Somatosensory System and Pain

Prof. Marshall Devor, Ph.D.Dept. of Cell & Animal Biology and Center for research on Pain Institute of Life SciencesHebrew University of Jerusalem

lecture 7: Descending control

פיסיולוגיה מורחב פיסיולוגיה מורחב 08-908-9

descending descending pathwayspathways

7th century, Battle of Handak shi,suni

Beecher HK (1946) Pain in Men Wounded in Battle. Ann Surg. Beecher HK (1946) Pain in Men Wounded in Battle. Ann Surg. 123:96–105: “Three-quarters of badly wounded men, although 123:96–105: “Three-quarters of badly wounded men, although

they havethey have received no morphine for hours... have so little received no morphine for hours... have so little pain that they do not want pain relief medication” pain that they do not want pain relief medication”

Stress-inducedStress-induced analgesiaanalgesia

Miczek et al.

A

nalg

esia

ש

חואל

MorphineMorphine analgesiaanalgesia

R

espo

nse

late

ncy

(sec

)0

10

20

0 Time after injection 80 min

morphine

vehiclemorphine + naloxone

hotplate test

naloxone.. μ receptor antagonist

multiple pinch control

Miczek et al.

A

nalg

esia

ש

חואל

Stress-inducedStress-induced analgesiaanalgesia

endogenous opioids(enkephalins neurotransmitter, endorphin circulation)

vehicle

naloxone

Endogenous OpioidsEndogenous Opioids enkephalins (neurotransmitter)enkephalins (neurotransmitter) endorphin (circulation)endorphin (circulation)

POMC

PAG (midbrainperiaqueductal grey)e- stim analgesia (hp)

[naloxone reversible]

Liebeskind et al. 1970s

pre post PAG stim/ μinject

hp r

espo

nse

late

ncy

PAG (midbrainperiaqueductal grey)e- stim analgesia (hp)

[naloxone reversible]

…. later morphine microinjection

Liebeskind et al. 1970s

WDR neuron

during PAG stimulation

PAG analgesia

PAG periaqueductal greyRVM rostro-ventromedial medullaNRM nucleus raphe’ magnusDLF dorsolateral funciculus

anterograde tracer

retrograde tracerarm

leg

cutDLF

Systemic morphine (and endogenousSystemic morphine (and endogenousopiates) acts primarily in the brainstem opiates) acts primarily in the brainstem to activate a descending control circuitto activate a descending control circuit

RVM

PAG

RVM

there is evidence that placebo analgesiamay be due to endogenous opioids

VAS (Visual Analog Scale)

worst painpossible

no pain

0 100

? באדםאך למדוד את הכאב

• regression to the meanregression to the mean• belief, expectation,conditioningbelief, expectation,conditioning

זמן

אבהכ

ת יד

מ

אמונה טפלהאמונה טפלה

placebo analgesia אינבו

internal mammary artery ligationsurgery for angina pain (1940s,50s) pain relief often >6 months

Arthroscopic surgery for osteoarthritisof the knee Moseley et NEJM 2002

"placebo effect""placebo effect"

"sham surgery" identical result

Advil, Neurofen

של "אפקט הפלצבו" placebo effect

סה"כ אפקט התרופה overall drug effect זמן

אבהכ

ת יד

מ ללא טיפול

טיפול פלצבו

טיפול תרופתי או כירורגי

אפקט התרופה נטו net drug effect

Drug efficacyDrug efficacy

Rainvilleet al. 1997

Pain perception under hypnotic suggestion (fixed stimulus)

intracutaneous capsaicinthen report pain intensity

Benedetti et al.

intracutaneous capsaicinthen 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 painPCA buprenorphinetold: nothing, either, analgesic

VA

S

cum

mul

ativ

ebu

pren

orph

ine

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 SciencesHebrew University of Jerusalem

lecture 7: Descending control

פיסיולוגיה מורחבפיסיולוגיה מורחב