title: Deep brain stimulation of the periaqueductal gray releases endogenous opioids in humans.
abstract: Deep brain stimulation (DBS) of the periaqueductal gray (PAG) is used in the treatment of severe refractory neuropathic pain. We tested the hypothesis that DBS releases endogenous opioids to exert its analgesic effect using [11C]diprenorphine (DPN) positron emission tomography (PET). Patients with de-afferentation pain (phantom limb pain or Anaesthesia Dolorosa (n=5)) who obtained long-lasting analgesic benefit from DBS were recruited. [11C]DPN and [15O]water PET scanning was performed in consecutive sessions; first without, and then with PAG stimulation. The regional cerebral tracer distribution and kinetics were quantified for the whole brain and brainstem. Analysis was performed on a voxel-wise basis using statistical parametric mapping (SPM) and also within brainstem regions of interest and correlated to the DBS-induced improvement in pain score and mood. Brain-wide analysis identified a single cluster of reduced [11C]DPN binding (15.5% reduction) in the caudal, dorsal PAG following DBS from effective electrodes located in rostral dorsal/lateral PAG. There was no evidence for an accompanying focal change in blood flow within the PAG. No correlation was found between the change in PAG [11C]DPN binding and the analgesic effect or the effect on mood (POMSSV) of DBS. The analgesic effect of DBS in these subjects was not altered by systemic administration of the opioid antagonist naloxone (400ug). These findings indicate that DBS of the PAG does indeed release endogenous opioid peptides focally within the midbrain of these neuropathic pain patients but we are unable to further resolve the question of whether this release is responsible for the observed analgesic benefit.
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, United Kingdom; Department of Neurosurgery & Pain Medicine, North Bristol NHS Trust, Bristol BS10 5NB, United Kingdom.
authors.forename: Hugh
authors.initials: H
authors.lastname: Sims-Williams
authors.affiliation: Imaging Sciences, MAHSC, University of Manchester, M20 3LJ, United Kingdom.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Matthews
authors.affiliation: Imaging Sciences, MAHSC, University of Manchester, M20 3LJ, United Kingdom.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Talbot
authors.affiliation: Department of Neurosurgery & Pain Medicine, North Bristol NHS Trust, Bristol BS10 5NB, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Love-Jones
authors.affiliation: Clinical Research Imaging Centre (CRiCBristol), University of Bristol, Bristol BS2 8DZ, United Kingdom.
authors.forename: Jonathan Cw
authors.initials: JC
authors.lastname: Brooks
authors.affiliation: Department of Neurosurgery & Pain Medicine, North Bristol NHS Trust, Bristol BS10 5NB, United Kingdom.
authors.forename: Nikunj K
authors.initials: NK
authors.lastname: Patel
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, United Kingdom; Department of Anaesthesia, University Hospitals Bristol, Bristol BS2 8HW, United Kingdom. Electronic address: Tony.Pickering@Bristol.ac.uk.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Pickering
mesh_terms: D000328:Adult; D002250:Carbon Radioisotopes; D046690:Deep Brain Stimulation; D004174:Diprenorphine / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000378:metabolism / Q000517:prevention & control*; D018847:Opioid Peptides / Q000378:metabolism*; D010147:Pain Measurement; D010487:Periaqueductal Gray / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011957:Receptors, Opioid / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D002250:Carbon Radioisotopes; D018847:Opioid Peptides; D011957:Receptors, Opioid; D004174:Diprenorphine
keywords: De-afferentation; Deep brain stimulation; Endogenous opioid; Pain; Periaqueductal gray; Positron emission tomography