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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