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Transcript
Ascending Projections
Derek Molliver, PhD
Ascending Projections
• Pain is the result of an integrated response from all levels of the
CNS
• Processing occurs at every level (including spinal)
• Functional distinctions between projection pathways are still the
subject of intense debate and active investigation:
– Specificity (labeled lines) vs convergence
• With that in mind, a great deal has been learned regarding the
transmission of nociceptive information to higher centers to yield
different components of the experience of pain.
»
»
»
»
Retrograde tracing studies
Antidromic/orthodromic activation
Brute force electrophysiology
Human lesion experiments (accidental or deliberate)
Processing of nociceptive information
Input
Modality
Intensity
Location
Temporal Profile
Output
Discriminative pain
Affect
Autonomic Activation
Motivation/behavior
Cognition
Memory
How do affect, cognition and autonomic tone
contribute to the experience of pain?
1
Dorsal column pathway: tactile sensation
Spinothalamic pathway: pain and thermal
2
Spinal cord Lamina I projection neurons
Specific subtypes form
Ņlabeled lines
Óto higher brain
centers
Cold-Specific
Itch-Specific
Nociceptor
-Specific
Sensual Touch-Specific
These neurons are also
histologically
distinct from one
another (bipolar,
stellate, etc.)
Project along the
LateralSpinothalamic
Tract
Lateral STT
w/ somatotopy
Somatotopic projection, small receptive fields
Spinal cord Lamina V projection neurons
Most areWide Dynamic Range Neurons
that receive
direct inputs from
bothnociceptorsand low threshold
mechanoreceptors.
Project along the
AnteriorSpinothalamic
Tract
Anterior STT
Limited somatotopy
Little somatotopy, large receptive fields
Spinal cord deep dorsal horn projection neurons (VI-VIII)
WDR neurons with large, complex receptive fields
No somatotopy
Respond best to limb movement-muscle and joint
Project along Anteriomedial Spinothalamic Tract
M. Caterina
Two major ascending pathways for pain
Lateral
Insular Cortex
Anterior Cingulate Cortex
(SI, SII)
Anterior
Primary somatosensory Cortex SI+SII
(Insular Cortex)
Medial thalamus
(intralaminar nuc: CL, MDvc, VPI, VMpo)
Lateral thalamus
(VPL, VPI, PO)
Lateral Spinothalamic Tract
Anterior Spinothalamic Tract
Superficial Dorsal Horn Neurons
Lamina I
Deep Dorsal Horn Neurons
Lamina V
Modality, spatial discrimination
Emotional content?
Intensity, temporal discrimination
Emotional content?
3
Labeled lines versus integrated input:
Conservation of sensory quality
Traditional view: integration of progressively convergent activity to cortex (Willis)
Specificity theory: Pain subserved by forebrain integration of labeled lines and
convergent systems providing interoceptive sense (Craig)
Lateral Spinothalamic Tract
Anterior Spinothalamic Tract
To Medial Thalamus
To Lateral Thalamus
Lamina I:
Modality-specific
Sm receptive fields
Somatotopic organization
Lamina V:
Wide dynamic range
larger, even bilateral receptive fields
No clear somatotopy
Deep dorsal horn:
Lg, complex receptive fields
Limited somatotopy (musculotopy)
Most responsive to limb movement
-muscle and joint
4
Coronal Section
Input from Lateral STT (LI)
Input from Anterior STT(LV)
SI
Cingulate
Ctx
SII
Insular
Ctx
CL
VPL (WDR)
Is lamina I an interoceptive nucleus?
A.D. Craig
Modality-specific nociception: mechanical, thermal, itch
Cutaneous input at neuroimmune interface: monitoring immune
surveillance
Peptidergic efferent role in tissue homeostasis
Direct lamina I projection to preganglionic sympathetic neurons
(Intermediolateral cell column)
Parabrachial projection to autonomic centers
Insular cortex as defining sense of “state of the body”
“interoceptive cortex”, as opposed to “exteroception”,
largely tactile.
5
Aδ & C afferents activate insula
M. Caterina
Craig (2002) Nature Rev Neurosci 3: 655-666.
Postsynaptic dorsal column pathway for visceral pain
-Most neurons in lumbar enlargement
-Mostly LIII-IV, X, medial deep dorsal horn
Midline myelotomy
Morphine-resistant colon cancer pain,
complete relief w/o medication for 3 mo (until death)
From: Willis, 1997 J Clin Neurophysiol, Volume 14:2-31
6
Projects to VPL thalamus
Responses of thalamic (VPL) neurons to sensory stimulation
after dorsal column or STT lesion (rat).
Cutaneous
Colorectal distension
%
Baseline
From: Willis, 1997 J Clin Neurophysiol, Volume 14:2-31
7
Deletion of lamina I afferents abolishes hyperalgesia,
not basal pain sensation
Most STT neurons in superficial dorsal horn express substance P receptor NK1
-Most NK1+ cells are STT and spino-parabrachial neurons
Substance P conjugated to ribotoxin saporin taken up selectively by NK1 cells
Formalin
CFA
Carrageenan
Nerve
Injury
Supraspinal serotonergic circuits regulating neuropathic
hypersensitivity (and gabapentin action)
10 mg/kg
100 mg/kg
SP-saporin reduces
Mechanical allodynia
Caused by nerve injury
Gabapentin inhibition of
firing is lost after SP-saporin
Also reduced by 5HT3 antagonist:
ondansetron
Safety Evaluation of Intrathecal Substance P-Saporin,
a Targeted Neurotoxin, in Dogs
NK1r immunoreactivity in laminae I/II (left) and lamina V (right) in dogs treated with PBS (top), 150
{micro}g SAP (middle), or 150 {micro}g SP-SAP (bottom)
Allen, J. W. et al. Toxicol. Sci. 2006 91:286-298; doi:10.1093/toxsci/kfj143
Update Oct 2008: Preclinical studies completed
Seeking FDA approval to initiate clinical trials in terminal cancer patients
Will target rheumatoid arthritis and CRPS.
8
2 classes of unmyelinated afferents in lamina II
Peptidergic
Non-peptidergic
Respond to NGF
Project to outer lamina II
Express neuropeptides:
CGRP
Substance P
Induce neurogenic inflammation
NGF-induced plasticity
Respond to GDNF family
Project to inner lamina II
No inflam neuropeptides
Inflammation?
Plasticity?
Superficial substantia gelatinosa interneurons project to lamina I
in monkey
J Neurophys 42:1590, 1979
Labeled lines for peptidergic vs nonpeptidergic afferents?
NaV1.8
PKCγ
NK1
NaV1.8
Braz et al,. 2005 Neuron 47:787
9
Additional spinal projections traveling with spinothalamic tract
(collaterals from STT):
-Spinoreticular
-Spinomesencephalic
-Spinolimbic
These centers also receive input from
somatosensory thalamus
Caudal spinoreticular Tract
Deep dorsal horn neurons, WDR
No clear somatotopy
Parabrachial Spinoreticular Tract
Superficial dorsal horn neurons
Nocic-specific
Relay of information for autonomic activation, descending antinociception,
projection to limbic centers for motivation/affect.
Spinomesencephalic Tract macaque)
-Projection to midbrain PAG and cuneiform nuc
Midbrain
-Arises from both superficial and deep STT cells
-Rough rostro-caudal somatotopy
-Receptive fields complex, often
widely-spaced patches
PAG: analgesia and regulation of aversive behavior
Cuneiform: midbrain locomotor center
Willis, 1997 J Clin Neurophysiol, 14:2-31
10
Limbic system receives direct input from spinal neurons
Also spinal input to nuc accumbens,
Involved in reward, attention, addiction
Pain and Emotion -Theories
• Autonomic responses and visceral sensations accompany
most emotion. The earliest theory hypothesized that
emotion is the result of basic sensations:
– Aristotle (350 BCE) - pain is an emotion
– James-Lange (1884-85) – emotions result from physical changes
- “we feel sorry because we cry, ... afraid because we tremble”
– Cannon-Bard (1920’s) – stimuli evoke appropriate autonomic
(fight or flight) and emotional responses in parallel.
• Emotions, visceral sensations, and pain involve many of
the same brain areas:
– Limbic
– Insular cortex
– Cingulate cortex
M. Caterina
Amygdala neurons sensitize in a model of arthritis
~80% neurons in rat amygdala central nuc (CeA) are WDR or noci-specific.
WDR neuron
WDR neuron receptive field
Mechanical stimulation of knee joint
Neugebauer and Li, 2003 J Neurophys 89:716
11
Modulation of pain by amygdala: affect and autonomic activation
-convergence of emotionality and nociceptive input
CeA neurons respond to noxious stimulation (from spino-parabrachial proj)
Exhibit sensitization to persistent pain
Lesions of CeA abolish stress-induced analgesia
Descending projections from CeA to PAG and RVM
(also forebrain (cognitive) and hypothalamus (autonomic))
Neugebauer and Li, 2003 J Neurophys 89:716
Basic emotions activate insula
Craig (2002) Nature Rev Neurosci 3: 655-666.
M. Caterina
Does ACC code affective components of pain (unpleasantness)?
Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC (1997) Pain affect encoded in
anterior cingulate gyrus but not somatosensory cortex. Science 277: 968-971.
M. Caterina
12
Imaging pain in Fibromyalgia
Areas of increased activation to noxious pressure in patients
SI, Ant Cing Ctx
Insula, sup temp
gyrus
SII
Insula,
Acc Cing Ctx,
STG
Inf parietal
Post Cing Ctx
Medial frontal gyrus
Cerebellum
Gracely et al., 2002 Arthritis & Rheumatism 46:1333
13