Kelly M Standifer

Contact Information:
Kelly M Standifer



 

Standifer, Kelly M. (HSC)
Professor and Chair

Department of:

College Of Pharmacy/Pharmaceutical Sciences -Professor and Chair

Center of:

OK Center for Neurosciences -Member

Education:

University of Florida, Gainesville, FL   PhD   1988

Professional Interest/Expertise/Specializations:
Research interests, ultimately, is to develop alternative therapeutic options (to morphine) for the treatment of severe pain. The newest member of the opioid receptor family, opioid receptor like-1 receptor (ORL1), and its endogenous agonist, orphanin FQ/nociceptin (OFQ/N), have been strongly implicated in the development of morphine tolerance. Chronic morphine treatment increases levels of OFQ/N; blocking the actions of OFQ/N significantly reduce the extent to which the analgesic actions of morphine are reduced. Using human neuronal cell lines that natively express mu and ORL1 receptors, we study the cellular mechanisms of ORL1 and mu opioid receptor activation (by the endogenous peptides OFQ/N and Dynorphin, and the synthetic agonists, DAMGO and morphine), and the cellular mechanisms of ORL1- and mu opioid receptor-mediated mu and ORL1 tolerance and cross-tolerance. Acutely, OFQ/N activates protein kinase C (PKC), which activates and translocates G protein-coupled receptor kinase 2 (GRK2) and GRK3 to the cell membrane where GRK2 can quickly desensitize the mu opioid receptor in the presence of a mu opioid agonist such as morphine. Our next step is to determine where these changes occur in vivo, and how they might be manipulated to reduce the extent of morphine tolerance development. ORL1 desensitization is produced by GRK3. Tolerance induced by prolonged exposure to OFQ/N and/or morphine treatment also involves GRK. Similar to morphine, prolonged OFQ/N treatment (24 h or more) upregulates GRK levels. Ultimately, though, it is the increased availability of GRK that produces the rapid tolerance and/or cross-tolerance upon challenge with an agonist. We are in the process of studying ORL1 phosphorylation sites, and how mutation of these sites affects receptor function.

Websites:

Dr. Standifer website profile

Research Projects:

Synergistic Chemo-siRNA Combination Therapy (DHHS/NIH/NCI - through Optimum Therapeutics)
Optimum Therapeutics Subcontract (NIH)
Modulation of Inflammatory Mechanisms Underlying Chronic Pain of Post Traumatic Stress Disorder:Prevention & Treatment (PHF)
Multi-Modal Protein and RNA Visualization and Quantification (PHF - equipment)
Development of Metabolic Syndrome in an Animal Model of PTSD (COP Seed)

Selected Publications:

Blast Overpressure Waves Induce Transient Anxiety and Regional Changes in Cerebral Glucose Metabolism and Delayed Hyperarousal in Rats
2015    Awwad HO, Goznalez LP, Tompkins P, Lerner M, Brckett DJ, Awasthi V, Standifer KM
Front Neurology
The Effect of Sustained Supraspinal Nociceptin/Orphanin FQ Administration on Nociceptive Sensitivity and NOP Receptor Activity and Expression in vivo.
2014    Donica CL, Simpson-Durand CD, Zhang Y and Standifer KM
Neuropharmacology
ERK1/2 mediated transcriptional regulation of GRK3 expression in neuronal cells.
   Salim S, Standifer KM, Eikenburg DC.
J Pharmacol Exp Ther 321: 51-59
Involvement of G protein-coupled kinase (GRK)3 and GRK2 in down-regulation of the a2b-adrenoceptor.
   Desai AN, Salim S, Standifer KM, Eikenburg DC
J Pharmacol Exp Ther 317, 1027-35
Distribution of Plasma Membrane-Associated Syntaxins 1 through 4 Indicates Distinct Trafficking Functions in the Synaptic Layers of the Mouse Retina.
   Sherry DM, Mitchell R, Standifer KM, du Plessis B
BMC Neuroscience 7:54
Orphanin FQ/nociceptin potentiates DAMGO-induced µ opioid receptor phosphorylation.
   Ozsoy HZ, Thakker DR and Standifer KM
Mol Pharmacol 68, 447-56
Cellular G protein-coupled receptor kinase levels regulate the sensitivity of the a2b-adrenergic receptor to undergo agonist-induced down-regulation.
   Desai AN, Standifer KM, Eikenburg DC
J Pharmacol Exp Ther 312, 767-73
Morphine induces Mu opioid receptor internalization in BE(2)-C human neuroblastoma cells.
   Ramirez VI and Standifer KM
Soc. Neurosci Abstr
Dynorphin A(2-17) is an opioid receptor like-1 receptor agonist.
   Standifer KM, Christensen JL, Gee JS and Mandyam CD
Society for Neuroscience abstract
Nociceptin/orphanin FQ (N/OFQ) induces mu opioid receptor internalization.
   Ramirez, VI, Sherry DM and Standifer KM
Society for Neuroscience abstract
Cellular GRK levels determine the threshold concentration for agonist-induced downregulation of the a2-AR.
   Gokhale AA, Standifer KM and Eikenburg DC
Experimental Biology
Simultaneous alpha2B- and beta2-adrenoceptor activation sensitizes the alpha2B-adrenoceptor for agonist-induced down-regulation.
   Desai AN, Standifer KM, Eikenburg DC
J Pharmacol Exp Ther. 311, 794-802
Nociceptin
   Kelly M. Standifer
xPharm: ExecutiveEditors: S.J. Enna and David B. Bylund; Publisher, Elsevier, Inc., New York.
http://www.xpharm.com/citation?Article_ID=9093
[Phe1-y-(CH2NH)Gly2]Nociceptin (1-13)NH2
   Kelly M. Standifer
xPharm. Executive Editors: S.J. Enna and David B. Bylund; Publisher, Elsevier, Inc., New York.
http://www.xpharm.com/citation?Article_ID=7699
Nociceptin Orphanin FQ (1-13)NH2
   Kelly M. Standifer
xPharm; Executive Editors: S.J. Enna and David B. Bylund; Publisher, Elsevier, Inc., New York.
http://www.xpharm.com/citation?Article_ID=9094
Mu opioid-induced desensitization of ORL1 and mu opioid receptors: Differential intracellular signaling determines receptor sensitivity.
   Mandyam CD, Thakker DR and Standifer KM
J Pharmacol Exp Ther.306, 965-972
Desensitization of a2A-adrenoceptor signaling by modest levels of adrenaline is facilitated by b2-adrenoceptor-dependent GRK3 up-regulation.
   Bawa T, Altememi GF, Eikenburg DC and Standifer KM.
Br J Pharmacol. 138, 921-931
Dynorphin A(2-17) is an opioid receptor-like1 receptor (ORL1) agonist. 6th Annual Pharmacy Student Research Conference ¿ Western Region. *Received Best Basic Science poster award
   Christensen JL, Mandyam CD and Standifer KM

Chronic co-activation of the a2B- and ß2-adrenoceptor (AR) facilitates desensitization of the a2B-AR. FASEB Abstract # 143.6
   A.A. Gokhale, K.M. Standifer and D.C. Eikenburg.

Orphanin FQ/nociceptin (OFQ/N) pretreatment potentiates DAMGO-induced mu opioid receptor phosphorylation.
   Ozsoy HZ, Mandyam CD and Standifer KM
Soc. Neurosci. Abstract
Intracellular signaling components determine the sensitivity of ORL1 and mu receptors to DAMGO-mediated desensititization.
   Standifer KM, Thakker DR and Mandyam CD
International Narcotics Research Conference, Perpignan, France
Orphanin FQ/nociceptin (OFQ/N) pretreatment potentiates DAMGO-induced mu opioid receptor phosphorylation.
   Ozsoy HZ, Mandyam CD and Standifer KM
International Narcotics Research Conference, Perpignan, France
Assessing opioid regulation of adenylyl cyclase activity in intact cells.
   Thakker, D.R., Ozsoy HZ and Standifer, K.M.
Methods in Molecular Medicine, vol 84. IN Opioid Research: Methods and Protocols (Pan, ZZ, ed.), pp 29-37. Humana Press, Totowa, New Jersey
Assessing opioid regulation of adenylyl cyclase activity in intact cells.
   Thakker DR, Ozsoy HZ, Standifer KM.
Methods in Molecular Medicine, vol 84. IN Opioid Research: Methods and Protocols (Pan, ZZ, ed.), pp 29-37. Humana Press, Totowa, New Jersey
Actions of dynorphin A peptides at ORL1 and m opioid receptors. 5th Annual Pharmacy Student Research Conference ¿ Western Region. *Received Best Basic Science poster award
   Christensen JL, Mandyam CD and Standifer KM

Nociceptin/Orphanin FQ Peptide Receptor Antagonist, JTC-801, Reverse Pain and Anxiety Symptoms in a Rat Model of PTSD.
   Zhang Y, Simpson-Durand CD and Standifer KM
Br. J. Pharmacol
Post-blast Treatment with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Antagonist Reduces Brain Ingury-induced Hypoxia and Signaling Protein in Vestibulomotor-related Brain Regions
   Awwad HO, Simpson-Durand C, Gonzalez LP, Tompkins P, Zhang Y, Lerner M, Brackett DJ, Sherry DM, Awasthi V, Stanififer KM
Scientifc Reoports
Sensitivity of alpha(2)-adrenoceptors to desensitization after chronic epinephrine treatment incrases in the presence of beta(2)-adrenoceptors.
   Bawa T, Altememi GF, Mandyam CD, Schwaarz LA, Eikenburg DC, Standifer KM.
BMC Pharmacol 7:16
Methylnaltrexone in the treatment of opioid-induced constipation.
   Greenwood-Van Meerveld B, Standifer KM.
Clin Exper Gastroenterol 1: 49-58
Naloxone benzothydrazone activates extracellular signal-regulated protein kinases and modulates nociceptin opioid peptide receptor activity.
   Thakker DR, Altememi GF, Mandyam CD, Ibrahim H, Ramirez VI, Standifer KM.
Am J Pharmacol Toxicol 2(2): 51-59
Keywords, Tags:
opioid, morphine,