Download Placebos in the CNS

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