1. Somatosensory System and Pain Prof. Marshall Devor, Ph.D. Dept. of Cell & Animal Biology and Center for research on Pain Institute of Life Sciences Hebrew University of Jerusalem lecture 7: Descending control 08-9 פיסיולוגיה מורחב 08-9 פיסיולוגיה מורחב

2. descending pathways pathways

3. 7 th century, Battle of Handak shi,suni Beecher HK (1946) Pain in Men Wounded in Battle. Ann Surg. 123:96–105: “Three-quarters of badly wounded men, although they have received no morphine for hours... have so little pain that they do not want pain relief medication”

4. Stress-induced analgesia analgesia Miczek et al. Analgesia אלחוש

5. Morphine analgesia analgesia Response latency (sec) 0 10 20 0 Time after injection 80 min morphine vehicle morphine + naloxone hotplate test naloxone.. μ receptor antagonist

6. multiple pinch control Miczek et al. Analgesia אלחוש Stress-induced analgesia analgesia endogenous opioids (enkephalins neurotransmitter,  endorphin circulation) vehicle naloxone

7. Endogenous Opioids enkephalins (neurotransmitter) enkephalins (neurotransmitter)  endorphin (circulation)  endorphin (circulation) POMC

8. PAG (midbrain periaqueductal grey) e- stim  analgesia (hp) [naloxone reversible] Liebeskind et al. 1970s

9. pre post PAG stim/ μinject hp response latency

10. PAG (midbrain periaqueductal grey) e- stim  analgesia (hp) [naloxone reversible] …. later morphine microinjection Liebeskind et al. 1970s

11. WDR neuron during PAG stimulation PAG  analgesia

12. PAG periaqueductal grey RVM rostro-ventromedial medulla NRM nucleus raphe’ magnus DLF dorsolateral funciculus anterograde tracer retrograde tracer arm leg cut DLF Systemic morphine (and endogenous opiates) acts primarily in the brainstem to activate a descending control circuit RVM PAG RVM

13. there is evidence that placebo analgesia may be due to endogenous opioids

14. VAS (Visual Analog Scale) worst pain possible no pain 0100 אך למדוד את הכאב באדם ?

15. regression to the mean regression to the mean belief, expectation,conditioning belief, expectation,conditioning זמן מידת הכאב אמונה טפלה placebo analgesia אינבו

16. internal mammary artery ligation surgery for angina pain (1940s,50s)  pain relief often >6 months Arthroscopic surgery for osteoarthritis of the knee Moseley et NEJM 2002 "placebo effect" "sham surgery"  identical result

17. Advil, Neurofen " אפקט של הפלצבו " placebo effect סה " כ אפקט התרופה overall drug effect  זמן מידת הכאב ללא טיפול טיפול פלצבו טיפול תרופתי או כירורגי אפקט התרופה נטו net drug effect Drug efficacy

18. Rainville et al. 1997 Pain perception under hypnotic suggestion (fixed stimulus)

19. intracutaneous capsaicin then report pain intensity Benedetti et al.

20. intracutaneous capsaicin then report pain intensity placebo analgesic cream placebo effect eliminated by (hidden) systemic naloxone

21. acupuncture ? homeopathy ? magnets ? crystals ? prayer ? physiotherapy ? RCTs randomized placebo-controlled trials

22. the placebo effect placebo post-thoracotomy pain PCA buprenorphine told: nothing, either, analgesic VAS cummulative buprenorphine dose

23. " בצד החיובי, סידרת לי את כאבי הגב "

24. primary sensory neurons

25. Somatosensory System and Pain Prof. Marshall Devor, Ph.D. Dept. of Cell & Animal Biology and Center for research on Pain Institute of Life Sciences Hebrew University of Jerusalem lecture 7: Descending control פיסיולוגיה מורחב