1. Placebos and Painkillers: Is Mind as Real as Matter? Luana Colloca and Fabrizio Benedetti 2005 in Nature Reviews Neuroscience Jess Benjamin Steele Taylor Celeste Parot January 30, 2008 http://www.annkullberg.com/Shows/2003/Hild.jpg

2. Pain Overview http://www.scripps.edu/cb/patapoutian/nocisensor.jpg http://www.laesieworks.com/spinal/pict/SpinalCord.jpg

3. Pain Overview www.nursece.com/onlinecourses/imagesPain/Fig2.gif

4. Pain Overview www.doctordeluca.com/Library/Pain/CP1NewDisease2K.htm

5. Pain Overview www.doctordeluca.com/Library/Pain/CP1NewDisease2K.htm

6. Centrally Mediated Pain Regulation 1) Appropriate activation of periaqueductal grey matter (PAG) in mesencephalon and opioid networks in thalamus Some Psychobiological Stimuli Associated With Internally Generated Analgesia: 1)Conditioned Anticipation of Pain Relief 2)Pain in Other Areas 3)Emotional Well Being 4)Concentration/Meditation 5)Hypnosis 6)Gate-Mediated Mechanical Stimuli http://www.doctordeluca.com/Library/Pain/Graphics/CP1NewDis-F2.bmp http://www.sciencemag.org/cgi/content/full/288/5472/1769

7. Centrally Mediated Pain Regulation Opiod-Mediated Inhibition Occurs Via: 1) K+ channel Activation (Hyperpolarization) 2) Ca2+ channel Deactivation (Reduced NT Release) 3) Other Mechanisms http://www.mona.uwi.edu/fpas/courses/physiology/neurophysiology/P ainRapheFeedback.jpg (notice the inhibition of retrograde substance p release into the periphery!)

8. Opioid Reinforcement Through Dopamine Signaling 1) 1) Reinforcement/addiction may be associated with impact on dopamine signaling 1) 1)Opiod mediated inhibition of GABAergic neurons tonically inhibiting DAergic neurons in ventral tegmental area (VTA) of mesencephalon (off + off = on) 1) 1)DA release into nucleus accumbens (reward center) and cognitive cortices thebrain.mcgill.ca/.../i_03_cr_que_1a.jpg

9. Isolating the Placebo Analgesia Pathways: The Chemical Players Remfentanil is an opioid agonist Remfentanil is an opioid agonist Comparison of brain imaging during remfentanil exposure and placebo-analgesia reveals similarities in the activated pathways Comparison of brain imaging during remfentanil exposure and placebo-analgesia reveals similarities in the activated pathways This supports the opioid hypothesis of the placebo- analgesic response This supports the opioid hypothesis of the placebo- analgesic response www.ym.edu.tw/rcinn/images/cp1-fg3.png Functional MRI http://www.nida.nih.gov/NIDA_notes/NNVol16N2/Positron.jpg Positron Emission Tomography

10. Isolating the Placebo Analgesia Pathways: The Chemical Players Proglutamide: a CCK antagonist that enhances placebo analgesia due to the facilitation of expectation pathways Proglutamide: a CCK antagonist that enhances placebo analgesia due to the facilitation of expectation pathways Based on double-blind paradigm one can erroneously conclude that Proglutamide has intrinsic analgesic activity Based on double-blind paradigm one can erroneously conclude that Proglutamide has intrinsic analgesic activity PET imaging and open-hidden paradigm provides more accuracy PET imaging and open-hidden paradigm provides more accuracy Therefore, Proglutamide IS the disturbance in double-blind studies Therefore, Proglutamide IS the disturbance in double-blind studies http://www.nature.com/nrn/journal/v6/n7/fig_tab/nrn1705_ F1.html

11. Isolating the Placebo Analgesia Pathways: The Chemical Players Naloxone is the prototypical opioid antagonist (and OD antidote) Naloxone is the prototypical opioid antagonist (and OD antidote) Naloxone reliably blocks placebo induced analgesia Naloxone reliably blocks placebo induced analgesia –But, only through conditioning with previous opioid-analgesic responses –Non-opiod associated placebo effects are naloxone insensitive Sumatriptan (5-HT agonist) Therefore, naloxone also blocks side- effects accompanying opioid- operating placebo responses Therefore, naloxone also blocks side- effects accompanying opioid- operating placebo responses –Respiratory depression –Cardiac depression Disturbance: In a double-blind study, naloxone appears to have a hyperalgesic effect (but not in open- hidden paradigms) Disturbance: In a double-blind study, naloxone appears to have a hyperalgesic effect (but not in open- hidden paradigms)