title: Building up analgesia in humans via the endogenous μ-opioid system by combining placebo and active tDCS: a preliminary report.
abstract: Transcranial Direct Current Stimulation (tDCS) is a method of non-invasive brain stimulation that has been frequently used in experimental and clinical pain studies. However, the molecular mechanisms underlying tDCS-mediated pain control, and most important its placebo component, are not completely established. In this pilot study, we investigated in vivo the involvement of the endogenous μ-opioid system in the global tDCS-analgesia experience. Nine healthy volunteers went through positron emission tomography (PET) scans with [11C]carfentanil, a selective μ-opioid receptor (MOR) radiotracer, to measure the central MOR activity during tDCS in vivo (non-displaceable binding potential, BPND)--one of the main analgesic mechanisms in the brain. Placebo and real anodal primary motor cortex (M1/2mA) tDCS were delivered sequentially for 20 minutes each during the PET scan. The initial placebo tDCS phase induced a decrease in MOR BPND in the periaqueductal gray matter (PAG), precuneus, and thalamus, indicating activation of endogenous μ-opioid neurotransmission, even before the active tDCS. The subsequent real tDCS also induced MOR activation in the PAG and precuneus, which were positively correlated to the changes observed with placebo tDCS. Nonetheless, real tDCS had an additional MOR activation in the left prefrontal cortex. Although significant changes in the MOR BPND occurred with both placebo and real tDCS, significant analgesic effects, measured by improvements in the heat and cold pain thresholds, were only observed after real tDCS, not the placebo tDCS. This study gives preliminary evidence that the analgesic effects reported with M1-tDCS, can be in part related to the recruitment of the same endogenous MOR mechanisms induced by placebo, and that such effects can be purposely optimized by real tDCS.
authors.affiliation: Headache & Orofacial Pain Effort (H.O.P.E.), Department of Biologic and Materials Sciences & Michigan Center for Oral Health Research (MCOHR), School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Marcos F
authors.initials: MF
authors.lastname: DosSantos
authors.affiliation: Headache & Orofacial Pain Effort (H.O.P.E.), Department of Biologic and Materials Sciences & Michigan Center for Oral Health Research (MCOHR), School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America; Translational Neuroimaging Laboratory, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Ilkka K
authors.initials: IK
authors.lastname: Martikainen
authors.affiliation: Headache & Orofacial Pain Effort (H.O.P.E.), Department of Biologic and Materials Sciences & Michigan Center for Oral Health Research (MCOHR), School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Thiago D
authors.initials: TD
authors.lastname: Nascimento
authors.affiliation: Translational Neuroimaging Laboratory, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Love
authors.affiliation: Headache & Orofacial Pain Effort (H.O.P.E.), Department of Biologic and Materials Sciences & Michigan Center for Oral Health Research (MCOHR), School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Misty D
authors.initials: MD
authors.lastname: DeBoer
authors.affiliation: Departments of Neurology and Rehabilitation & Regenerative Medicine, Columbia University, New York, New York, United States of America.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Schambra
authors.affiliation: Department of Biomedical Engineering, The City College of New York, New York, New York, United States of America.
authors.forename: Marom
authors.initials: M
authors.lastname: Bikson
authors.affiliation: Translational Neuroimaging Laboratory, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Jon-Kar
authors.initials: JK
authors.lastname: Zubieta
authors.affiliation: Headache & Orofacial Pain Effort (H.O.P.E.), Department of Biologic and Materials Sciences & Michigan Center for Oral Health Research (MCOHR), School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America; Translational Neuroimaging Laboratory, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Alexandre F
authors.initials: AF
authors.lastname: DaSilva
mesh_terms: D000328:Adult; D000698:Analgesia / Q000379:methods*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000704:Analysis of Variance; D005260:Female; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000378:metabolism*; D049268:Positron-Emission Tomography; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D065908:Transcranial Direct Current Stimulation / Q000379:methods*
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; C017114:carfentanil; D005283:Fentanyl