Effect of lithium salts on neuropathological syndromes of spinal origin

Experiments on noninbred rats were made to study the influence of lithium hydroxybutyrate on two patterns of spinal cord pathology: the generalized myoclonus and painful syndrome of spinal origin. The syndromes were induced by generators of pathologically enhanced excitation in the ventral and dorsal horns of the spinal cord. The effects of lithium chloride and sodium hydroxybutyrate were examined to compare the influence of lithium (cation) and hydroxybutyrate (anion) components to elucidate the role of each of the components. Lithium hydroxybutyrate appeared more effective, since it inhibited the generator of pathologically enhanced excitation in the appropriate structures, provoking the anticonvulsant effect in myoclonus and suppressing the painful syndrome.     

Analgesia following electrostimulation of midbrain nuclei of rats with a pain syndrome of spinal origin]

The effect of electrostimulation of the mesencephalic grey matter and of the dorsal nucleus raphe on physiological pain produced by nociceptive stimulation (compression of the tail or the skin on the limb by a clamp) and on pathological pain (the pain syndrome of spinal origin) were studied in experiments on albino rats. Pathological pain was induced by creating a generator of pathologically enhanced excitation in the dorsal horn of the spinal cord by local disturbance of the inhibitory mechanisms with the aid of tetanus toxin. It was shown that electrostimulation of the indicated areas abolished both physiological and pathological pain. A conclusion was drawn that analgesia produced by electrostimulation of certain structure of the brain was connected not only with augmentation of the descending inhibition in the spinal cord as in the case of physiological pain caused by peripheral nociceptive stimulation (as shown by several authors), but also with the block of excitation at the supraspinal level. This mechanism should play a decisive role in analgesia realization in the pain syndrome of central origin, both under experimental and natural conditions.     

Effects of γ-acetylenic GABA and γ-vinyl GABA on electrically-induced spinal cord convulsions and on spinal cord GABA concentration

The effects of γ-acetylenic GABA and γ-vinyl GABA on electrically-induced spinal cord convulsions were compared to the effects of these same drugs on spinal cord GABA concentration. The data show that the effects of these two compounds on seizure activity do not correlate either positively or negatively with changes in GABA concentration. Although both drugs produced marked increases in the amount of GABA in the spinal cord, their effects on spinal cord convulsions were qualitatively different and failed to correlate temporally with alterations in GABA concentration.     

A comparison of the glutamate release inhibition and anti-allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain

The effects of treatment with the anti-convulsant agents, lamotrigine and riluzole were compared with gabapentin in a rat experimental model of neuropathic pain. Rats were treated intraperitoneally, with gabapentin (30, 100 and 300 mg/kg), lamotrigine (2, 10 and 50 mg/kg) or riluzole (6 and 12 mg/kg) prior to, and every 12 h for 4 days following chronic constriction injury (CCI) of the sciatic nerve. Mechanical and cold sensitivity were assessed prior to surgery (baseline) and then at 4, 8 and 12 days following CCI. The four-day treatment with each of the agents was effective at producing reductions in the development of mechanical and cold hypersensitivity for periods ranging from the fourth to 12th day. The highest doses of each of the agents were also assessed on formalin-induced nociceptive behaviors and on formalin-induced increases in extracellular glutamate (Glu) and aspartate (Asp) in the spinal cord dorsal horn (SCDH) of awake behaving rats using in vivo microdialysis. Nociceptive scores in formalin test were significantly decreased by gabapentin (300 mg/kg i.p.) and riluzole (12 mg/kg i.p.), but not by lamotrigine (50 mg/kg i.p.). Formalin-induced increases in glutamate levels in SCDH were lowered significantly, as compared with the controls, with all drugs both in the first phase and second phases, with the greatest effects for riluzole and gabapentin. Similar suppressive effects of the drugs were observed on formalin-induced increases in spinal aspartate, except that gabapentin and lamotrigine produced effects only during the second phase. Riluzole produced profound and prolonged reductions in the spinal levels of glutamate and aspartate both for basal and formalin-stimulated release. In conclusion, the results suggest that the anti-convulsant agents gabapentin, lamotrigine and riluzole may reduce the development of hyperalgesia in a rat model of neuropathic pain by reducing the spinal release of glutamate. Riluzole's pronounced suppressive effects on spinal EAA levels is attributed to its established role as a glutamate release inhibitor and an enhancer of glutamate transporter activity.     

Effect of myelopeptides on physiological and pathological pain

The action of bone marrow low-molecular peptides (myelopeptides) was studied in the models of physiologic and pathologic pain. Myelopeptides were demonstrated to have a pronounced analgetic effect: they increased the latent period of the rats' response in the hot plate test (physiologic pain) and suppressed severe spinal pain syndrome induced by the generator of pathologically enhanced excitation in the dorsal horn of the spinal cord (pathologic pain). In the experiments with naloxone (an opiate receptor blocker) the data on the opiate properties of myelopeptides were further substantiated. The analgetic effect of myelopeptides can be compared to that of morphine and promedol. Myelopeptides even in considerable doses did not have the side effects characteristic of the majority of opiate analgesics. Therefore, they may be recommended for clinical trials.     

Myoclonus: analysis of monoamine, GABA, and other systems

Myoclonus is a clinical term meaning a quick involuntary jerk, seen in normal subjects under certain circumstances, including sleep, and in certain disease states. It is important as a symptom that may impair function and as an indicator of neurological dysfunction. Not until patients with myoclonus and major functional disability were reported in the 1960s was attention given to understanding its basis and pharmacotherapy. Reports of myoclonus developing after anoxic brain injury, and its response to treatment with the serotonin precursor 5-hydroxytryptophan (5-HTP), drew special attention. Further experience showed that only a few patients with myoclonus benefit from 5-HTP therapy. Benzodiazepines (BDZs) are often helpful in the treatment of myoclonus. Their beneficial effects decline with chronic administration because of drug tolerance, and the theoretical basis for BDZ responses remains unclear. The relationships between myoclonus, clonus, and epilepsy are discussed, as is the possible contribution of slow signaling transmembrane receptors to synchronization of motoneuron firing, which is suggested as a hallmark of myoclonus. Myoclonus may originate in many CNS sites, but the brain-stem reticular formation is especially relevant to myoclonus. Brain-stem serotonin neurons have special influence on spinal motoneurons, on startle responses, and on myoclonus. Among 5-HT receptors, 5-HT1A receptors are related to some forms of myoclonus, although 5-HT2 receptors are also implicated. GABAA receptors are related to some forms of myoclonus. Blockade of GABAA receptors or GABA synthesis regularly evokes convulsive seizures, but administration of many GABA agonists and some GABA uptake blockers paradoxically may evoke myoclonus. Injection of GABA receptor blockers into some brain areas has anticonvulsant effects. Stimulation of GABAA receptors may therefore promote or antagonize myoclonus depending on which GABA receptors are involved, the state of the system, etc. The role of glycine receptors is well established in some animal models, but has yet to be clearly established for human myoclonus. Opiates may produce myoclonus when given intrathecally or in high dosage. The concept of excitant anesthetics and special function of certain GABA receptors is discussed.     

Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs.

OBJECTIVE--To estimate the prevalence of important side effects in patients with malignant disease who were receiving high doses of morphine as part of their palliative treatment. DESIGN--Data on patients were collected over 12 months. SETTING--Two palliative care units in Western Australia. PATIENTS--19 Patients with malignant disease who were receiving morphine either subcutaneously or orally as the main analgesic. 10 Patients receiving a total daily dose of morphine of at least 500 mg orally or 250 mg parenterally were enrolled in the study. The other 9 patients were enrolled after an important problem thought to be related to the morphine had been identified. All of the patients were taking drugs to supplement the treatment. INTERVENTIONS--The dose of morphine or route of administration, or both, was changed in three patients. MAIN OUTCOME MEASURE--Determination of the prevalence of side effects in the patients. Assessment of the relation of any side effects with the supplemental drugs taken by the patients. MAIN RESULTS--Plasma morphine and electrolyte concentrations were measured and a full history taken for each patient. Thirteen of the 19 patients had an important side effect; 12 of them had myoclonus and one had hyperalgesia of the skin. Plasma morphine concentrations were similar in patients with and without myoclonus, ranging from 158 to 3465 nmol/l and 39 to 2821 nmol/l respectively. Eight of the patients with side effects were taking an antipsychotic drug concurrently compared with none of those without side effects. A greater proportion of patients with side effects were taking the antinauseant drug thiethylperazine (6/13 v 2/6) and at least one non-steroidal anti-inflammatory drug (10/13 v 2/6), whereas a smaller proportion were taking a glucocorticosteroid (3/13 v 4/6). The estimated prevalence of important side effects in the total population of patients receiving palliative treatment in the two units was 2.7-3.6%. CONCLUSIONS--Myoclonus as a side effect of treatment with morphine is more likely to occur in patients taking antidepressant or antipsychotic drugs as antiemetics or as adjuvant agents or non-steroidal anti-inflammatory drugs for additional analgesia. If a patient develops myoclonus the best approach may be to change the supplemental treatment.     

Effect of the spinal pain syndrome on pain reactions caused by nociceptive thermal stimuli

It has been shown that the reaction of both limbs to thermal pain stimulation was suppressed during spinal pain syndrome development caused by generators of pathologically enhanced excitation (GPEE) formed in the dorsal horns of the spinal cord lumbosacral segments on one side. The analgetic effect on physiological pain was retained long after pain syndrome disappearance (48 hours), the effect was bilateral and was independent of the type of agent producing GPEE. It was shown that neuronal activity in the antinociceptive system key structure (nucleus raphe dorsal) increases. It is assumed that physiological pain relief is caused by enhanced activity in antinociceptive system structures in pain syndrome.     

Ketamine Does Not Produce Relief of Neuropathic Pain in Mice Lacking the β-Common Receptor (CD131)

Neuropathic pain (NP) is a debilitating condition associated with traumatic, metabolic, autoimmune and neurological etiologies. Although the triggers for NP are diverse, there are common underlying pathways, including activation of immune cells in the spinal cord and up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Ketamine, a well-known NDMAR antagonist, reduces neuropathic pain in a sustained manner. Recent study has shown that the novel 11-amino acid peptide erythropoietin derivative ARA290 produces a similar, long-lasting relief of NP. Here, we show that both drugs also have similar effects on the expression of mRNA of the NMDAR, as well as that of microglia, astrocytes and chemokine (C-C motif) ligand 2, all-important contributors to the development of NP. Although the effects of ketamine and ARA 290 on NP and its molecular mediators suggest a common mechanism of action, ARA 290 has no affinity for the NMDAR and acts specifically via the innate repair receptor (IRR) involved in tissue protection. We speculated therefore, that the IRR might be critically involved in the action of ketamine on neuropathic pain. To evaluate this, we studied the effects of ketamine and ARA 290 on acute pain, side effects, and allodynia following a spared nerve injury model in mice lacking the β-common receptor (βcR), a structural component of the IRR. Ketamine (50 mg/kg) and ARA 290 (30 µg/kg) produced divergent effects on acute pain: ketamine produced profound antinociception accompanied with psychomotor side effects, but ARA290 did not, in both normal and knock out mice. In contrast, while both drugs were antiallodynic in WT mice, they had no effect on NP in mice lacking the βcR. Together, these results show that an intact IRR is required for the effective treatment of NP with either ketamine or ARA 290, but is not involved in ketamine’s analgesic and side effects.     

The effects of intraspinal L-NOARG or SIN-1 on the control by descending pathways of incisional pain in rats

The modulation by spinal nitric oxide (NO) of descending pathways travelling through the dorsal lateral funiculus (DLF) is a mechanism proposed for the antinociceptive effects of drugs that changes the NO metabolism. In this study we confirm that a surgical incision in the mid-plantar hind paw of rats reduces the threshold to mechanical stimulation with von Frey filaments. The incisional pain was further increased in rats with ipsilateral DLF lesion. Intrathecal L-NOARG (50-300 microg), or SIN-1 (0.1-5.0 microg) reduced, while SIN-1 (10 and 20 microg) intensified the incisional pain in rats with sham or effective lesion of the DLF. Stimulation of the dorsal raphe (DRN) or anterior pretectal (APtN) nuclei with stepwise increased electrical currents (7, 14, 21, 28 and 35 microA r.m.s.) produced a current-related reduction of the incisional pain. These nuclei activate pain inhibitory pathways that descend to the spinal cord mainly through the DLF. Intrathecal SIN-1 (5 microg) reduced, SIN-1 (20 microg) decreased and L-NOARG (150 microg) did not change the EC50 for the DRN or APtN stimulation-induced reduction of incisional pain. We conclude that the antinociceptive effects of L-NOARG or low doses of SIN-1 are independent on the activity of descending pain control pathways travelling via the DLF, but the antinociceptive effect of stimulating electrically the DRN or APtN can be summated to the effect of low dose of SIN-1 or overcome by the high dose of SIN-1.     

Relief of dental pain by ice massage of the hand.

Patients suffering from acute dental pain were treated with ice massage of the web between the thumb and index finger of the hand on the same side as the painful region. Control groups received tactile massage alone or with explicit suggestion that the massage was intended to alleviate their pain. Changes in pain intensity produced by the procedures were measured with the McGill Pain Questionnaire. Ice massage decreased the intensity of the dental pain by 50% or more in the majority of patients. Furthermore, the pain reductions produced by ice massage were significantly larger than those produced by tactile massage alone or with explicit suggestion. The results indicate that ice massage has pain-reducing effects comparable to those of transcutaneous electrical stimulation and acupuncture. The fact that cold signals are transmitted to the spinal cord exclusively by A-delta fibres and not by C fibres provides a potential method for differentiating the various feedback systems that mediate analgesia produced by different forms of intense sensory input. Ice massage provides a simple method for the palliative control of pain in dental clinics.     

A Single Intrathecal or Intraperitoneal Injection of CB2 Receptor Agonist Attenuates Bone Cancer Pain and Induces a Time-Dependent Modification of GRK2

The objective of this study was to explore the potential role of G-protein-coupled receptor kinase 2 (GRK2) in the progression of cannabinoid 2 receptor (CB2) agonist-induced analgesic effects of bone cancer pain. Female Sprague–Dawley rats, weighing 160–180 g, were utilized to establish a model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. JWH-015, a selective CB2 agonist, was injected intrathecally or intraperitoneally on postoperative day 10. Bone cancer-induced pain behaviors—mechanical allodynia and ambulatory pain—were assessed on postoperative days ?1 (baseline), 4, 7, and 10 and at post-treatment hours 2, 6, 24, 48, and 72. The expressions of spinal CB2 and GRK2 protein were detected by Western Blotting on postoperative days ?1 (baseline), 4, 7, and 10 and at post-treatment hours 6, 24, and 72. The procedure produced prolonged mechanical allodynia, ambulatory pain, and different changes in spinal CB2 and GRK2 expression levels. Intrathecal or intraperitoneal administration of JWH-015 alleviated the induced mechanical allodynia and ambulatory pain, and inhibited the downregulation of spinal GRK2 expression. These effects were in a time-dependent manner and reversed by pretreatment of CB2 selective antagonist AM630. The results affirmed CB2 receptor agonists might serve as new treatment targets for bone cancer pain. Moreover, spinal GRK2 was an important regulator of CB2 receptor agonist-analgesia pathway.     

Abnormal oscillatory synchronisation in the motor system leads to impaired movement

Converging data suggest that abnormal synchronised oscillatory activity in the basal ganglia may contribute to bradykinesia in patients with Parkinson's disease. This synchrony preferentially occurs over 10-30 Hz, the so-called beta band. Correlative evidence has been supplemented by experiments in which direct stimulation of the basal ganglia in the beta band slows movement. Yet questions remain regarding the small scale of the latter effects and whether synchrony is an early or even obligatory feature of parkinsonism. Nevertheless, the principle that abnormally synchronised activity in the beta band can disrupt the function finds a precedent in the syndrome of cortical myoclonus. Here, pathologically synchronised discharges of pyramidal neurons are transmitted to the healthy spinal cord. The result is the synchronous discharge of motor units leading to rhythmic jerking.     

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

Although pain is regarded traditionally as neuronally mediated, recent progress shows an important role of spinal glial cells in persistent pain sensitization. Mounting evidence has implicated spinal microglia in the development of chronic pain (e.g. neuropathic pain after peripheral nerve injury). Less is known about the role of astrocytes in pain regulation. However, astrocytes have very close contact with synapses and maintain homeostasis in the extracellular environment. In this review, we provide evidence to support a role of spinal astrocytes in maintaining chronic pain. In particular, c-Jun N-terminal kinase (JNK) is activated persistently in spinal astrocytes in a neuropathic pain condition produced by spinal nerve ligation. This activation is required for the maintenance of neuropathic pain because spinal infusion of JNK inhibitors can reverse mechanical allodynia, a major symptom of neuropathic pain. Further study reveals that JNK is activated strongly in astrocytes by basic fibroblast growth factor (bFGF), an astroglial activator. Intrathecal infusion of bFGF also produces persistent mechanical allodynia. After peripheral nerve injury, bFGF might be produced by primary sensory neurons and spinal astrocytes because nerve injury produces robust bFGF upregulation in both cell types. Therefore, the bFGF/JNK pathway is an important signalling pathway in spinal astrocytes for chronic pain sensitization. Investigation of signaling mechanisms in spinal astrocytes will identify new molecular targets for the management of chronic pain.     

An experimental model of deafferented pain in the cat

Deafferentation hyperactivity, produced unilaterally in the neurons of the subnucleus caudalis of the spinal trigeminal nucleus (STNcd) in cats by left Gasserian ganglionectomy, was studied neurochemically and electrophysiologically. Analysis of neuronal activities on both sides of the STNcd was done 11-63 days after the denervation. On the denervated side, 37 (57%) of the 65 neurons identified showed deafferentation hyperactivity. Continuous and spontaneous firing of these hyperactive neurons were inhibited neither by the intraventricular administration of morphine or enkephalinamide nor by the electrical stimulation of periaqueductal gray. In contrast, the facilitation of the pain perceptive neuronal activities in the STNcd of the nondenervated side was remarkably inhibited, both by the administration of the same drugs and by periaqueductal gray stimulation. The deafferentation hyperactivity produced in this experiment in the STNcd of the denervated side might have a close physiological relationship to the deafferented pain of clinical patients.     

Antinociceptive action of intrathecal neurotensin in mice

Neurotensin has been demonstrated to be analgesic in rodents. This study used intrathecal injection of neurotensin in unanesthetized mice to evaluate the effect of the peptide at the spinal level on unconditioned behavior. Intrathecal administration of neurotensin produced dose-related inhibition of locomotor activity and of the response elicited by subcutaneous hypertonic saline. The effects of the peptide in the tail flick assay were variable and it produced no inhibition of the behavioral response to intrathecal substance P. The results indicate that neurotensin antinociception at the spinal level does not result from locomotor impairment, may be somewhat selective for chemically induced pain, and may be mediated by a presynaptic action on primary afferent fibers.     

Contributions of spinal d-amino acid oxidase to bone cancer pain

d-Amino acid oxidase (DAAO), a FAD-dependent peroxisomal flavoenzyme that catalyzes oxidation of d-amino acids to hydrogen peroxide, is distributed in the spinal cord almost exclusively expressed within astrocytes. The present study aims to explore potential contributions of spinal DAAO to the development of bone cancer pain and morphine tolerance to analgesia. Tibia inoculation of carcinoma cells produced mechanical allodynia (but not heat hyperalgesia), in synchronous with induction of DAAO expression and DAAO enzymatic activity, as well as activation of spinal astrocytes marked by GFAP. Subcutaneous and intrathecal injection of the specific DAAO inhibitor CBIO (5-chloro-benzo[d]isoxazol-3-ol) blocked mechanical allodynia in a dose- and time-dependent manner in tumor-bearing rats, with maximum inhibition of 40–50?%. Multi-daily intrathecal injections of the DAAO gene silencer siRNA/DAAO also yielded anti-allodynic effects by approximately 40?% and the analgesia remained for at least 6?days. Subcutaneous injection of CBIO suppressed the production of spinal hydrogen peroxide and GFAP expression.?7-Day multiple bi-daily injections of CBIO produced anti-allodynia without inducing self-tolerance to analgesia or cross-tolerance to morphine, and concurrent injections of CBIO with morphine produced apparent additive anti-allodynia and completely prevented morphine tolerance in behaviors and spinal expression of μ-opioid receptors. Our results provide the first evidence that spinal DAAO contributes to the development of morphine tolerance to analgesia and bone cancer pain accounting for 40–50?% pain status, probably via production of hydrogen peroxide leading to activation of astrocytes. The unique characterizations of DAAO inhibitors make them a potential for the treatment of cancer pain when they are administered alone or in combination with morphine.     

TNS-evoked long loop effects.

Local analgesia can be produced by transcutaneous electrical stimulation of peripheral nerves. This is used in the treatment of chronic pain states. Its clinical effectiveness depends on two points; namely (1) the stimulation has to be perceptible, and (2) paresthesias elicited by TNS must be localized in the area of pain. To verify this in healthy subjects we produced an experimental pain by radiant heating of the skin and tested the analgesic effect of TNS. TNS stimuli parameters (duration, amplitude and frequency) were determined so that double blind conditions were given. Stimulation with small rectangular pulses showed the best analgesic effect especially at a stimulation rate of 100 Hz. The stimulation of various nerves showed that most of the analgesic effects depend on spinal level mechanisms but probably long loop effects are involved.     

多次100Hz TENS治疗慢性炎症痛的适宜参数和可能的神经化学机制研究

本工作在单发佐剂性关节炎慢性痛模型大鼠上比较观察了不同时间间隔和不同强度的多次１００Ｈｚ经皮神经电刺激（ＴＥＮＳ）的治疗效果,并对炎症和ＴＥＮＳ过程中Ｐ物质（ＳＰ）和强啡肽的变化规律及其作用进行了初步探讨。     

Induction of pain facilitation by sustained opioid exposure: relationship to opioid antinociceptive tolerance

Opioid analgesics are frequently used for the long-term management of chronic pain states, including cancer pain. The prolonged use of opioids is associated with a requirement for increasing doses to manage pain at a consistent level, reflecting the phenomenon of analgesic tolerance. It is now becoming clearer that patients receiving long-term opioid therapy can develop unexpected abnormal pain. Such paradoxical opioid-induced pain, as well as tolerance to the antinociceptive actions of opioids, has been reliably measured in animals during the period of continuous opioid delivery. Several recent studies have demonstrated that such pain may be secondary to neuroplastic changes that result, in part, from an activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM). One mechanism which may mediate such pain facilitation is through the increased activity of CCK in the RVM. Secondary consequences from descending facilitation may be produced. For example, opioid-induced upregulation of spinal dynorphin levels seem to depend on intact descending pathways from the RVM reflecting spinal neuroplasticity secondary to changes at supraspinal levels. Increased expression of spinal dynorphin reflects a trophic action of sustained opioid exposure which promotes an increased pain state. Spinal dynorphin may promote pain, in part, by enhancing the evoked release of excitatory transmitters from primary afferents. In this regard, opioids also produce trophic actions by increasing CGRP expression in the dorsal root ganglia. Increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance as manipulations which block abnormal pain also block antinociceptive tolerance. Manipulations that have blocked enhanced pain and antinociceptive tolerance include reversible and permanent ablation of descending facilitation from the RVM. Thus, opioids elicit systems-level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin and enhanced release of excitatory transmitters from primary afferents. Adaptive changes produced by sustained opioid exposure including trophic effects to enhance pain transmitters suggest the need for careful evaluation of the consequences of long-term opioid administration to patients.