The present thesis aims to contribute to a better understanding of the mechanisms underlying the development of long-lasting pain.
Animal models of long-term potentiation (LTP) induced by noxious stimuli are extensively used to study cellular memory of nociceptive information. The present thesis investigates, by electrophysiology and positron emission tomography (PET), the correlation between spinal LTP and supraspinal nociceptive processing, assessing both the effect on neuronal metabolic activity and opioidergic neurotransmission. Also, this thesis evaluates two new PET tracers for targeting opioid receptors (OR), and a 3-D brain atlas system for enhanced interpretation of tomographic image data.
After spinal LTP induced by high-frequency stimulation (HFS) of the sciatic nerve, PET studies indentified metabolic changes and reduced opioid neurotransmission in brain regions involved in pain modulation, emotions, learning and memory. These findings indicate an insufficient inhibition in the descending pain modulatory network, which might explain the maintenance of spinal LTP and cause states of abnormal pain sensitivity.
The evaluation of two novel OR PET ligands verified their use for investigating changes in OR availability during in vivo animal PET studies.
List of papers. Papers II and III are removed from the thesis due to copyright restrictions.
Paper I Three-dimensional atlas system for mouse and rat brain imaging data Hjornevik T, Leergaard TB, Darine D, Moldestad O, Dale AM, Willoch F, and Bjaalie JG Front Neuroinform (2007) 1:4 This Document is protected by copyright and was first published by Frontiers. All rights reserved. It is reproduced with permission DOI: 10.3389/neuro.11.004.2007
Paper II Hjornevik T, Jacobsen LM, Qu H, Bjaalie JG, Gjerstad J, and Willoch F Metabolic plasticity in the supraspinal pain modulating circuitry after noxious stimulus-induced spinal cord LTP PAIN (2008) 140:456-464 DOI: 10.1016/j.pain.2008.09.029
Paper III Marton J, Schoultz BW, Hjornevik T, Drzezga A, Yousefi BH, Wester HJ, Willoch F, and Henriksen G Synthesis and Evaluation of a Full-Agonist Orvinol for PETImaging of Opioid Receptors: [11C]PEO J. Med. Chem. (2009) 52(18):5586–5589 DOI: 10.1021/jm900892x
Paper IV Hjornevik T, Schoultz BW, Marton J, Gjerstad J, Drzezga A, Henriksen G, and Willoch F Spinal long-term potentiation is associated with reduced opioid neurotransmission in the rat brain. Submitted version. Clin Physiol Funct Imaging (2010) 30(4):285–293 The definitive version is available at www3.interscience.wiley.com DOI: 10.1111/j.1475-097X.2010.00939.x
Paper V Schoultz BW, Hjornevik T*, Willoch F, Marton J, Noda A, Murakami Y, Miyoshi S, Nishimura S, Årstad E, Drzezga A, Matsunari I, and Henriksen G. Evaluation of the Kappa-Opioid Receptor Selective Tracer [11C]GR103545 in Awake Rhesus Macaques. Submitted version. Eur J Nucl Med Mol Imaging (2010) 37:1174–1180 The original publication is available at www.springerlink.com DOI: 10.1007/s00259-010-1384-6