PAIN !!! DENT/OBHS 131 Neuroscience 2009

Pain…. Is a submodality of somatosensation Is the perception of unpleasant or aversive stimulation (sensory and emotional experience) Warns of injury (physiological relevance) Is highly individual and subjective

General topics Brief review of somatosensation Anatomical pathways Substance P Nociceptors Gating theory Descending control Opioids / morphine Placebo effects

Learning Objectives Describe the course of the spinothalamic (and trigeminal) tract(s) from dermatome to cortex Describe the types of fibers carrying pain information, including their relative conduction velocities, substances they release and where they terminate in the spinal cord and periphery Discuss how the major types of nociceptors respond to damage / injury Know that other ascending pathways are involved in pain transmission Discuss the descending regulation of noxious information signaling Explain how ascending pain information is “gated” in the spinal cord

Dual ascending sensory pathways Dorsal columns / ML Anterolateral system Several distinct pathways convey different aspects of pain - see later e.g. spinothalamic - awareness and location of pain

Small DRG processes enter the cord:, Afferents Lissauer’s tract Superficial layers of dorsal horn Ventral White Commissure (VWC) III Sub P synapse in the substantia gelatinosa, then cross in the VWC and ascend. Pain and temperature

Learning Objective #2 Describe the types of fibers carrying pain information, including their relative conduction velocities, substances they release and where they terminate in the spinal cord and periphery

C fibers use two transmitters: substance P and glutamate Substance P released with strong stimuli Act to enhance and prolong the action of glutamate acting on AMPA receptors

Afferent termination in dorsal horn Many nociceptive fibers terminate in layer I (marginal layer) and II (substantia gelatinosa) of dorsal horn of spinal cord Some pain and non- noxious sensory (e.g., proprioception) into other layers (including ventral horn - important for reflexes)

Conduction velocities Nociceptive afferents in peripheral nerve Fast sharp pain and slow dull burning pain myelination & axon diameter

Nociceptors are free nerve endings

Learning Objective #3 Discuss how the major types of nociceptors respond to damage / injury

Harmful stimuli activate nociceptors Nociceptors are peripheral free endings of primary sensory DRG and trigeminal ganglia neurons Membrane contains receptors Classes (all located in skin and deep tissues) Thermal - extreme temperatures – A  fibers Mechanical - intense pressure – A  fibers - sharp pain Polymodal - intense mechanical, chemical or thermal stimuli – C fibers (unmyelinated) – dull burning Nociceptors

Chemical nociceptors 3. vasodilation / extravasation (neurogenic inflammation) 1. Damaged cells (endothelial / platelets) - release chemicals: activate & sensitize (HYPERALGESIA) free nerve endings arachidonic acid cyclo-oxygenase (ASPIRIN) 2. local & central effects

Thermal nociceptors… …..are a separate group (interestingly including the heat-sensitive capsaicin receptor ) and are members of the transient receptor potential (TRP) gene family (non-selective cation channel) Activated by extreme temp: 45 C Pain & Temperature (STT) pictured are “normal” thermoreceptors (also free nerve endings)

Mechanical nociceptors…… …….are activated by very strong stimuli

Sensitization of nociceptors

Pain pathways sensitize!!!!! After tissue damage, the sensation to pain to subsequent stimuli is increased at primary site of injury Occurs in primary and secondary (surrounding) areas Thresholds decrease or magnitude of pain from suprathreshold stimuli increases - HYPERALGESIA Painful response to otherwise innocuous mechanical stimulus - ALLODYNIA With severe persistent injury, C fibers fire repetitively or “wind up” resulting in increased glutamate release in spinal cord that activates NMDA receptors – synaptic plasticity

Learning Objective #1 Describe the course of the spinothalamic (and trigeminal) tract(s) from dermatome to cortex

Spinothalamic Cross Direct to multiple thalamus

Pain pathways through thalamus VPL / VPM (neospinothalamic) receive nociceptive specific and other sensory inputs spinothalamic tract (STT & TTT) project to primary somatosensory cortex neurons have small receptive fields - injury location Intralaminar complex (paleospinalthalamic) receive nociceptive specific inputs Includes projections from the spinoreticulothalamic tract diffuse cortical projections

Learning Objective #4 Know that other ascending pathways are involved in pain transmission

Ascending pain pathways Spinoreticular tract; to reticular formation of pons / medulla (level of attention); and onto thalamus Spinomesencephalic tract; to mesencephalic reticulum, lateral periqaueductal grey in midbrain; and on to hypothalamus and limbic system (emotion and memory integration)

Spinoreticular Collaterals - medulla Synapses - pons Spinoreticulothalamic tract

Spinomesencephalic Synapse - midbrain Descending control

Learning Objective #5 Discuss the descending regulation of noxious information signaling

Direct stimulation of PAG - specifically reduces sensation of pain Descending control

NA (opioids) 5-HT opioids Descending pathways can regulate relay of nociceptive information in the spinal cord Other transmitters

Local circuit interneurons….. …in the spinal cord: integration of ascending and descending information to modulate nociception Placebo effect

Learning Objective #6 Explain how ascending pain information is “gated” in the spinal cord

Gating control hypothesis of pain

Cortical representation of pain VPL / VPM project to primary somatosensory cortex and then to secondary somatosensory cortex: Awareness, location and “intensity” of pain Medial thalamus projects to anterior insular cortex: Autonomic / visceral component of pain Intralaminar nuclei of medial thalamus projects to anterior cingulate cortex (limbic association cortex): Emotional component of pain (circuit of Papez)

Referred pain Convergence of somatic and visceral afferents on lamina V Silent nociceptors: normally not active but firing threshold reduced by various insults