Pain cognition versus pain intensity in patients with endometriosis: toward personalized treatment.

OBJECTIVE: To explore how pain intensity and pain cognition are related to health-related quality of life (HRQoL) in women with endometriosis. DESIGN: Cross-sectional questionnaire-based survey. SETTING: Multidisciplinary referral center. PATIENT(S): Women with laparoscopically and/or magnetic resonance imaging-proven endometriosis (n = 50) and healthy control women (n = 42). INTERVENTION(S): For HRQoL, two questionnaires: the generic Short Form Health Survey (SF-36) and the Endometriosis Health Profile 30 (EHP-30). For pain cognition, three questionnaires: the Pain Catastrophizing Scale (PCS), the Pain Vigilance and Awareness Questionnaire (PVAQ), and the Pain Anxiety Symptoms Scale (PASS). For pain intensity, the verbal Numeric Rating Scale (NRS). MAIN OUTCOME MEASURE(S): Association between pain intensity and pain cognition with HRQoL in women with endometriosis, and the differences in HRQoL and pain cognition between women with endometriosis and healthy controls. RESULT(S): Health-related quality of life was statistically significantly impaired in women with endometriosis as compared with healthy control women. The variables of pain intensity and pain cognition were independent factors influencing the HRQoL of women with endometriosis. Patients with endometriosis had statistically significantly more negative pain cognition as compared with controls. They reported more pain anxiety and catastrophizing, and they were hypervigilant toward pain. CONCLUSION(S): Pain cognition is independently associated with the HRQoL in endometriosis patients. Clinicians should be aware of this phenomenon and may consider treating pain symptoms in a multidimensional, individualized way in which the psychological aspects are taken into account. In international guidelines on management of women with endometriosis more attention should be paid to the psychological aspects of care.

Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats.

Acute treatment with positive allosteric modulators (PAMs) of mGlu1 and mGlu5 metabotropic glutamate receptors (RO0711401 and VU0360172, respectively) reduces the incidence of spike-and wave discharges in the WAG/Rij rat model of absence epilepsy. However, from the therapeutic standpoint, it was important to establish whether tolerance developed to the action of these drugs. We administered either VU0360172 (3 mg/kg, s.c.) or RO0711401 (10 mg/kg, s.c.) to WAG/Rij rats twice daily for ten days. VU0360172 maintained its activity during the treatment, whereas rats developed tolerance to RO0711401 since the 3rd day of treatment and were still refractory to the drug two days after treatment withdrawal. In response to VU0360172, expression of mGlu5 receptors increased in the thalamus of WAG/Rij rats after 1 day of treatment, and remained elevated afterwards. VU0360172 also enhanced mGlu5 receptor expression in the cortex after 8 days of treatment without changing the expression of mGlu1a receptors. Treatment with RO0711401 enhanced the expression of both mGlu1a and mGlu5 receptors in the thalamus and cortex of WAG/Rij rats after 3-8 days of treatment. These data were different from those obtained in non-epileptic rats, in which repeated injections of RO0711401 and VU0360172 down-regulated the expression of mGlu1a and mGlu5 receptors. Levels of VU0360172 in the thalamus and cortex remained unaltered during the treatment, whereas levels of RO0711401 were reduced in the cortex at day 8 of treatment. These findings suggest that mGlu5 receptor PAMs are potential candidates for the treatment of absence epilepsy in humans.

Negative expectations facilitate mechanical hyperalgesia after high-frequency electrical stimulation of human skin.

BACKGROUND: High-frequency electrical stimulation (HFS) of human skin induces not only an increased pain sensitivity in the conditioning area but also an increased pain sensitivity to mechanical punctate stimuli in the non-conditioned surrounding skin area. The aim of the present study was to investigate whether this heterotopically increased mechanical pain sensitivity can be facilitated through the induction of negative expectations. METHODS: In two independent conditions [a nocebo (n = 15) and control condition (n = 15)], we applied mechanical pain stimuli before, directly after, 10 min and 20 min after HFS in the skin area surrounding the conditioning area, and measured the reported pain intensity [visual analogue scale (VAS)]. All subjects (of both conditions) received a written instruction about the HFS protocol, but only the instruction in the nocebo condition was extended by the following text (in Dutch): 'After the HFS, your skin will become more sensitive to the pinprick stimulation'. RESULTS: Our results clearly show that induced expectations of increased mechanical pain sensitivity after HFS facilitates the reported pain intensity after HFS more than when no information is given. CONCLUSIONS: This study shows for the first time that brain mechanisms, via the induction of negative expectations, can facilitate heterotopic mechanical hyperalgesia after HFS of human skin.

Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats.

Absence epilepsy is generated by the cortico-thalamo-cortical network, which undergoes a finely tuned regulation by metabotropic glutamate (mGlu) receptors. We have shown previously that potentiation of mGlu1 receptors reduces spontaneous occurring spike and wave discharges (SWDs) in the WAG/Rij rat model of absence epilepsy, whereas activation of mGlu2/3 and mGlu4 receptors produces the opposite effect. Here, we have extended the study to mGlu5 receptors, which are known to be highly expressed within the cortico-thalamo-cortical network. We used presymptomatic and symptomatic WAG/Rij rats and aged-matched ACI rats. WAG/Rij rats showed a reduction in the mGlu5 receptor protein levels and in the mGlu5-receptor mediated stimulation of polyphosphoinositide hydrolysis in the ventrobasal thalamus, whereas the expression of mGlu5 receptors was increased in the somatosensory cortex. Interestingly, these changes preceded the onset of the epileptic phenotype, being already visible in pre-symptomatic WAG/Rij rats. SWDs in symptomatic WAG/Rij rats were not influenced by pharmacological blockade of mGlu5 receptors with MTEP (10 or 30 mg/kg, i.p.), but were significantly decreased by mGlu5 receptor potentiation with the novel enhancer, VU0360172 (3 or 10 mg/kg, s.c.), without affecting motor behaviour. The effect of VU0360172 was prevented by co-treatment with MTEP. These findings suggest that changes in mGlu5 receptors might lie at the core of the absence-seizure prone phenotype of WAG/Rij rats, and that mGlu5 receptor enhancers are potential candidates to the treatment of absence epilepsy. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy.

Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1α receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

The brain 5HTergic response to an acute sound stress in rats with generalized (absence and audiogenic) epilepsy.

The brain serotoninergic (5HTergic) system of epileptic subjects can influence their vulnerability to stress. We studied the putative dependency of 5HT neurotransmission parameters on emotional stress, and the presence, types and severity of seizures using rats with genetic generalized (absence and/or audiogenic) epilepsy, of WAG/Rij and Wistar strains. The animals were stressed by exposure to a short aversive noise or left without sound stimulation. Tissue concentrations of 5HT, tryptophan (TRT) and 5-hydroxyindolacetic acid (5HIAA) were assessed by HPLC. The stressor activated the 5HTergic system within thalamus (5HIAA elevated), frontal cortex (5HT, TRT elevated), hypothalamus (increased TRT) in all rats. However, the normal (non-epileptic) rats displayed the highest response in the frontal cortex and the lowest one in the thalamus, as compared to the epileptic rats. Absence-epileptic rats exhibited higher thalamic 5HIAA increase than their controls. Significant correlations existed between propensity of absence epilepsy and 5HTergic parameters measured in the cortex and hypothalamus of absence-epileptic rats. No major difference was found between groups with and without audiogenic epilepsy. The results imply that the stress response depends on the presence of epileptic pathology and the seizure type and severity. The brain 5HT may be involved in the control of the paroxysms and behaviour in absence-epileptic subjects.

An effective correlation dimension and burst suppression ratio of the EEG in rat. Correlation with sevoflurane induced anaesthetic depth.

BACKGROUND AND OBJECTIVE: Anaesthesiologists need parameters that measure the depth of anaesthesia. In the context of this need, the present study investigated in rats how two variables from the electroencephalogram, the burst suppression ratio and effective correlation dimension correlated with a measure of anaesthetic depth as measured in the strength of a noxious withdrawal reflex. METHODS: Eight rats were exposed to different inspiratory concentrations of sevoflurane, each rat in two separate experiments. In the first experiment, spontaneously breathing animals could move freely and no painful stimuli were applied. In the second experiment, in mechanically ventilated restrained anaesthetized rats, the withdrawal reflex was measured every 80 s. In both experiments the electroencephalogram was continuously recorded. The concentration in the effector compartment was estimated using a first order two compartment model. Correlation dimension was computed following the Grassberger/Procaccia/Takens approach with optimized parameter settings to achieve maximum sensitivity to anaesthetic drug effects and enable real-time computation. The Hill, equation was fitted to the data, describing the effect as a function of sevoflurane concentration. RESULTS: Good correlations of Depth of Anaesthesia with correlation dimension as well as burst suppression ratio were established in both types of experiments. Arousal by noxious stimuli decreased burst suppression ratio and increased correlation dimension. The effective sevoflurane concentration associated with 50% of the maximum effect (C50) was higher in experiment II (stimulation) than in experiment I (no stimulation): i.e. for correlation dimension 2.18% vs. 0.60% and for burst suppression ratio 3.07% vs. 1.73%. The slope factors were: gammaCD = 4.15 vs. gammaCD = 1.73 and gammaBSR = 5.2 vs. gammaBSR = 5.4. Correlation dimension and burst suppression ratio both correlated with the strength of the withdrawal reflex with correlation coefficients of 0.46 and 0.66 respectively (P < 0.001). CONCLUSIONS: Both correlation dimension and burst suppression ratio are related to anaesthetic depth and are affected by noxious stimuli. The relationship between anaesthetic depth and burst suppression ratio is confirmed and the potential of correlation dimension is demonstrated.

On-off intermittency in time series of spontaneous paroxysmal activity in rats with genetic absence epilepsy.

In the present paper we consider the on-off intermittency phenomena observed in time series of spontaneous paroxysmal activity in rats with genetic absence epilepsy. The method to register and analyze the electroencephalogram with the help of continuous wavelet transform is also suggested.

The relationship between hippocampal EEG theta activity and locomotor behaviour in freely moving rats: effects of vigabatrin.

The relationship between hippocampal electroencephalogram (EEG) theta activity and locomotor speed in both spontaneous and forced walking conditions was studied in rats after vigabatrin injection (500 mg/kg i.p.). Vigabatrin increased the percentage of time that rats spent being immobile. During spontaneous walking in the open field, the speed of locomotion was increased by vigabatrin, while theta peak frequency was decreased. Vigabatrin also reduced the theta peak frequency during forced (speed controlled) walking. There was only a weak positive correlation (r=0.22) between theta peak frequency and locomotor speed for the saline condition. Furthermore, vigabatrin abolishes the weak relationship between speed of locomotion and theta peak frequency. Vigabatrin and saline did not differ in the slope of the regression line, but showed different offset points at the theta peak frequency axis. Thus, other factors than speed of locomotion seem to be involved in determination of the theta peak frequency.

Enhanced re-habituation of the orienting response of the human event-related potential.

Previous studies found the amplitude of the orienting response (OR) of the human event-related potential to decrease with repeated stimulus presentations. This decrease has been suggested to reflect short-term habituation and/or long-term habituation, both of which are learning processes. However, this earlier research failed to provide direct evidence supporting this claim. The present study attempted to show that the OR pattern shares one important feature of habituation: an enhanced response decrement across stimulus-presentation blocks (enhanced re-habituation). Participants received four blocks of 25 auditory stimulus presentations and showed an OR decrement both within (short-term habituation) and across (long-term habituation) blocks. Importantly, the OR decreased more rapidly during later than initial trial blocks, suggesting enhanced re-habituation. The latter result supports the notion that the amplitude decrement reflects an elementary learning process.

Rat models of genetic absence epilepsy: what do EEG spike-wave discharges tell us about drug effects?

Electroencephalographic studies in the WAG/Rij rats of Nijmegen and genetic absence epileptic rats of Strasbourg (GAERS), two genetic models for human generalized absence epilepsy, illustrate the usefulness of drug-electroencephalogram (EEG) interaction studies. In the EEG of both types of rats, spontaneously occurring spike-wave discharges are present. For drug discovery, a model with predictive validity is imperative, and both the WAG/Rij and the GAERS models seem adequate. The present paper discusses effects on spike-wave discharges of various compounds that are clinically used. Not only new antiepileptic drugs, such as remacemide, loreclezole, lamotrigine, tiagabine, gabapentin, progabide and levetiracetam are evaluated, but also drugs used for other purposes, such as etomidate and fentanyl-fluanisone for anesthesia, opioidergic drugs and drugs used for strokes. It is shown that some new antiepileptic drugs, such as tiagabine, have spike-wave discharge-increasing properties, while other drugs are worth studying in clinical trials for antiabsence treatment. Furthermore, it is shown that many commonly used drugs such as analgesics, anesthetics and drugs to treat stroke generally enhance spike-wave discharges. It can be concluded that EEG monitoring is imperative for the discovery and development of potentially antiepileptic compounds and that genetic rat models such as the WAG/Rij or GAERS, to a large extent, can reliably predict clinical efficacy of various types of compounds as well as alert us of potentially adverse effects.

AMPA and GABA(B) receptor antagonists and their interaction in rats with a genetic form of absence epilepsy.

The effects of combined and single administration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 7,8-methylenedioxy-1-(4-aminophenyl)-4-methyl-3-acetyl-4,5-dihydro-2,3-benzodiazepine (LY 300164), and of the GABA(B) receptor antagonist gamma-aminopropyl-n-butyl-phosphinic acid (CGP 36742), on spontaneously occurring spike-wave discharges were investigated in WAG/Rij rats. LY 300164 had minor effects; only the highest dose (16 mg/kg) reduced the number of spike-wave discharges in a short time window. CGP 36742 was more effective as it significantly reduced the number of spike-wave discharges and shortened their duration at the doses of 25 and 100 mg/kg. The ED(50) values for the inhibition of spike-wave discharges by LY 300164 and CGP 36742 in a time window 30-60 min after injection were 15.5 and 16.6 mg/kg, respectively. The ED(50) of CGP 36742 was reduced to 8.0 mg/kg when this antagonist was administered in combination with LY 300164 (6 mg/kg). The interaction between the two antagonists appeared to be additive according to isobolographic analysis. Importantly, CGP 36742 and LY 300164 administered either alone or in combination had no apparent effects on behavior. These results may provide information for a rational approach to polytherapy for the treatment of generalized absence epilepsy.

Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed.

PURPOSE: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches. METHODS: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. RESULTS: Thirty-nine papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. CONCLUSIONS: There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy.

Effects of diazepam on auditory evoked potentials of rats elicited in a ten-tone paradigm.

The effect of diazepam on sensory gating was studied in rats by measuring diazepam effects on auditory evoked potentials (AEPs) elicited in a ten-tone paradigm. Trains of 10 repetitive tone-pip stimuli were presented. Rats (n = 8) received 4 mg x kg(-1) diazepam subcutaneously or vehicle, counterbalanced over two sessions. Diazepam decreased the amplitude of the middle-latency P30 component and increased the amplitudes of the late-latency N60 and P67 components. The increase in the late-latency components might be due to a diazepam-induced decrease in arousal. Stimulus repetition decreased the amplitudes of the middle-latency N18 and P30 components in both conditions. This suggests that automated neuronal recovery functions underlying sensory gating remain intact with diazepam. In the vehicle condition, the amplitude of the late-latency P67 decreased with stimulus repetition, but not in the diazepam condition. This suggests a diazepam-induced decrease of behaviourally mediated habituation.

The influence of diazepam on the electroencephalogram-evoked potential interrelation in rats.

Though being a sedative, diazepam increases beta-activity in the electroencephalogram (EEG). Diazepam also affects auditory evoked potentials (AEPs). We investigated if the effect of diazepam on AEPs could be ascribed to its beta-increasing effect. Eight rats received vehicle and diazepam counterbalanced. AEPs were ranked in ten categories according to the percentages of beta-activity in the pre-stimulus electroencephalogram (EEG). With vehicle, the P(29), N(51) and P(67) AEP components increased and cross-correlation coefficients (CCCs) declined with increasing beta-activity. With diazepam AEP components and CCCs remained unchanged. All AEPs with diazepam closely resembled the AEP of the lowest beta-category obtained with vehicle. We conclude that the effect of diazepam on AEPs can not be ascribed to its beta-enhancing effect. Diazepam disrupts the normal AEP-EEG relation such that diazepam-effects on AEPs seem to reflect the sedative effects of diazepam and not its beta-increasing effects.

A molecular model for the synergic interaction between gamma-aminobutyric acid and general anaesthetics.

Within the context of the discussion about rational polytherapy, we determined the effects of four anaesthetics on the binding of [3H]t-butylbicycloorthobenzoate ([3H]TBOB) to the GABA(A) receptor complex in the presence of several concentrations of GABA (gamma-aminobutyric acid), in order to build a molecular model that can describe and quantify the interactions between the compounds. The empirical isobole method revealed that GABA and the anaesthetics acted synergically in displacing [3H]TBOB. This synergy could be described by a simple molecular model in which both GABA and the anaesthetics displaced [3H]TBOB allosterically and in which GABA allosterically enhanced the binding of the anaesthetics. To get information about the interaction between GABA and anaesthetics, we used [3H]TBOB as a tracer ligand. The model indicated that GABA enhanced the affinity of thiopental 3.0-fold, propofol 5.0-fold, the neuroactive steroids Org 20599 3.5-fold and Org 20549 13-fold. Insight into the molecular mechanism and strength of these interactions can help clinicians to choose therapeutically optimal drug and dose combinations: a step towards rational polytherapy.

Effects of polytherapy compared with monotherapy in antiepileptic drugs: an animal study.

Although monotherapy in epilepsy treatment is frequently advocated, this is not based on studies with equal drug loads. This study was performed to investigate the experimental background of polytherapy with standardized drug loads. Dose-dependent effects on grip strength, accelerod performance, and spontaneous behavior of rats was used to study the effect of combining valproate and ethosuximide. The potency of the drugs (combination) was obtained by fitting the sigmoid Emax equation to the data. Drug interaction was assessed using the isobologram method and quantified by comparing equivalent drug loads with their 95% confidence intervals. We found that the effects of valproate and ethosuximide combine in a simple additive way in the grip strength experiment as well as in the accelerod experiment. In the behavioral studies, however, a higher drug load of the combination was needed to obtain the same amount of sedation, signifying infra-additivity. Infra-additivity of sedative effects is an important finding because this is by far the most frequent side effect mentioned in human studies. However, assessment of the therapeutic effect of the combination will have to be completed before a preference for mono- or polytherapy, based on the balance of adverse effects and efficacy, can be expressed.

Selective serotonin reuptake inhibitors may enhance responses to noxious stimulation.

The acute effects of various doses of two selective serotonin reuptake inhibitors (fluoxetine and fluvoxamine) on thermal and electrical stimulation-induced pain were investigated in drug-naive Wistar rats. The hot-plate and the tail-flick test and the noxious-induced withdrawal test were used. The two drugs had no effects on heat-induced pain behavior. However, the two compounds enhanced the motor responses induced by noxious electrical stimulation. These data contrast to what is generally found for tricyclic antidepressants and suggest a modality specific pain system. Cardiac and blood pressure were also found to change, but these changes were not correlated to changes in nociception. Taken together, the data suggest that the acutely administered selective serotonin reuptake inhibitors may exacerbate an acute type of pain.

Time course of chronic diazepam effects on the auditory evoked potential of the rat.

The time course of chronic diazepam effects on auditory evoked potentials was studied in rats. Auditory evoked potentials were elicited by background and target tones in a passive oddball paradigm. Diazepam was administered by slow release implants to establish constant blood concentrations. Recordings were made during 21 days of treatment and 9 days after treatment ceased. Diazepam increased the amplitude of the P40 component and decreased the amplitude of the P72-P102 components elicited by background tones. Diazepam increased the amplitude of the P40-P48 component and decreased that of the N58 component elicited by target tones. These effects remained constant during treatment. Diazepam further decreased the amplitude of the P102 component elicited by target tones. This effect became more distinct over time. No group differences were found 9 days after treatment. The constant drug effects on middle-latency components (P40-P48) might reflect diazepam-induced changes in sensory information processing. The decreased long-latency component (P102) might reflect a diminished attention to, or discrimination of, target tones. The time course of this effect might reflect diazepam-enhanced habituation.