Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α<Subscript>2</Subscript>δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

The α₂δ-1 subunit of the voltage-gated Ca²⁺ channel (VGCC) is a molecular target of gabapentin (GBP), which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the α₂δ-1 subunit to the presynaptic membrane, resulting in decreased neurotransmitter release. We previously showed that GBP has an anti-allodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated administration in a rat model of central post-stroke pain (CPSP) hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the α₂δ-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the α₂δ-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of α₂δ-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the α₂δ-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor α₂δ-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.     

Late-onset thermal hypersensitivity after focal ischemic thalamic infarcts as a model for central post-stroke pain in rats

Central post-stroke pain (CPSP) is a neuropathic pain syndrome that often develops in a delayed manner after thalamic stroke. Here, we describe a new model of CPSP by stereotaxic thalamic injection of endothelin-1. Stroke rats (n=12), but not saline-injected controls (n=12), developed a progressive, contralateral cutaneous thermal hyperalgesia over 4 weeks, without motor deficits. Lesions were highly focal and mainly affected the ventral posterior thalamic complex. Tchis model reproduces the infarct location and delayed hypersensitivity typical of CPSP, and may be useful to investigate its pathophysiology and test therapies targeting recovery and pain after thalamic stroke.     

Electrical Thalamic Stimulation in the Anterior Part of the Ventral Posterolateral Nucleus for the Treatment of Patients With Central Poststroke Pain

ObjectivesThe effects of thalamic stimulation of the anterior part of the ventral posterolateral nucleus (VPLa) for central poststroke pain (CPSP) and the pain-related electrophysiological characteristics of this structure were investigated.Materials and MethodsNine patients with CPSP manifesting as hemibody pain were enrolled. Stereotactic thalamic VPLa stimulation was implemented, and intraoperative electrophysiological studies on hyperactive and unstable discharges (HUDs) and responses to sensory and electrical stimulation were performed in the sensory thalamus. A preoperative somatosensory-evoked potential (SEP) study was carried out in all nine patients and in eight other patients with localized pain.ResultsThe patients were classified into two groups: a HUD-dominant group (group H, n = 5) and a sensory response-dominant group (group R, n = 4). HUDs were frequently encountered in the thalamic VPLa in the former group. The total number of HUDs and the number along the trajectory to the VPLa in group H were significantly larger than those in group R. The improvements on the pain numeric rating scale in group H were significantly higher than those in group R two years after surgery. The amplitude ratio of the SEP N20s in the ipsilateral to the contralateral side of CVD lesion in the study group was significantly lower than in the localized pain group.ConclusionsAdequate and stable pain relief with thalamic VPLa stimulation is obtainable in patients with CPSP who exhibit hyperactivity and electrical instability along the trajectory to this nucleus. Both responders and nonresponders were found to have severe dysfunction of the lemniscal system.     

脑卒中后中枢性疼痛

脑卒中后中枢性疼痛（CPSP）是脑卒中后与病灶有关的、在瘫痪躯体的一部分、持续或间断的及同时伴有感觉异常为主要特点的疼痛。由于临床医生对CPSP重视不足,导致患者长期处于疼痛状态,影响日常生活质量。为更好了解CPSP,本文就其流行病学、病理生理、临床特点及药物治疗做一综述。     

Thalamic stroke: correlation of clinical symptoms, somatosensory evoked potentials, and CT findings

We studied 18 patients with a single ischemic thalamic lesion, who had somatosensory disturbances and/or central pain in the opposite hemibody, by correlating their clinical symptoms, somatosensory evoked potentials (SEPs), and computed tomography (CT) findings. Patients were divided into three groups: (1) those with somatosensory deficits, central pain, and abnormal SEPs, which comprised two thirds of the patients (classic thalamic pain syndrome), (2) those with somatosensory deficits, no central pain, and abnormal SEPs (analgetic thalamic syndrome), and (3) those with almost normal sense perception, central pain, and normal SEPs (pure algetic thalamic syndrome). CT evidence of a paramedian or anterolateral thalamic lesion might be an indicator for the development of central pain, because these types of infarctions occurred only in patients with the classic thalamic syndrome or the pure algetic thalamic syndrome. The differentiation of the thalamic syndrome into three subtypes is of prognostic value, because patients with a loss of cortical SEPs and a posterolateral ischemic thalamic lesion on the CT scan probably will not exhibit central pain.     

Systemic gabapentin and S(+)-3-isobutyl-γ-aminobutyric acid block secondary hyperalgesia

Gabapentin (GBP) and S(+)-3-isobutyl-γ-aminobutyric acid (IBG) are anticonvulsant agents which are effective against many clinical and experimental neuropathic pain states. We examined the efficacy of these agents in a new rat model of secondary mechanical hyperalgesia generated by a mild thermal injury. Under brief halothane anesthesia, an injury was induced by applying one heel to a hot surface (52.5°C) for 45 s. GBP, IBG or saline was injected i.p. just prior to the injury. Mean mechanical withdrawal threshold (MWT) was determined using von Frey hairs before and at 30 min intervals for 3 h following the injury. MWT outside the injury area decreased post-injury (secondary hyperalgesia, allodynia), but primary (site of injury) mechanical hyperalgesia was not observed. Secondary hyperalgesia exhibited a tendency toward recovery over time. Time to onset of the anti-allodynic effect of GBP was 30–60 min. The minimum effective GBP dose was 100 mg/kg; 300 mg/kg GBP totally inhibited the drop in MWT, but was accompanied by pronounced sedation. Anti-allodynic effects of IBG were apparent at the first post-injury measure of MWT (30 min). Thirty milligrams per kilogram was the minimum effective dose; 100 mg/kg IBG totally blocked the allodynia with minimal side effects. Our findings demonstrate a dose-dependent blockade of the mechanical sensitivity caused by a mild thermal injury by both GBP and IBG. Results indicate that IBG is more effective than GBP in this model at doses which do not cause sedation. These observations support the suggested use of these or related γ-amino acid analogues as an effective treatment for post-operative pain.     

Post-stroke pain case study: clinical characteristics, therapeutic options and long-term follow-up

Central post-stroke pain (CPSP) is a syndrome characterized by sensory disturbances and neuropathic pain. In 40%−60% of CPSP patients, the onset of central pain following a stroke occurs more than 1 month after the stroke, creating a source of diagnostic uncertainty or significant delay in treatment since healthcare providers familiar with CPSP may no longer be caring for the patient when the symptoms occur. In addition to chronic pain, the presence of somatosensory abnormalities is the most important diagnostic corollary of CPSP. Neuropathic or central pain has been estimated to occur in up to 8% of patients after a stroke, and about 18% of stroke patients with a somatosensory disturbance will develop CPSP. Although largely a matter of conjecture, it is generally agreed that damage to spinothalamic sensory pathways plays a significant role in the pathogenesis of CPSP. A comprehensive examination of the patient for sensory deficits is essential before treatment can be initiated. Functional disturbances such as depression, anxiety and sleep disturbances are significant comorbid conditions associated with CPSP; the physician should incorporate an assessment of these potential comorbidities into the examination. Treatment options for CPSP are limited; at present, amitriptyline is the drug of first choice. Other drugs including antidepressants, anticonvulsants, antiarrhythmics, opioids and N -methyl- d -aspartate antagonists may provide relief for some patients who do not respond to amitriptyline. Included in this review is a case study outlining the challenges of managing the patient with CPSP.     

A Randomized,Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain: A Pilot Trial

ObjectivesCentral poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment.Materials and MethodsThis prospective, randomized, double-blind, sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which may transmit TMS effects in pain control.ResultsWe prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17–20% pain relief), with no difference between M1, S2, or sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response.ConclusionsS2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.     

Central post-stroke pain in Wallenberg syndrome]

We analyzed clinical characteristics of central post-stroke pain (CPSP), constant and burning pain, in 32 patients with Wallenberg syndrome due to infarction. CPSP developed in 44% (14/32) of the patients; 8 in acute stage (within 4 days after the stroke) and 8 in chronic stage(10-120 days after the stroke). Apart from one exceptional case, CPSP was present in the hypalgesic side of face and extremities. In 9 cases of typical type (Currier's distribution of sensory disturbance), CPSP occurred in the ipsilateral face to the lesion during acute stage. Among them, 2 cases developed severe lancinating pain in chronic stage. In 5 cases of ventral type, it occurred in the contralateral extremities during chronic stage. Spino- and trigemino-thalamic tract are injured but medullary reticular formation is intact in Wallenberg syndrome. It is, therefore, considered that CPSP in Wallenberg syndrome is caused by denervation sensitivity of "paleo-reticulothalamic" tract within the reticular formation.     

Post-stroke tactile allodynia and its modulation by vestibular stimulation: a MEG case study

Background – There is behavioural evidence that caloric vestibular stimulation (CVS) can alleviate central pain. Several such patients have also noted that it reduces tactile allodynia, an especially ill‐understood phenomenon in these patients. Aims of the study – The first aim is to use magnetoencephalography (MEG) to study neural activity associated with tactile allodynia in central post‐stroke pain (CPSP). The second is to assess how this would be affected, if at all, by CVS. The third is to assess the ability of the VESTAL solution for MEG to detect anterior cingulate activation. Methods – A 58‐year‐old woman with CPSP, and marked unilateral tactile allodynia, participated in a MEG study with imaging pre‐ and post‐CVS. Results – Tactile simulation within the patient’s allodynic area resulted in contralateral activation of the primary motor and anterior cingulate cortices, which had normalized 24 h post‐CVS. Conclusions – We suggest that the unexpected primary motor cortex activation in response to light touch in the allodynic area arises from inappropriate activation of a normal mechanism, which may occur when a threat to homeostasis is present, to lower motor thresholds and allow for more rapid performance of corrective actions. We propose this may be mediated by the interoceptive cortex in the dorsal posterior insula.     

A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies

Abstract. Background: Painful HIV-associated sensory neuropathies (HIV-SN) are a common complication of HIV infection. The pathogenesis is unknown and the treatment very limited. Gabapentin (GBP) is effective in painful diabetic neuropathy and postherpetic neuralgia and its effectiveness on painful HIV-SN has been reported anecdotally. Design: Multicenter, prospective, randomised, double-blind, placebo-controlled study. Methods: Patients were followed for a 1-week screening, a 4-week double-blind and a 2-week open treatment phase. GBP was initiated at 400 mg/d, titrated over 2 weeks to 1200 mg/d, and then either maintained at this level or—if not beneficial—titrated to 2400 mg/d. After 4 weeks the medication was unblinded and the patient had the choice to begin, to maintain or to increase GBP to 3600 mg/d. The primary outcome measure was an improvement in median pain on the Visual Analogue Scale (VAS) from the screening week compared to the 4^th treatment week. A secondary efficacy measure was the median sleep score (VAS). Results: 15 patients received GBP and 11 placebo. In each group one patient dropped out during the doubleblind phase. Median pain (GBP 5.1; placebo 4.7) and sleep score (GBP 4.5; placebo 5.6) did not differ between both groups at baseline. In the GBP-group there was a significant decrease of the pain to 2.85 (–44.1 %) as well as of the sleep VAS to 2.3 (–48.9 %). No significant decrease in the pain (median VAS=3.3, –29.8 %) as well as in the sleep score (median VAS=4.95, –11.6 %) was observed in the placebo-group. GBP was generally well tolerated. The most frequent side effect was somnolence reported in 80% of GBP-treated patients. Conclusions: GBP was more effective than placebo in reducing pain and sleep interference in patients with HIV-SN.     

卒中后中枢痛的研究进展

卒中后中枢痛是卒中后发生的中枢性神经病理性疼痛综合征,主要表现为与脑损伤区域相对应的躯体部位的疼痛与感觉异常。目前由于临床对卒中后中枢痛缺乏重视,致使患者长期遭受疼痛困扰,严重影响生活质量。为更全面了解卒中后中枢痛,本文对其流行病学、临床特点、病理生理及治疗进展等进行综述。     

Anticonvulsant Efficacy of Gabapentin on Kindling in the Immature Brain

Summary: The anticonvulsant and motor effects of gabapentin (GBP) were evaluated in rat pups aged 16–17 days. Fourteen‐day‐old rat pups received an implanted stimulating electrode in the amygdala unilaterally. Kindled seizures were produced on day 16 of life by repeatedly applying an electrical current stimulus to the amygdala electrode. Animals received kindling stimulation until they achieved three consecutive generalized convulsions. On day 17, rat pups received one of four doses of GBP 10, 25, 50, or 100 mg/kg. After receiving GBP, rat pups again received electrical stimulation to the amygdala electrode to determine the extent to which GBP prevented the kindled seizure. Anticonvulsant effects were found at doses as low as 10 mg/kg. A separate group of naïve rats received GBP to determine the motor effects of each treatment dose. Impaired motor performance, quantified as time on a balance beam, occurred at doses of ≥50 mg/kg. In summary, our data indicate that in immature rats, GBP exerts an anticonvulsant effect against kindled seizures at doses that do not significantly impair motor performance.     

Deletion of the CCK2 receptor gene reduces mechanical sensitivity and abolishes the development of hyperalgesia in mononeuropathic mice

Previous studies suggest that cholecystokinin (CCK) is implicated in the modulation of pain sensitivity and the development of neuropathic pain. We used CCK(2) receptor deficient (CCK(2) (-/-)) mice and assessed their mechanical sensitivity using Von Frey filaments, as well as the development and time course of mechanical hyperalgesia in a model of neuropathic pain. We found that CCK(2) (-/-) mice displayed mechanical hyposensitivity, which was reversed to the level of wild-type animals after administration of naloxone (0.1-10 mg/kg). On the other hand, injection of L-365260 (0.01-1 mg/kg), an antagonist of CCK(2) receptors, decreased dose-dependently, mechanical sensitivity in wild-type mice. The mechanism of reduced mechanical sensitivity in CCK(2) (-/-) mice may be explained by changes in interactions between CCK and opioid systems. Indeed, CCK(2) (-/-) mice natively expressed higher levels of lumbar CCK(1), opioid delta and kappa receptors. Next, we found that CCK(2) (-/-) mice did not develop mechanical hyperalgesia in the Bennett's neuropathic pain model. Induction of neuropathy resulted in decrease of lumbar pro-opiomelanocortin (POMC) gene expression in wild-type mice, but increase of POMC expression in CCK(2) (-/-) mice. In addition, induction of neuropathy resulted in further increase of opioid delta receptor in CCK(2) (-/-) mice. Gene expression results indicate up-regulation of opioid system in CCK(2) (-/-) mice, which apparently result in decreased neuropathy score. Our study suggests that not only pain sensitivity, but also mechanical sensitivity and the development of neuropathic pain are regulated by antagonistic interactions between CCK and opioid systems.     

Central pain: “new” syndromes and their evaluation

Central pain syndrome is defined as pain associated with a lesion of the central nervous system. It has a low incidence but is frequently intractable and does not have effective treatment. The cause of central pain is speculative; however, the single common sensory abnormality in patients with central pain is interruption of spinothalamocortical nociceptive pathways. It appears that severe central nervous system lesions, with total destruction of ascending sensory systems, do not lead to a central pain syndrome; and that setting of mild, moderate, or severe disruption of the anterolateral ascending system with partial or complete preservation of the dorsal column/medial lemniscus functions is most frequently associated with central pain syndrome. Furthermore, even during remission, dysesthesias and pain could be triggered by additional afferent input to the large fiber/dorsal column/medial lemniscus system and, once established, they may not be abolished byadditional deafferentation. © 1993 John Wiley & Sons, Inc.     

Muscimol-scopolamine interactions in the rat brain: a study with 2-deoxy-D-[1-14C]glucose

The 2-deoxy-D[1-14C]glucose method of Sokoloff was used to measure local cerebral glucose utilization (LCGU) in rats after injections of the GABA receptor agonist, muscimol (1.6 mg/kg and 4.0 mg/kg, i.v.); the muscarinic receptor antagonist, scopolamine (0.4 mg/kg and 2.0 mg/kg, i.v.); or combinations of both drugs. The aim was to identify brain regions where functional effects of GABAergic-cholinergic interactions could be seen. As noted previously, muscimol reduced LCGU in many brain regions. In contrast, scopolamine alone had no effect on LCGU in most brain regions; however, decreases were seen in the medial geniculate body, medial thalamic nucleus, and auditory and frontal cortical areas. Scopolamine increased LCGU in the cerebellar vermis and mesencephalic reticular formation. Although muscimol alone did not significantly affect LCGU in the external plexiform layer of the olfactory bulb or the anterior, periventricular, and parafascicular thalamic nuclei, rats treated with 0.4 mg/kg of scopolamine before 4.0 mg/kg of muscimol had LCGU decrements in those brain regions. Furthermore, the muscimol-induced decrease in LCGU in the medial cortex was enhanced by prior treatment with 0.4 mg/kg of scopolamine. In contrast, in certain brain regions where muscimol alone reduced LCGU (locus ceruleus; central gray matter; striatum; ventral, medial, reunients , and rhomboid thalamic nuclei; and the auditory cortex), scopolamine pretreatment antagonized these decrements. These findings suggest that endogenous cholinergic and GABAergic systems act antagonistically in some brain regions. However, in other brain regions, cholinergic transmission is required for full expression of GABAmimetic effects on LCGU.(ABSTRACT TRUNCATED AT 250 WORDS)     

Caffeine prevents antihyperalgesic effect of gabapentin in an animal model of CRPS‐I: evidence for the involvement of spinal adenosine A1 receptor

This study was designed to determine whether 3 weeks of gabapentin treatment is effective in alleviating neuropathic pain‐like behavior in animal models of complex regional pain syndrome type‐I and partial sciatic nerve ligation (PSNL). We investigated the contribution of adenosine subtypes to the antihyperalgesic effect of gabapentin by examining the effect of caffeine, a non‐selective adenosine A₁ and A₂ receptor antagonist or 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX), a selective adenosine A₁ subtype receptor antagonist on this effect. Neuropathic pain was produced by unilateral prolonged hind paw ischemia and reperfusion (I/R) or PSNL procedures which resulted in stimulus‐evoked mechanical hyperalgesia. After procedures, animals received gabapentin (10, 30, or 100 mg/kg intraperitoneal, respectively), caffeine (10 mg/kg intraperitoneal or 150 nmol intrathecally) or DPCPX (3 µg intrathecally) alone or in combination. Mice were tested for tactile mechanical hyperalgesia at 1, 2, and 3 weeks following procedures. Gabapentin produced dose‐related inhibition of mechanical hyperalgesia over a 3‐week period, and this effect was blocked by concomitant caffeine or DPCPX administration 1 week after injuries. The results of this study demonstrated that the mechanism through which gabapentin produces its effect may involve the activation of adenosine A₁ subtype receptor.     

Neurophysiological, pharmacological and behavioral evidence for medial thalamic mediation of cocaine-induced dopaminergic analgesia.

These studies examined the effects of cocaine on thalamic neurons that respond maximally either to noxious or to innocuous somatic stimulation. Cocaine attenuated high intensity electrically-evoked nociceptive responses of all 25 units studied in the parafascicular and central lateral nuclei of the medial thalamus. A dose of 1 mg/kg intravenously (i.v.) suppressed medial thalamic unit discharge evoked by both noxious somatic stimulation (49.4 +/- 8.7% of control response) and spinal cord stimulation (76.2 +/- 6.6% of control response). The effect of cocaine on unit responses to noxious somatic stimulation was dose-related in the range of 0.3-3.5 mg/kg i.v. and was attenuated by eticlopride, a D-2 selective dopamine receptor antagonist. Morphine also suppressed noxious somatic evoked responses of medial thalamic units in a dose-dependent manner. Units in the lateral (ventrobasal) thalamus (n = 4) that responded only to innocuous stimuli were not affected by cocaine at doses up to 3.5 mg/kg i.v. Ibotenic acid lesions in the parafascicular nucleus of the medial thalamus attenuated the analgesic effect of cocaine in the formalin test. These results suggest that both cocaine and the parafascicular nucleus interact with dopaminergic mechanisms that attenuate nociceptive spinal projections to the medial thalamus.     

Representation of somatosensory modalities in pathways ascending from the spinal anterolateral funiculus to the thalamus demonstrated by lesions in man

Patients with cordotomies (16), and brainstem (17) or thalamic (30) infarcts, all except cordotomies verified by magnetic resonance imaging (MRI), have been subjected to quantitative sensory perception threshold testing (QST) for touch (von Frey), mechanical pain, sharpness, innocuous warmth and cold, and heat pain in the maximally affected body area and its unaffected contralateral mirror image region. Some patients were tested twice at widely spaced time intervals; no qualitative differences were found. Results show that all modalities are dissociable from one another by lesions at all levels tested, so that there must be separable representation for each of the six modalities tested. In the lower (crossed symptoms and signs), but not the upper (uncrossed symptoms), deficits for all modalities (except for touch) were more marked than at higher levels. At the level of the thalamus, deficits for innocuous and noxious thermal modalities but not for mechanical pain were recorded in the case of lesions of the principal somatosensory relay nucleus (VPL/Vc), while more medial thalamic lesions resulted in deficits for mechanical pain but not for heat pain or innocuous thermal modalities; there is a marked deficit for sharpness caused by lesions at both thalamic sites.