Dr. Wilcox and colleagues are engaged in research into the spinal neurotransmission of pain and mechanisms underlying hyperalgesia, analgesia and analgesic tolerance. Studies of both excitatory and inhibitory neurotransmission in the rodent spinal cord apply behavioral, lectrophysiological (both in vivo and in vitro), immunocytochemical and molecular techniques.
Behavioral experiments define biologically relevant interactions, which are then examined at the cellular and molecular level using the more reductionist approaches. A key feature of research projects in this laboratory is open collaboration with laboratories located both here and at other universities.
One major thrust of these investigations examines neurotransmitters thought to mediate major components of excitatory neurotransmission from primary afferent sensory fibers to secondary projection neurons in spinal cord dorsal horn: the excitatory amino acids (EAAs) like glutamate and the neurokinins like substance P. Intense or prolonged excitatory transmission via both these pathways is thought to evoke long term synaptic plasticity and excitotoxicity, which may underlie the development of some chronic pain states.
A second major focus of work in the laboratory is the characterization of several inhibitory neurotransmitters, their receptors and drugs that interact with those receptors, which together modulate this excitation. The neurotransmitters, enkephalin, serotonin and noradrenaline, inhibit various components of the incoming excitatory pain message in the dorsal horn via a number of inhibitory receptor subtypes. We are characterizing the interactions between these receptor subtypes and localizing them using optogenetic mice, transgenic mice, antisense oligonucleotides and immunocytochemical techniques.
A recent offshoot of this second major focus is the invention and characterization of a combination of opioid analgesics that silences chronic pain in the periphery at very low doses through a synergistic drug-drug interaction. The two opioid receptor subtypes mediating this synergistic interaction are the mu- and delta-opioid receptors, and the mu-opioid receptor agonist, loperamide (tradename Imodium), is excluded from the brain by the blood-brain barrier. Therefore, the combination manifests neither of the brain-mediated side effects of addiction and lethal respiratory depression seen so often with other frequently prescribed mu-opioid receptor agonists like morphine, oxycodone, hydromorphone and fentanyl. The university’s Office of Technology Transfer is working closely with Dr. Wilcox, collaborators and outside companies to transition the combination through the safety testing required for FDA approval (http://license.umn.edu/technologies/20160199_pain-therapy-without-the-ri...).
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
- Bruce DJ, Peterson CD, Kitto KF, Akgün E, Lazzaroni S, Portoghese PS, Fairbanks CA, Wilcox GL. Combination of a δ-opioid receptor agonist and loperamide produces peripherally-mediated analgesic synergy in mice. Anesthesiology. 2019;131(3):649-663.
- Peterson CD, Kitto KF, Akgün E, Lunzer MM, Riedl MS, Vulchanova L, Wilcox GL, Portoghese PS, Fairbanks CA. Bivalent ligand that activates mu opioid receptor and antagonizes mGluR5 receptor reduces neuropathic pain in mice. Pain. 2017;158(12):2431-2441.
- Barney CC, Tervo R, Wilcox GL, Symons FJ. A case-controlled investigation of tactile reactivity in young children with and without global developmental delay. Am J Intellect Dev Disabil. 2017;122(5):409-421.
- Uhelski ML, Bruce DJ, Séguéla P, Wilcox GL, Simone DA. In vivo optogenetic activation of Nav1.8+ cutaneous nociceptors and their responses to natural stimuli. J Neurophysiol. 2017;117(6):2218-2223.
- Barney CC, Merbler AM, Quest K, Byiers BJ, Wilcox GL, Schwantes S, Roiko SA, Feyma T, Beisang A, Symons FJ. A case-controlled comparison of postoperative analgesic dosing between girls with Rett syndrome and girls with and without developmental disability undergoing spinal fusion surgery. Paediatr Anaesth. 2017;27(3):290-299.
- Chabot-Doré AJ, Millecamps M, Naso L, Devost D, Trieu P, Piltonen M, Diatchenko L, Fairbanks CA, Wilcox GL, Hébert TE, Stone LS. Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors. Neuropharmacology. 2015;99:285-300.
- Wilcox CE, Mayer AR, Teshiba TM, Ling J, Smith BW, Wilcox GL, Mullins PG. The subjective experience of pain: An fMRI study of percept-related models and functional connectivity. Pain Med. 2015;16(11):2121-33.
- Symons FJ, ElGhazi I, Reilly BG, Barney CC, Hanson L, Panoskaltsis-Mortari A, Armitage IM, Wilcox GL.Can biomarkers differentiate pain and no pain subgroups of nonverbal children with cerebral palsy? A preliminary investigation based on noninvasive saliva sampling. Pain Med. 2015;16(2):249-56.
- Chabot-Doré AJ, Schuster DJ, Stone LS, Wilcox GL. Analgesic synergy between opioid and α2 -adrenoceptors. Br J Pharmacol. 2015;172(2):388-402.
- Schuster DJ, Metcalf MD, Kitto KF, Messing RO, Fairbanks CA, Wilcox GL. Ligand requirements for involvement of PKCε in synergistic analgesic interactions between spinal μ and δ opioid receptors. Br J Pharmacol. 2015;172(2):642-53.
- Stone LS, German JP, Kitto KF, Fairbanks CA, Wilcox GL. Morphine and clonidine combination therapy improves therapeutic window in mice: synergy in antinociceptive but not in sedative or cardiovascular effects. PLoS One. 2014 Oct 9;9(10):e109903.
- Schuster DJ, Kitto KF, Overland AC, Messing RO, Stone LS, Fairbanks CA, Wilcox GL. Protein kinase Cε is required for spinal analgesic synergy between delta opioid and alpha-2A adrenergic receptor agonist pairs. J Neurosci. 2013;33(33):13538-46.
Current Graduate Students:
Rebecca Speltz Paiz (Neuroscience, University of Minnesota).
Former Graduate Students:
Kristin Schreiber (Ph.D. 2004, Neuroscience, University of Minnesota).
Daniel Schuster (Ph.D. 2013, Neuroscience, University of Minnesota).
Aaron Overland (Ph.D. 2010, Neuroscience, University of Minnesota).
Cory Jo Goracke-Postle (Ph.D. 2007, Neuroscience, University of Minnesota).
Lois Jean Kehl (Ph.D. 1996, Neuroscience, University of Minnesota).
Rogene Eichler West (Ph.D. 1996, Neuroscience, University of Minnesota).
Laura Stone (Ph.D. 1999, Neuroscience, University of Minnesota).