Repetitive transcranial magnetic stimulation induced analgesia depends on N-methyl-d-aspartate glutamate receptors

Abstract

We investigated the role of glutamate N-methyl-d-aspartate (NMDA) receptors in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). In a randomized, double-blind, crossover study, we compared the effects of ketamine and placebo on the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex/premotor cortex (DLPFC/PMC) stimulation. Three groups of 12 healthy volunteers underwent active rTMS (10Hz, 80% resting motor threshold, 1,500 pulses per session) of the right M1, active stimulation of the right DLPFC/PMC, or sham stimulation during 2 experimental sessions 2 weeks apart. Cold pain thresholds were measured on the left thenar eminence before and 1 hour after cortical stimulation, to evaluate the analgesic effects of rTMS. Ketamine (0.15 mg/kg in a 10-minute bolus followed by continuous infusion of 6 μg/kg per minute until the end of rTMS) or placebo (saline) were administered intravenously during cortical stimulation. We also systematically measured cortical excitability parameters (resting motor threshold, suprathreshold motor-evoked potentials, short intracortical inhibition, and intracortical facilitation) before and after treatment, to investigate the possible relationship between changes in cortical excitability and rTMS-induced analgesia. Ketamine injection significantly decreased the analgesic effects of both M1 and DLPFC/PMC stimulation. The decrease in the analgesic effect of rTMS was not associated with changes in cortical excitability parameters, which were not influenced by rTMS following the administration of either saline or ketamine. Thus, rTMS-induced analgesia depends on glutamate NMDA receptors and may involve long-term potentiation-like mechanisms.

High frequency repetitive transcranial magnetic stimulation to the left dorsolateral prefrontal cortex modulates sensorimotor cortex function in the transition to sustained muscle pain

“…In contrast, the active rTMS group showed lower levels of muscle soreness, disability in hand function and muscle hyperalgesia, supporting the notion that activation of the left DLPFC is a possible target for pain modulation (Borckardt et al, 2014;Mylius et al, 2012;Taylor et al, 2013). Although the mechanisms involved in this analgesic effect are still debated, possible mechanisms of left DLPFC rTMS analgesia could include activation of the descending modulatory endogenous opioidergic system (Taylor et al, 2013), or the involvement of other mechanisms, such as cognitive behavior or mood state, mediated by glutamatergic, dopaminergic and serotonergic systems (Cho & Strafella, 2009;Ciampi De Andrade et al, 2014;Sibon et al, 2007).…”

“…For instance, using neuroimaging techniques, nociceptive stimuli in healthy subjects have shown a response of the left DLPFC (Freund et al, 2009). In addition, rTMS of the left DLPFC has been applied as a therapeutic target in short-lasting experimentally induced pain (Ciampi De Andrade et al, 2014;Taylor et al, 2012), as well as post-surgical pain (Borckardt et al, 2008, Borckardt et al, 2014, indicating that left DLPFC rTMS has a modulatory effects on pain detection. In addition, left DLPFC has several reciprocal connections with brain regions associated with sensorimotor cortical excitability, including the caudate nucleus, putamen, substantia nigra, and the thalamus (Alexander, 1986;Aron et al, 2007;Chudler & Dong, 1995;Middleton, 2002), making it reasonable to propose that left DLPFC stimulation modulates the sensorimotor cortical excitability through its effects on subcortical regions (Fierro et al, 2010).…”

Endogenous central suppressive mechanisms regulating cough as potential targets for novel antitussive therapies

“…[41]). Furthermore, there is certainly corroborating evidence from studies variously involving patients with neurodegeneration, pharmacological interventions and transcranial magnetic stimulation that dysfunction, antagonism or inhibition of the DLPFC attenuates placebo effects [24,28,42,43], while stimulation of the DLPFC may induce analgesia [44,45]. Similarly, while altered descending control is widely considered an important contributing factor in the development of aberrant pain syndromes [36 ,37], the current focus in this regard is to develop treatments that combat the central sensitization processes that likely underpin the alterations in descending control rather than directly targeting the descending inhibitory pathways per se.…”

O efeito da estimulação magnética transcraniana repetitiva do córtex pré-frontal dorsolateral esquerdo na dor central decorrente de acidente vascular cerebral

“…De acordo com estudos sobre dor experimental realizados em voluntários saudáveis, demonstrou-se que a EMTr do M1 e do CPFDL modifica o processamento central das percepções térmicas ao frio e ao calor e pode modular as redes neuroniais envolvidas no processamento da dor evocada pelo frio de Andrade et al, 2014 (Lorenz et al, 2003;Brighina et al, 2011 (Hadley et al, 2011), corroborando as evidências do presente estudo.…”

“…anteriormente (Ahdab et al, 2010) ao ponto recomendado de 5 cm, que corresponde, de fato, ao córtex prémotor (CPM)/CPFDL (de Andrade et al, 2014). A metodologia de localização da bobina sobre a região do CPM/CPFDL esquerdo empregado no presente estudo é a mesma utilizada na maioria das pesquisas sobre a EMTr na depressão (PascualLeone et al, 1996;George et al, 2000;Fitzgerald et al, 2002;Rumi et al, 2005;Rosa et al, 2006) (Eisendrath, 1995;Gallagher;Verma, 2004) ou com AVC (Herrmann et al, 1995;Hackett;Anderson, 2005;Loubinoux et al, 2012).…”