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Pain, Mechanisms, Cellular Substrate, Modulation

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  1. 1. Pain
  2. 2. Significance of Pain Pain is adaptive Alerts us to danger Motivates escape and avoidance learning Motivates recuperation Congenital insensitivity to pain Pain is partly subjective Influenced by expectations and emotions
  3. 3. IASP Definition of Pain Pain is a sensory and emotional experience associated with actual tissue damage or described in terms of such damage pain is a sensory experience associated with activation of nociceptors and pain pathways pain is an emotional experience tissue damage is not necessary
  4. 4. Pain Chronicity Acute - Transient / Recurrent - Reversible Chronic - Long lasting/Reversible - Persistent / Irreversible
  5. 5. Types of Pain Chemical, mechanical pressure, and extreme heat All mediated through nociceptors All go through a common pathway in the brain Once activated, nociceptors become sensitized (hyperalgesic) for the duration of an injury
  6. 6. Pathological Pain - Chronic Pain Inflammation or nerve damage Arthritis Neuropathic pain Back pain Migraine Degenerative diseases (MS) 80% of doctor visits 70 billion in health care costs and reduced productivity Current clinical treatments are based on animal research
  7. 7. Using Animal Models to Study Pain Acute pain: gradually incremented stimuli applied to tail or paw and determine intensity of stimulation required to elicit a withdrawal or vocalization response. Chronic pain: unilateral inflammation of the paw or joint, nerve ligation, etc. Measure guarding of limb, hyperreactivity to heat or mechanical stimulation, or reduced locomotor activity. Electrophysiology and histology
  8. 8. Justification for animal models Pain is a complex biological and psychological process that must be investigated in a living organism. Animal research has led to advances in understanding pain and its treatment. Animal rights movement creating barriers to laboratory animal research on pain.
  9. 9. Pain Transmission & Modulation Research has clarified that the experience of pain is due to the combined activity of distinct systems that transmit and modulate pain. 1) Ascending Pain Transmission: Bottom-up process of pain transmission provides the brain with information about tissue damage. 2) Descending Pain Modulation: Top down process of pain modulation regulates pain transmission.
  10. 10. Ascending Pain Transmission Pathway The ascending neural pain pathway is only a 3 neuron relay The major convergence point is the ventral posterior lateral nucleus of the thalamus, which relays the signal to limbic and cortical areas Ascending Pain Pathway (Purves, 2001).
  11. 11. Descending Pain Modulation Pathway The Descending Pain Pathway – The Periaqueductal Grey (PAG) is the major convergence point. Descending pain pathway (Purves, 2001).
  12. 12. Pain Transmission Pathway Primary afferent nociceptors respond to intense thermal, mechanical, and chemical stimuli. Located in all pain sensitive regions of te body. Activated by chemicals (bradykinin, prostaglandins, histamine, etc.) released during tissue damage and inflammation, causing transmission of action potentials.  Axons of these neurons carry the signal into the cord, release neurotransmitters that activate pain transmission neurons in the dorsal horn of the spinal cord. Pain transmission neurons carry this signal to various regions of the brain where it is processed and evaluated. E.g., spinothalamic tract neurons carry the signal from the spinal cord to specific thalamic nuclei, which have reciprocal connections with somatosensory cortex - map of body
  13. 13. Neural Pathways of Pain Anatomically related to the cutaneous senses Free nerve endings  The sensitive terminals of pain neurons are not surrounded by special capsules or end organs as are the endings of touch and temperature receptors  Free nerve endings can be found in all body tissues from which pain is sensed, from the skin to the pulp of the teeth.
  14. 14. Transduction of Pain Tissue Damage and Chemoreceptors Substance P, Histamine, Bradykinin, Serotonin, K+ C Fibers (Type 4) with chemoreceptors And the Immune System
  15. 15. Two Types of Peripheral Pain Neurons A-delta fibers  Thick, myelinated, fast conducting neurons  Mediate the feeling of initial fast, sharp, highly localized pain. C fibers  Very thin, unmyelinated, slow-conducting  Mediate slow, dull, more diffuse, often burning pain.
  16. 16. Central Pain Pathways: Fast Pain Fast pain and A-delta fibres     A-delta fibers synapse on cells in the spinal cord that lead to an area of the thalamus called the ventrobasal complex ventrobasal complex also receives neurons that mediate touch sends its output to the somatosensory cortex allows us to localize where pain originates
  17. 17. Central Pain Pathways: Slow Pain Slow pain and C fibres  C fibres synapse on cells in the spinal cord  Relays to a midline nucleus in the thalamus and  to the limbic system  responsible for motivational and emotional aspects of pain  Those connections are important for the interpretation of pain.
  18. 18. Sensitization of Pain Transmission Pain transmission system can be sensitized by noxious stimuli. Explains many chronic pain syndromes where pain perception is distorted  Allodynia - lowering of pain thresholds to normally non-noxious stimuli  Hyperalgesia - lowering of pain thresholds to noxious stimuli  Secondary hyperalgesia - spread of pain and hyperalgesia to uninjured areas  Spontaneous pain - pain in absence of noxious stimulation, “pain memory”
  19. 19. Multiple Pain Mechanisms • Nociception • Peripheral sensitization • Central sensitization • Decreased inhibition/ Structural reorganization
  20. 20. Multiple Pain Symptoms • Spontaneous Pain Superficial/Deep Continuous/Intermittent • Evoked Pain Thermal/Mechanical Allodynia Hyperalgesia
  21. 21. Nociception Transduction Conduction Transmission Modulation Noxious stimulus “Ouch” Pain primary sensory neuron central neuron
  22. 22. Nociception – Transduction Nociceptor Activators Cold Heat Bradykinin Mechanical B1/B2 DRASIC/mDEG H+ CRM1 VR1 ASIC TRPV3 generator potential action potentials COX-2 Insensitive
  23. 23. Transmission/Modulation VGCC COX-2 Insensitive GABAA Adensosine Opiate CB1 Glutamate Activity AMPA Sub P mGluR NMDA NK1 Afferent Central Terminal Dorsal Horn Neuron
  24. 24. Nociception is not COX2 Sensitive
  25. 25. Mechanisms of Neuropathic Pain Central sensitization Non painful information is processed as painful Transmission of painful information is facilitated Allodynia Hyperalgesia Complex Regional Pain Syndrome Fibromyalgia
  26. 26. Sensitization of pain transmission Both peripheral and central mechanisms mediate sensitization and contribute to the development and maintenance of pathological pain. Peripheral: Peptides (bradykinin, histamine, prostaglandin) released at injury site sensitize peripheral nerve endings of primary nociceptors Central: axons from primary nociceptors release peptides (e.g.,substance P, neurokinin-A, CGRP, CCK) and excitatory amino acids (e.g., glutamate). Peptides act to amplify excitatory effects of glutamate, creating a burst of nociceptor activity causing a long-lasting hyperreactivity of dorsal horn neurons. Mechanism underlies hyperalgesia. Central Sensitization, a form of LTP that depends on the concurrent activation of NMDA receptors (glutamate) and NK-1 tachykinin receptors by neurokinin A and substance P.
  27. 27. Neuropathic Pain Pain caused by damage to nervous system Involves peripheral and central sensitization e.g., peripheral nerve cut, crushed, partial denervation and inflammation e.g., MVA, diabetes, MS, herpes zoster Nerve damage causes spontaneous shooting, stabbing, or burning pain over time. Local pain and then spreads. Allodynia to touch. Central sensitization occurs in spinal cord, brainstem, thalamus, and cortex, where neurons exhibit spontaneous activity, lowered thresholds, receptive field expansion. Paralleled by anatomical reorganization at each level of the pathway. E.g., phenotypic switching in cord, somatosensory map
  28. 28. Phantom Limb Pain Pain originating from the absent limb Pain memories of pre-amputation pain Animal models of injury prior to deafferentation increase autonomy behavior Preemptive analgesia blocks it by blocking the afferent barrage that leads to central sensitization Reorganization of somatosensory cortex after deafferentation pain Top down effects
  29. 29. Etiological Factors inflammation/tissue damage/nerve lesions Pain Mechanism Pain Syndromes post-operative/arthritic/back pain/neuropathic
  30. 30. Inflammatory and Neuropathic Pain Chemical mediators are released from damaged tissue and inflammatory cells. Some inflammatory mediators directly activate nociceptors, while others act together to sensitize the pain pathway. Neuropathic pain
  31. 31. Peripheral Sensitization Reduced Transduction Threshold Innocuous/Noxious stimulus Primary hyperalgesia Primary heat allodynia Inflammation primary sensory neuron central neuron
  32. 32. Peripheral Sensitization Macrophage Na ive Skin Mast cell 6h 12h PG VR1 PGS Cox-2 EP/IP H+ Ca2+ IL1β, IL6 TNFα AA Tissue damage COX-2 Sensitive PKC PKA (SNS/SNS2) Primary sensory neuron peripheral terminal There are prostanoid and non-prostanoid sensitizers
  33. 33. Central Sensitization Increased Pain Responsiveness Noxious stimulus Secondary hyperalgesia Tactile allodynia Irritants primary sensory neuron Tissue damage Inflammation central neuron
  34. 34. Central Sensitization – Central Pain Hypersensitivity Aβ fibre mechanoreceptor innocuous stimulus innocuous stimulus Weak synapse Increased synaptic strength non-painful sensation painful sensation Brush-Evoked Mechanical Allodynia
  35. 35. Relevance to human pain Cutaneous Hyperalgesia - e.g, burn pain - primary hyperalgesia at site of burn, secondary hyperalgesia in surrounding skin. allodynia - touch sensitivity Primary hyperalgesia linked to prolonged changes in excitability of peripheral nociceptors and central neurons. Secondary hyperalgesia due to sensitization of dorsal horn neurons and expansion of their receptive fields
  36. 36. Central Sensitization - Acute Phase src NMDA Activity Glutamate Sub P Central Terminal AMPA mGluR NK1 Tyr S/T pERK PKC S/T Ca2+ PKA IP3 COX-2 Insensitive
  37. 37. tR NA Na ïve 1H r 2H rs 4H rs 6H rs 12 Hr s 24 Hr s 48 Hr s COX-2 Induction in the Spinal Cord - Inflammation COX-2 β-actin
  38. 38. 7 d h 11 72 24 11 h 12 0 10 h Sh am Cox-2 is not induced in the Spinal Cord by Peripheral Nerve Injury Cox2 β−Actin 88 97 5 2 Cox2 band intensity
  39. 39. Central Sensitization Late Phase (Inflammation) Primary sensory neuron central terminal + EP + EP/IP Nociceptive dorsal horn neuron + PGE2 COX-2 Glycine receptor Inhibitory interneuron – EP COX-2 Sensitive
  40. 40. There are COX-2 sensitive peripheral and central components of inflammatory pain Cox-2 inhibitors can only act when COX-2 is induced - time lag for induction There are non-prostanoid contributors to inflammatory pain - ceiling effect Peripheral nerve injury may not be sensitive to COX-2 inhibitors
  41. 41. Etiology A B C Mechanism 1 2 3 Symptom α β γ
  42. 42. Etiology A B C Mechanism 1 2 3 Symptom α β γ
  43. 43. Need to differentiate Analgesic and Anti-hypersensitivity drugs Temporal and Intensity characteristics of pain do not reflect mechanisms and may not be useful predictors of analgesic action Pain Mechanisms and Drug Mechanisms may provide the most useful input for determining Indication and Efficacy
  44. 44. Need mechanism sensitive/specific outcome measures in addition to global pain scores Need clinical trials that validate mechanistic hypotheses Need to consider labeling claims in light of action of a drug with specific pain mechanism(s) as well as empirical clinical data on efficacy Are there global analgesics?
  45. 45. Descending Pain Modulation The brain and higher psychological processes can alter the activity of the pain transmission system. The brain can amplify or inhibit incoming pain signals through descending modulatory pathways.
  46. 46. Gate control theory •Ronald Melzack and Patrick Wall (1965, 1982) For pain to be experienced, input from •peripheral pain neurons must pass through a gate located at the point where •they enters the spinal cord and lower brain stem.
  47. 47. Descending Pain ControlAmygdala Cingulate Cortex & Emotional states Periaqueductal Gray    Opioid Receptors Projects to Raphe Nuclei Raphe Nuclei    Project down to dorsal horn and Spinal 5 Nucleus Serotonin (5-HT) Inhibits Ascending Systems  Substance P release by Primary Afferents Locus Coeruleus  Norepinephrine Stress-Induced Analgesia
  48. 48. Descending Pain Modulation Pathway The Descending Pain Pathway – The Periaqueductal Grey is the major convergence point. Descending pain pathway (Purves, 2001).
  49. 49. Pain-inhibiting System •Periaqueductal gray (PAG) –PAG neurons have excitatory connections with inhibitory interneurons in the spinal cord –These inhibitory interneurons prevent ascending neurons to relay pain messages to the brain –Stimulation produced analgesia •Endorphins or endogenous opioids -Receptors for exogenous opioids -Microinjection of opioids - PAG, intrathecal -Endogenous opioids - POMC-endorphins, enkephalins, dynorphin –The spinal cord inhibitory interneurons release endorphins –Endorphins are inhibitory neurotransmiters –Opiate epidurals inhibit ascending pain signal
  50. 50. No perception of pain To thalamus Opiate receptor Periagueductal gray matter Reticular formation Noxious stimulus Endogenous opiate Transmission of pain impulses to brain blocked Substance P Afferent pain fiber Nociceptor
  51. 51. Inhibition of ascending pain pathways Important anatomical connections between descending brain regions and the dorsal horn of the spinal cord. There are a number of opioids that exist naturally in the brain that can reduce pain. Electrical stimulation or pharmacological administration in the PAG produces profound analgesia.
  52. 52. Descending Regulation Endorphins exert multiple effects that include suppressing the release of glutamate from presynaptic terminals and inhibiting neurons by hyperpolaring their postsynaptic membranes.
  53. 53. Targets of Pain Therapies Pharmacotherapy Non-opioid analgesics Opioid analgesics Nerve Blocks Adjuvant analgesics (neuropathic, musculoskeletal) Electrical Stimulation Transcutaneous electrical nerve stimulation (TENS) Percutaneous electrical nerve stimulation (PENS) Alternative methods Gottschalk et al., 2001 Acupuncture Physical Therapy Chiropractics Surgery
  54. 54. Nonopioid neurotransmitters involved in pain modulation Serotonin (5-HT), Norepinephrine (NE) 5-HT containing neurons in rostral ventral medulla (RVM) and NE containing neurons in the pons send projections to the spinal cord which modulate pain transmission Neurochemical lesions of these systems attenuates morphine analgesia, intrathecal injections of 5-ht and NE induce analgesia Antidepressant drugs increase 5-HT and NE, used in arthritis, migraine, herpes zoster pain
  55. 55. Descending Inhibition and Facilitation Cells in brainstem nuclei can inhibit and facilitate pain transmission (Fields, 1992) Off Cells - inhibit transmission and firing rate increased by opioids On Cells - enhance transmission, show increased firing rates before withdrawal responses and associated with enhanced pain during opioid abstinence Conclude: pain modulation is bi-directional
  56. 56. Influence on pathological pain? A decrease in tonic descending inhibition contributes to chronic pain. Increased on-cell activity may generate pain in the absence of pain. Activity of these cells may mediate the effects of psychological states on pain perception, e.g., anxiety and attention which increase pain in animals and humans
  57. 57. Activation of Pain Inhibitory Systems Intense sensory stimulation counterirritation - rubbing, acupuncture, vibration, TENS, Gate Control Theory Stressful or Frightening Stimuli - potentially threatening stimuli and cues that predict their occurrence.  Cat exposure  Context conditioning CS (place)-->US (shock) CR (analgesia) UR (analgesia)
  58. 58. Memorial Processes Shock induced hypoalgesia  Distractor study in animals  Distractor study in humans Scopolamine study Placebo analgesia - a form of conditioned analgesia
  59. 59. Afferent Regulation