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

descending pathways pathways

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”

Stress-induced analgesia analgesia Miczek et al. Analgesia אלחוש

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

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

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

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

pre post PAG stim/ μinject hp response latency

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

WDR neuron during PAG stimulation PAG  analgesia

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

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

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

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

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

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

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

intracutaneous capsaicin then report pain intensity Benedetti et al.

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

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

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

" בצד החיובי, סידרת לי את כאבי הגב "

primary sensory neurons

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