RESUMEN
BACKGROUND: The mechanisms of pain perception in individuals with masochistic behaviour (MB) remain poorly documented. We hypothesized that MB is associated with context-specific changes in descending pain modulation. METHODS: We compared the effects of four standardized sets of images with positive (erotic), negative (mutilations), masochistic or neutral emotional valences on the RIII nociceptive reflex evoked by electrical stimulation of the sural nerve and recorded on the ipsilateral biceps femoris in 15 controls and 15 men routinely engaging in MB. We systematically assessed the RIII reflex threshold and recruitment curves (up to the tolerance threshold), thermal (heat and cold) pain thresholds measured on the upper and lower limbs and responses to the pain sensitivity questionnaire, to compare basal pain perception between our two groups of participants. We also assessed anxiety, depression, empathy, alexithymia, high sensation seeking and catastrophizing, to investigate their potential influence on the emotional modulation of pain. RESULTS: Thermal pain thresholds, RIII reflex recruitment curves, and responses to the psychological and pain sensitivity questionnaires were similar in the two groups. Neutral, positive and negative images modulated the RIII reflex similarly in the two groups. By contrast, masochistic images induced a significant (p < 0.01) decrease in RIII reflex responses in subjects with MB, whereas it tended to increase these responses in control subjects. CONCLUSIONS: Our data suggest that psychological profile, basal pain sensitivity and the emotional modulation of pain are normal in individuals with MB but that these subjects selectively engage descending pain inhibition in the masochistic context. SIGNIFICANCE: Decrease pain perception related to masochistic behaviours is associated with specific activation of descending pain inhibition.
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Umbral del Dolor , Dolor , Estimulación Eléctrica , Humanos , Masculino , Percepción del Dolor/fisiología , Umbral del Dolor/fisiología , Reflejo/fisiologíaRESUMEN
Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18-75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: -0.048 ± 0.02; 95% CI: -0.09 to -0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: -0.003 ± 0.01; 95% CI: -0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.
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Neuralgia/terapia , Manejo del Dolor/métodos , Estimulación Magnética Transcraneal/métodos , Adulto , Anciano , Corteza Prefontal Dorsolateral/fisiología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Corteza Motora/fisiología , Resultado del TratamientoRESUMEN
BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) at high frequency (>5 Hz) induces analgesic effects, probably by activating pain modulation systems. A new rTMS paradigm--theta burst stimulation (TBS)--consists of bursts of three pulses at 50 Hz repeated five times per second. Like high frequency rTMS, both intermittent and prolonged continuous TBS (iTBS and pcTBS) lead to a facilitation of cortical excitability. OBJECTIVES: (1) to evaluate the analgesic effects of neuronavigated iTBS and pcTBS, comparing them with those of classical high frequency rTMS (10 Hz) over the left M1, (2) to elucidate the role of conditioned pain modulation (CPM) in the antinociceptive effect of rTMS and (3) to investigate possible correlations between analgesia and cortical excitability. METHODS: Fourteen healthy volunteers participated in four experimental sessions, carried out in a random order (iTBS, pcTBS, 10 Hz rTMS or sham). Cold pain threshold, CPM and cortical excitability measurements were carried out before and after rTMS. RESULTS: We found that the analgesic effects of 10 Hz rTMS and pcTBS were significantly superior to those of sham rTMS. Moreover, pcTBS was significantly more effective than 10 Hz rTMS (P = 0.026). Analgesia did not seem to be driven by changes in CPM or cortical excitability. CONCLUSION: Prolonged cTBS has considerable clinical potential, as it has a shorter treatment duration (by a factor 8) and stronger analgesic effects than the classical high frequency protocol. Studies in patients are required to confirm the potential of this new stimulation paradigm for clinical applications.
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Analgesia/métodos , Corteza Motora/fisiología , Estimulación Magnética Transcraneal/métodos , Adulto , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Masculino , Inhibición Neural/fisiología , Umbral del Dolor , Ritmo Teta , Factores de TiempoRESUMEN
BACKGROUND: Chronic pain and opioid consumption may trigger diffuse hyperalgesia, but their relative contributions to pain vulnerability remain unclear. OBJECTIVES: To assess preoperative opioid-induced hyperalgesia and its postoperative clinical consequences in patients with chronic pain scheduled for orthopaedic surgery. DESIGN: A prospective observational study. SETTINGS: Raymond Poincare teaching hospital. PATIENTS: Adults with or without long-term opioid treatment, scheduled for orthopaedic surgery. PRIMARY OUTCOME MEASURE: Preoperative hyperalgesia was assessed with eight quantitative sensory tests, in a pain-free zone. SECONDARY OUTCOME MEASURES: Postoperative morphine consumption and pain intensity were evaluated using a numerical rating scale (NRS) in the recovery room and during the first 72âh. RESULTS: We analysed results from 68 patients (28 opioid-treated patients and 40 controls). Mean daily opioid consumption was 42â±â25âmg of morphine equivalent. The opioid-treated group displayed significantly higher levels of preoperative hyperalgesia in three tests: heat tolerance threshold (47.1°C vs. 48.4°C; Pâ=â0.045), duration of tolerance to a 47°C stimulus (40.2 vs. 51.1âs; Pâ=â0.03) and mechanical temporal summation [1.79 vs. 1.02 (ΔNRS10-1); Pâ=â0.036]. Patients in the opioid-treated group consumed more morphine (19.1 vs. 9.38âmg; Pâ=â0.001), had a higher pain intensity (7.6 vs. 5.5; Pâ=â0.001) in the recovery room and a higher cumulative morphine dose at 72âh (39.8 vs. 25.6âmg; Pâ=â0.02). CONCLUSION: Chronic pain patients treated with low doses of opioid had hyperalgesia before surgery. These results highlight the need to personalise the management of patients treated with opioids before surgery. TRIAL REGISTRATION: ID-RCB 2011-A00304-37.
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Analgésicos Opioides/efectos adversos , Dolor Crónico/tratamiento farmacológico , Hiperalgesia/inducido químicamente , Morfina/efectos adversos , Procedimientos Ortopédicos/efectos adversos , Dolor Postoperatorio/inducido químicamente , Anciano , Analgésicos Opioides/administración & dosificación , Estudios de Casos y Controles , Dolor Crónico/diagnóstico , Dolor Crónico/fisiopatología , Femenino , Francia , Hospitales de Enseñanza , Humanos , Hiperalgesia/diagnóstico , Masculino , Persona de Mediana Edad , Morfina/administración & dosificación , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Dolor Postoperatorio/diagnóstico , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
In Alzheimer's disease, amyloid beta peptide (Aß) accumulation is associated with hippocampal network dysfunction. Intrahippocampal injections of Aß induce aberrant inhibitory septohippocampal (SH) network activity in vivo and impairment of memory processing. In the present study, we observed, after hippocampal Aß treatment, a selective loss of neurons projecting to the medial septum (MS) and containing calbindin (CB) and/or somatostatin (SOM). Other GABAergic neuronal subpopulations were not altered. Thus, the present study identifies hippocamposeptal neuron populations as specific targets for Aß deposits. We observed that in Aß-treated rats but not in controls, glutamate agonist application induced rhythmic bursting in 55% of the slow-firing neurons in the medial septum. This suggests that hippocampal Aß can trigger modifications of the septohippocampal pathway via the alteration of a specific neuronal population. Long-range hippocamposeptal GABA/calbindin neurons, targets of hippocampal amyloid deposits, are implicated in supporting network synchronization. By identifying this target, we contribute to the understanding of the mechanisms underlying deleterious effects of Aß, one of the main agents of dementia in Alzheimer's disease.
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Péptidos beta-Amiloides/toxicidad , Hipocampo/patología , Neuronas/patología , Potenciales de Acción/fisiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/administración & dosificación , Animales , Hipocampo/metabolismo , Hipocampo/fisiología , Masculino , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Vías Nerviosas/fisiología , Neuronas/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.
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Angiopatía Amiloide Cerebral/fisiopatología , Hipocampo/fisiopatología , Memoria/fisiología , Tabique del Cerebro/fisiopatología , Ritmo Teta , Ácido gamma-Aminobutírico/metabolismo , Potenciales de Acción , Péptidos beta-Amiloides/metabolismo , Animales , Angiopatía Amiloide Cerebral/patología , Hipocampo/patología , Masculino , Neuronas/patología , Neuronas/fisiología , Periodicidad , Ratas , Ratas Sprague-Dawley , Reconocimiento en Psicología/fisiología , Percepción Espacial/fisiología , Percepción Visual/fisiologíaRESUMEN
Cholinergic and GABAergic neurons in the medial septum-diagonal band of Broca (MS-DB) project to the hippocampus where they are involved in generating theta rhythmicity. So far, the functional properties of neurochemically identified MS-DB neurons are not fully characterized. In this study, MS-DB neurons recorded in urethane anesthetized rats and in unanesthetized restrained rats were labeled with neurobiotin and processed for immunohistochemistry against glutamic acid decarboxylase (GAD), parvalbumin (PV), and choline acetyltransferase (ChAT). The majority of the 90 labeled neurons (75.5%) were GAD+. Among them, 34.0% were also PV+, but none were ChAT+. Only 8.8% of the labeled neurons were found ChAT+. Remaining neurons (15.5%) were not identified. In anesthetized rats, all of the PV/GAD+ and 65% of GAD+ neurons exhibited burst-firing activity at the theta frequency. PV/GAD+ neurons displayed higher discharge rate and longer burst duration compared with GAD+ neurons. At variance, all of the ChAT+ neurons were slow-firing. Cluster-firing and tonic-firing were observed in GAD+ and unidentified neurons. In unanesthetized rats, during wakefulness or rapid eye movement sleep with hippocampal theta, the bursting neurons were PV/GAD+ or GAD+, whereas all of the ChAT+ neurons were slow-firing. Across the sleep-wake cycle, the GABAergic component of the septohippocampal pathway was always more active than the cholinergic one. The fact that cholinergic MS-DB neurons do not display theta-related bursting or tonic activity but have a very low firing rate questions how acetylcholine exerts its activating role in the septohippocampal system.
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Anestesia , Neuronas/fisiología , Tabique del Cerebro/fisiología , Animales , Colina O-Acetiltransferasa/metabolismo , Electrofisiología , Glutamato Descarboxilasa/metabolismo , Hipocampo/fisiología , Inmunohistoquímica , Masculino , Neuronas/metabolismo , Parvalbúminas/metabolismo , Ratas , Ratas Sprague-Dawley , Restricción Física , Tabique del Cerebro/citología , Tabique del Cerebro/metabolismo , Ritmo TetaRESUMEN
GABAergic septohippocampal neurons play a major role in the generation of hippocampal theta rhythm, but modulatory factors intervening in this function are poorly documented. The neuropeptide somatostatin (SST) may be one of these factors, because nearly all hippocampal GABAergic neurons projecting to the medial septum/diagonal band of Broca (MS-DB) express SST. In this study, we took advantage of the high and selective expression of the SST receptor sst2A in MS-DB to examine its possible role on theta-related activity. Immunohistochemical experiments demonstrated that sst2A receptors were selectively targeted to the somatodendritic domain of neurons expressing the GABAergic marker GAD67 but were not expressed by cholinergic neurons. In addition, a subpopulation of GABAergic septohippocampal projecting neurons expressing parvalbumin (PV) also displayed sst2A receptors. Using in vivo juxtacellular recording and labeling with neurobiotin, we showed that a number of bursting and nonbursting neurons exhibiting high discharge rates and brief spikes were immunoreactive for PV or GAD67 and expressed the sst2A receptor. Microiontophoresis applications of SST and the sst2A agonist octreotide (OCT) showed that sst2A receptor activation decreased the discharge rate of both nonbursting and bursting MS-DB neurons and lessened the rhythmic activity of the latter. Finally, intraseptal injections of OCT and SST in freely moving rats reduced the power of hippocampal EEG in the theta band. Together, these in vivo experiments suggest that SST action on MS-DB GABAergic neurons, through sst2A receptors, represents an important modulatory mechanism in the control of theta activity.
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Electroencefalografía , Hipocampo/efectos de los fármacos , Receptores de Somatostatina/fisiología , Somatostatina/farmacología , Ácido gamma-Aminobutírico/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Electroencefalografía/efectos de los fármacos , Hipocampo/fisiología , Inyecciones , Iontoforesis , Masculino , Vías Nerviosas/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Octreótido/administración & dosificación , Octreótido/farmacología , Parvalbúminas/análisis , Ratas , Ratas Sprague-Dawley , Receptores de Somatostatina/agonistas , Receptores de Somatostatina/efectos de los fármacos , Tabique Pelúcido/citología , Somatostatina/administración & dosificaciónRESUMEN
Ghrelin, an endogenous ligand for the GHS receptor, stimulates GH secretion and gastrointestinal motility and has orexigenic effects. In this study, the relationships between ghrelin, GH secretion, feeding behavior, and sleep-wake patterns were investigated in adult male rats. The half-life of exogenous ghrelin (10 microg i.v.) in plasma was about 30 min. Repeated administration of ghrelin at 3- to 4-h intervals (one during lights-on and two during lights-off periods) increased GH release and feeding activity, and decreased rapid eye movement sleep duration. Endogenous plasma ghrelin levels exhibited pulsatile variations that were smaller and less regular compared with those of GH. No significant correlation between GH and ghrelin circulating levels was found, although mean interpeak intervals and pulse frequencies were close for the two hormones. In contrast, ghrelin pulse variations were correlated with food intake episodes in the lights off period, and plasma ghrelin concentrations decreased by 26% in the 20 min following the end of the food intake periods. A positive correlation between ghrelin levels and active wake was found during the first 3 h of the dark period only. In conclusion, ghrelin, in addition to affecting GH secretion, gastrointestinal motility, and feeding activity, also modifies sleep-wake patterns. However, a direct action of ghrelin per se or the indirect effects of feeding (and all of its attendant metabolic sequelae) on sleep cannot be differentiated. Moreover, ghrelin secretion is pulsatile and directly related to feeding behavior only.