1. How the number of learning trials affects placebo and nocebo responses
Luana Colloca, Predrag Petrovic, Tor D. Wager, Martin Ingvar, Fabrizio Benedetti

2. Terms
Placebo - is a sham or simulated medical intervention that can produce a (perceived or actual) improvement
Nocebo – unpleasant response or reaction caused by a placebo drug or condition.

3. Review!
=related

4. Analgesic Pathway

5. Responses to pain induce activity in antinociceptive pathways
Responses to pain induce activity in antinociceptive pathways.  This activity begins when pain information transmitted by the spinothalamic tract reaches the brainstem and thalamus (A above).  Activation of periaqueductal gray and the nucleus raphe magnus induces endorphin and enkephalin release and binding to "opioid" receptor systems.  Sympathetic and parasympathetic influences within the spinal cord facilitate inactivation of antinociceptive pathways.  Most of the endorphin and enkephalin receptors (70%) are localized presynaptically, substantial pain signal attenuation occurs before information reaches the dorsal horn (B above).  Such information may be further attenuated by enkephalin-induced dynorphin activity at the level the cord (C above).  
Dynorphin activates -type opioid receptors localized on inhibitory interneurons, activation of which induces release of the inhibitory neurotransmitter GABA. The mechanism by which -opioid receptor activation limits spinal cord cellular activity may be by means of closure of  N-type Ca2+ channels.  Interaction of GABA with its receptor results in dorsal horn neuronal hyperpolarization thus impeding transmission of the pain information.  Reduction of visceral pain may occur particularly by this approach.
Enkephalin binds to -type opioid receptors which appear on nociceptive neurons when they actively transmit pain information.  Furthermore, these receptors are often localized on presynaptic vesicles that contain neurotransmitter and following release receptor protein is incorporated into presynaptic membrane.  Active nociceptors, because of preferential binding, are therefore more sensitive than inactive nociceptive receptors to endogenous opiates.  This idea may be relevant in explaining how opioid analgesics appear to relieve ongoing pain but do not prevent sensing of pain subsequent to new injuries.

6. Placebo analgesia Some placebo analgesia blocked by naloxone
Placebo affect = opioid modulated pathway
ACC may control placebo response
ACC activity increased by acute pain, opioid analgesia, and placebo analgesia
ACC  PAG
Anterior cingulate cortex

7. A model neuronal network explaining placebo analgesia-related activation of ACC neurons. Placebo leads to activation of inhibitory neurons within the ACC. These inhibitory neurons then release an inhibitory neurotransmitter, GABA. GABA acts on postsynaptic GABA receptors to inhibit ACC neurons that are involved in pain perception. In some neurons, endogenous neuropeptides such as enkaphalin (Enk) may also be released to produce similar inhibitory effects (a). Inhibitory neurons may also affect ACC neurons that form descending facilitatory innervations with the spinal cord dorsal horn. Activation of inhibitory neurons within the ACC causes the reduction of descending facilitatory influences. The reduced facilitatory influence on spinal nociceptive transmission therefore produces analgesic effects.

8. ACC Nociceptive and Analgesic Effects

9. Expectation and Placebo Analgesia

10. Expectation and Placebo Analgesia

11. Factors Influencing Placebo
Cognitive Factors
Expectation of pain relief trigger opioids in CNS
Classical Conditioning
Associations between active analgesics, pain relief, and therapeutic surroundings
Responders and Non-responders

12. Materials Electric stimulation to foot
randomized which foot
100 microseconds
Yellow, green, or red light before shock

13. Methods Group 1: one session of conditioning
Group 2: four sessions of conditioning
Both groups:
Non-painful stimuli test
Painful stimuli test

14. Test Types Non-painful Painful
Intensity of stimulation above Aβ fiber threshold but below nociceptive Aδ and C fiber threshold
Painful
Above nociceptive Aδ and C fiber threshold levels

15. VAS Scoring Subjects scored perception and pain (0-10 VAS)
T and t levels prior to testing
Pain rated after conditioning and test
(which convey non-painful tactile information)
Visual analogue scale

18. Testing Procedure

19. Results (group 1)

20. Results (group 1)

21. Results (group 2)

22. Results (group 2)
Speculate that there is ACC inhibition occuring to modify perception of Green Light placebo…

23. Placebo/Nocebo relationship
Correlation for group 1 pain condition

24. Placebo/Nocebo relationship
Negative correlation for group 2 no pain condition

25. Placebo/Nocebo relationship
No correlation for pain condition

26. Average VAS Response

27. Results Summery Short conditioning period Long conditioning period
No lasting effects for non-painful condition
Only painful nocebo effect endured
Long conditioning period
Both placebo and nocebo effects endured

28. Discussion Conditioning is needed for placebo and nocebo effects
Both conscious and subconscious learning shape behavior
Past experience with pain relief effect the efficacy of treatment
Clinical usage of placebo and avoidance of nocebo

29. Unrelated…