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PHM142 Fall 2016 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson What is Placebo? A Nocebo? • placebo: an inert substance/kind of treatment that is a “lookalike” of a real treatment/substance - used in blind trials as a comparator to see the efficacy of new drugs - intertwined in scheduling of certain pharmaceuticals (e.g. birth control) • placebo effect: a beneficial psycho-physiological effect produced by placebo - an effect similar to patients who are on opioids (pain management drug) - mid-frontal gyrus region • nocebo effect: placebo treatment resulting in negative side effects The CNS, Neurotransmitters & Components • central nervous system (CNS): brain and spine • synapse: junction between 2 nerve cells; pre-synaptic and post-synaptic ends - calcium channels - exocytosis of neurotransmitters in secretory vesicles - ligand-gated receptors on postsynaptic ends • neurotransmitter: chemical messenger - acetylcholine: all pre-ganglionic nerve cells - dopamine: pleasure, memory, sleep, memory http://antranik.org/wp-content/uploads/2012/04/synapse.jpg Receptors & Pain • nociception: sensory nervous system's response to certain harmful stimuli • opioid receptors: group of inhibitory G protein-coupled receptors with opioids as ligands/agonists (morphine especially) - mu, kappa & gamma - found at brain, spine & GI tract http://www.proteopedia.org/wiki/i mages/thumb/5/57/Rec.gif/200pxRec.gif • cholecystokinin (CCK) B receptors: Gprotein coupled receptors, bind peptide hormones CCK & gastrin - found primarily at CNS, lesser amounts at GI tract - regulate nociception & induce anxiety - also regulate hunger & memory http://dericbownds.net/uploaded_images/Placebo_Nocebo.jpg Endogenous Opioid Pathway • Endogenous opioid action inhibits pain • Increased activation at mu-opioid receptor measured using PET scans • Levels of endorphins (specifically Peak B) in the CSF increased after placebo administration in chronic pain patients http://www.the-scientist.com/?articles.view/articleNo/38989/title/Painand-Progress/ Endogenous Opioid Pathway • Naloxone: Mu-Opioid Receptor Antagonist • When naloxone is administered following a placebo, it inhibits the analgesic effect of the placebo • This is similar to what occurs with other opioid (“painkilers”), such as morphine, hydrocodone, & fentanyl http://ocw.tufts.edu/Content/41/lecturenotes/530115/530158 Cholecystokinin-8 (CCK-8) • CCK-8 modulates a person’s experience of pain • CCK-8, inhibits the action of opioids - “anti-opioid peptide” • Elevated CCK mRNA in rats tolerant to morphine • CCK-8 knocked-down by antisense vectors, reduced mRNA levels and peptide production - leading to increased analgesia http://www.choprafoundation.org/health/a-better-way-to-approachpain-and-americas-pain-pill-epidemic/ Cholecystokinin-8 (CCK-8) • Proglumide: CCK receptor antagonist • Patients given placebo, then given a dose of proglumide • Patients noted increased analgesia • Effects only observed with higher doses of drug • Unspecific binding of proglumide to CCK-receptor - result could actually stem from other mechanisms, further investigation is required http://physrev.physiology.org/content/93/3/1207 Dopamine & Pain & Analgesia • Inhibition of Pain: Dopamine – Parkinson’s http://www.leafscience.com/wp-content/uploads/2014/05/marijuana-and-dopamine-2.jpg • Burning Mouth Syndrome, Fibromyalgia, Restless Leg Syndrome • Analgesic Properties & Dopamine Antagonists Dopamine = Analgesia = Pain Dopamine & Pain Plasticity • Mice Model • Acute Pain vs. Chronic Pain http://gogreenpestcontrol.ca/wp-content/uploads/2015/02/000656_lg.jpg • A11 (dopamine-containing neurons) – Toxin removed chronic pain signal http://www.healthable.org/wp-content/uploads/2016/05/Chronic-Pain.jpg Dopamine & Placebo • Placebo = endogenous dopamine (Dorsal & Ventral Striatum) • Ventral Striatum related to Reward Processes • Reward Circuitry http://acoustics.org/wp-content/uploads/2014/10/Lawless_Figure1.jpg General Findings from Studies of the Placebo Effect on Pain: • Enhance the endogenous opioid pathway – Their actions can be modulated by levels of CCK • Increase dopamine release leading to an increase in analgesia – Increase analgesia = decrease in pain http://www.nature.com/nrn/journal/v6/n7/full/nrn1705.html Examples of Other Effects of Placebo on the CNS: Parkinson’s Disease: • Patient demonstrating increased dopamine release after receiving the placebo Depression: • Fluoxetine (serotonin-uptake inhibitor) and placebo produced similar effects on the orbitofrontal cortex and ventral striatum http://journals2.scholarsportal.info.myaccess.library.utoronto.ca/details/03621642/v48ino ne/33_mopapeadat.xml?q=Fabrizio%20Benedetti&search_in=AUTHOR&sub=#BIB27 http://journals2.scholarsportal.info.myaccess.library.utoronto.ca/details/03621642/v48inone/33 _mopapeadat.xml?q=Fabrizio%20Benedetti&search_in=AUTHOR&sub=#BIB27 “Maybe we should invest in placebos” by Chris Madden http://www.drugsdb.com/blog/the-placebo-effect.html Summary Slide • Placebo => an inert substance used as a comparator in many different drug trials • Opioid receptors are a group of inhibitory G protein-coupled receptors that play a role in pain modulation • Proposed Mechanisms of Action: – Placebo administration has been found to enhance the activation of muopioid receptors and increase the levels of endorphins (natural “painkillers”) in the body • CCK-8 inhibits the placebo’s effect on the mu-opioid receptor • Suppression of CCK-8 action, increases the pain analgesia response of a placebo – Placebo increases the release of endogenous dopamine (in the dorsal and ventral striatum), and it is suspected that this may be involved in analgesia • The placebo effect is observed in other CNS disorders in addition to pain – The mechanisms of actions may involve different neurotransmitters, hormones and pathways that modulate the activity of the CNS References Amanzio, M., & Bendetti, F. (1999). Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus Conditioning activated specific subsystems. Journal of Neuroscience, 19(1), 484-494. American Cancer Society. 2015. Placebo effect. http://www.cancer.org/treatment/treatment andsideeffects/treatmenttypes/placebo-effect (accessed Oct 29, 2016). Benedetti, F. (2008). Mechanisms of placebo and placebo-related effects across diseases and treatments. Annual Review of Pharmacology and Toxicology, 48, 33-60. doi:10.1146/annurev.pharmtox.48.113006.094711 Bendetti, F., Amanzio, M., & Maggi, G. (1995). Potentiation of placebo analgesia by proglumide. The Lancet, 346(8984) 1231. doi:10.1016/s0140-6736(95)92938-x De la Fuente-Fernandez, R., & Stoessl, A.J. (2004). The biochemical bases of the placebo effect. Sci Eng Ethics, 10, 143-150. De la Fuente-Fernández, R., Lidstone, S., Stoessl, A.J. (2006). Placebo effect and dopamine release. Journal of Neural Transmission. Supplementa. (70):415-418. Ding, X. Z., & Bayer, B. M. (1993). Increases of CCK mRNA and peptide in different brain areas following acute and chronic administration of morphine. Brain Research, 625(1), 139-144. doi:10.1016/0006-8993(93)90146-e Kim, J.Y., Tillu, D.V., Quinn, T.L., Mejia, G.L., Shy, A., Asiedu, M.N., Murad, E., Schumann, A.P., Totsch, S.K., Sorge, R.E., et al. (2015). Spinal dopaminergic projections control the transition to pathological pain plasticity via a D1/D5-mediated mechanism. Journal of Neuroscience. 35(16):6307-6317. References Lipman, J.J., Miller, B.E., Mays, K.S., Miller, M.N., North, W.C., & Byrne, W.L. (1990). Peak B endorphin concentration in cerebrospinal fluid: reduced in chronic pain patients and increased during the placebo response. Psychopharmacology, 102(1), 112-116. doi:10.1007/bf00245754 News Medical Life Science. 2016. Scientists pinpoint the brain region responsible for ‘placebo effect’ in pain relief. http://www.ne Ws-medical.net/news/20161027/Scientists-pinpoint-the-brain-region-responsible-for-e28098placebo-effects28099-inpainrelief.aspx (accessed Oct 29, 2016). Tang, N., Dong, H., Wang, X., Tsui, Z., & Han, J. (1997). Cholecystokinin antisense RNA increases the analgesic effect induced by electroacupuncture or low dose morphine: conversion of low responder rats into high responders. Pain, 71(1), 71-80. doi:10.1016/s0304-3959(97)03341-1 Zubieta, J. et al. (2005). Placebo Effects Mediated by Endogenous Opioid Activity on -Opioid Receptors. Journal of Neuroscience, 25(34), 7754-7762. doi:10.1523/jneurosci.0439-05.2005