, the tadpole spinal cord is a useful preparation in which to study the dynamic properties of normal non-transformed glia as influenced by a changing neuronal population, whereas the frog FT is a unique preparation for the study of some properties of normal glia largely in the absence of neurons.

The filum terminale of the frog spinal cord. Light and electron microscopic observations.

The filum terminale, or terminal portion of the spinal cord, was studied in normal adult frogs (Rana pipiens) bu means of light and electron microscopy. Astroglial cells are the predominant elements in this region. The rostral portion of the filum terminale consists mainly of (1) a peripheral dense ring of myelinated and some unmyelinated nerve fibers, and processes of astrobytes terminating at the subpial space; (2) an intermediate zone, in which astrocytes are the main cellular elements in addition to a few degenerated neurons; and (3) a central region where the central canal is lined by dark and light ependymal cells. In the caudal portion of the filum terminale, the amount of neuropil is greatly reduced. This region os formed mainly by astrocytic glial cells and very few neuronal elements. The central canal in the caudal portion is located ventrally and contains a lining consisting almost exclusively of dark ependymal cells.

Fibrous myopathy. A rheumatic complication of drug abuse.

A progressive fibrous myopathy may result from chronic intramuscular drug abuse. This complication may mimic other rheumatic disorders and early recognition may prevent disability. The patient described here presented with fixed flexion and extension contracture of hips and knees, respectively, after abusing meperidine and other agents for 3 years. Soft tissues of thighs and buttocks were "wood hard," EMG showed absence of action potentials in affected muscles, and biopsy revealed extensive replacement of muscle with dense, acellular fibrous tissue. Possible mechanisms are discussed.

Ultrastructural observations in the frog spinal cord in relation to the generation of primary afferent depolarization.

The spatial distribution of different types of synaptic boutons over the motoneuron cell body and dendrites was studied both in the normal and in the chronically deafferented frog spinal cord. In both preparations, endings with S-type (spherical) vesicles were more numerous than those with F (flat) vesicles, the S F synapse ratio being approximately constant when measured at the soma, the proximal dendrites or the fine dendrites. However, the proportion of S boutons, as well as the proportion of degenerated boutons of afferent fibers in close apposition with other boutons, was higher on the fine dendrites in the lateral neuropile than on the motoneuron cell body and proximal dendrites, and in all cases significantly higher than the proportion of F boutons showing close appositions with other boutons. Degenerated boutons from descending fibers were found to synapse over the motoneuron cell body and proximal dendrites, but these boutons were rarely seen to be closely apposed to other boutons. The possible relation of these findings to the mechanisms generating primary afferent depolarization is discussed.