1. nociceptor
    pain receptor
  2. nociception
    perception of pain
  3. algesia
    sensitivity to pain
  4. analgesia
    reduced sensitivity to pain
  5. esthetic
    perception of sensation
  6. four stages of nociception
    • 1. transduction
    • 2. transmission: nerve sends signal to CNS and the process invloves several neurons
    • 3. Perception
    • 4. Modulation: altered transmission
  7. nociceptors
    pain receptors

    • Free nerve endings: stimulated or Activated
    • by extreme (high threshold):
    • -temperature: >42C,<10 C,
    • -mechanical damage crush, prick, cut
    • -chemicals from: substances released following tissue damage
    • damaged cells (PG, cytokines, lactic acid,K+, H+),
    • plasma (precursor to bradykinin),
    • WBCs (histamine, serotonin, cytokines),
    • substance P
  8. Nociception fibers
    –Type A delta fibers: transmit immediate sharp pain( has myelin and large axon/fiber, 10%)

    –Type C fibers: transmit dull throbbing pain that persists after removal of sharp stimulus( small fiber/axon without myelin, 90%)

    *majority of pain is stimulated along Type C fibers

    *Perception: Pain can be described as sharp (first pain) and more delayed and longer lasting (second pain)
  9. nociceptor location
    • Skin,
    • joints,
    • vessel walls,
    • thoracic/abdominal viscera

    –Most have large receptive fields
  10. stimulation of nociceptor
    • –Direct damage & chems released at site
    • –Tissue injury leads to:
    • Formation of Bradykinin~~~activates PLA2
    • - Cox Activity ~~~ enhanced PG formation
    • –PG do not initiate pain but lowers threshold of fibers (sensitize)
    • -other mediators: K+, H+, ATP, histamine, substance P

    *Substance P is relased at site by nociceptor

    • Hyperalgesia: enhanced sensitivity and responsivity to stimulation in the area around the tissue damage: stimuli not normally painful perceived as & painful stimuli is “more so” e.g.
    • sunburn
  11. Lateral Spinothalamic Tract
    • –1st Order Neuron (nociceptor)
    • •Periphery to spinal
    • cord
    • –2nd Order Neuron
    • •Decussate in spinal cord
    • •Spinal cord to thalamus
    • –3rd Order Neuron
    • •To primary sensory cortex
    • •To cortical association areas (parietal)
    • •To limbic region
    • • widespread cortical activation)/can’t just cut cortical regions and get rid of pain
  12. A delta fibers
    localized perception of pain
  13. C fibers
    • connections to many brain regions.
    • Non localized
  14. Nociception
    • Neural Processing of Pain Sensations in Brain
    • –Awareness and interpretation of pain
    • –Regions involved: 1˚ sensory cortex, Association
    • cortex, Limbic region

    • Pain Threshold and Tolerance
    • –Pain Threshold: Similar from person to person
    • –Tolerance:Varies widely from person to
    • person (or same person)
    • Influenced by circumstances/culture

    • Pain Expression
    • –How communicated to others?
    • –Highly variable à assessment difficult
  15. Nociception
    • *Within Spinal Cord
    • –1) Other sensory input to dorsal horn modifies nociceptive signal
    • –2) Descending output pathways from Brain to Dorsal Horn

    • *At Nociceptor Ending or Within Brain
    • –1) Chemicals released at nociceptor: Most cause hyperalgesia
    • –2) Endogenous opioids in brain reduce pain perception: Enkephalins, endorphins, dynorphins
  16. Modulation at Level of Spinal Cord
    • *Input From Other Sensory Receptors
    • –Often initiated by person: Rubbing, pressing, shaking
    • –Co-stimulation of large myelinated Abeta fibers: Lessen progression of pain to the brain

    • *Output From Brain
    • e.g. PAG in brainstem
    • –1) Presynaptic inhibition: Enkephalins reduce Substance P release at Dor. Horn
    • 2) Descending pathways (from brain) project to dorsal horn & ultimately inhibit discharge of spinothalamic tract neurons, therefore decrease pain transmission
  17. Referred Pain
    Sensory Confusion
    • *Pain is felt in uninjured part of body when pain originates at another location
    • –Visceral and somatic sensations that travel along same spinal segment
    • *Examples
    • –Pain of heart attack à discomfort felt in left upper chest and left arm
    • –Pain of appendicitis à navel and right lower quadrant

    • *Possibilities for phenomena
    • –Synapse on same 2nd order neuron in dorsal horn
    • –Brain is more "accustomed" to receiving sensation from the peripheral structure than from the viscera, it may interpret
    • the pain as originating from there
  18. Overview of Eicosanoid Pathway
    Arachidonic Acid Metabolism
    • •AA is important precursor for biosynthesis of eicosanoids
    • •AA released from Membrane by PLA2
    • •PG,TX, LTs: short lived, locally acting, potent compounds
    • PGs/prostaglandins: activate inflammatory response, pain, fever, GI: inhibit acid secretion,
    • Increase protective mucus; increase blood flow in kidneys
    • Constrict bronchi
    • Misc effects: induce uterine contraction & can induce labor
    • •TX-thromboxane-from platelets,
    • stimulates constriction & clot formation
  19. Biological Actions of Arachidonic Acid Various Metabolites
    Sensitize Pain Receptors (PG)

    Promote Inflammation (PG, LT)

    Induce Fever (PG, LT)

    Protect Gastrointestinal Tract (PG)

    Increase Platelet Aggregation (TB, PG)

    Influence Vascular Smooth Muscle (PG, LT, TB)

    Contract Bronchiolar Smooth Muscle (LT)

    Stimulate Gastrointestinal Smooth Muscle (PG)
  20. NSAIDS Analgesics
    • *Extracts from Willow Tree Bark
    • –Used to lessen pain
    • –Active ingredient : Salicylic Acid

    *Bayer makes Acetylsalicylic Acid (Aspirin) - 1899 –Acetylation of salicylic acid “Gold Standard” NSAID

    • *Acetaminophen
    • Non-steroidal analgesic: (inhibits COX-3 possibly)

    *Ibuprofen, Naproxen and Others
  21. NSAIDS Analgesics
    Aspirin – The Four A’s
    • *Overview of Analgesic Use
    • –For mild to moderate pain (minor aches & pains)
    • Decreased sensitizing PG
    • Anti-inflammatory effect
    • –Duration of action = 4-6 hr & mainly given orally

    • *Nonselective Cyclooxygenase Inhibitor
    • -Irreversible acetylation of COX-1 and COX-2
    • Cox 1 & Cox 2 involved w/ring closure & adding
    • Oxygen to convert AA to PG/Aspirin prevents AA from entering active site of enzyme

    • *Other beneficial actions
    • Anti-inflammatory//Anti-pyretic
    • Anti-thrombotic/ no blood clotting
  22. Aspirin – Adverse Effects
    • *Increased Bleeding Time
    • –Inhibition of Thromboxanes mainly
    • –Stop aspirin one week prior to surgery

    • *High Dose or Chronic Use
    • –Toxic CNS effects:
    • –Tinnitis
    • –Headache, dizziness
    • –Mental confusion
    • –Nausea, vomiting, diarrhea

    • *Gastric Ulcers
    • –Due to blockade of protective actions of prostaglandins
    • –Can get aspirin induced gastric bleeding
  23. NSAIDS Analgesics
    Reversible Inhibitors of COX-1, COX-2:
    Ibuprofen (Advil, Motrim)
    –4 A’s, but weaker anti-thrombotic

    –Duration of Action = ~4 hr

    –Fewer GI side affects
  24. NSAIDS Analgesics
    Reversible Inhibitors of COX-1, COX-2

    Naproxen (Aleve)

    NSAIDS Analgesics
    Reversible Inhibitors of COX-1, COX-2
    –4 A’s, but weaker anti-thrombotic

    –Duration of Action = ~8 hr

    –Fewer GI side effects
  25. NSAIDS Analgesics
    Reversible Inhibitors of COX-1, COX-2

    Indomethacin (Indocin)
    –4 A’s, but weaker anti-thrombotic

    –More potent anti-inflammatory agent

    –GI side effects, headaches, dizziness
  26. Other Analgesics
    Tylenol, Excedrin, various cold medicines

    • *Not a NSAID (No effect on COX-1, COX-2)
    • –No anti-inflammatory action
    • –No anti-thrombic action
    • *Mechanism unclear (COX-3 inhibition?)
    • –Analgesic
    • –Anti-pyretic
    • *Duration of Action = ~4 hr
    • *Minimal GI side affects
    • *Overdose: severe hepatotoxicity
    • –Don’t mix with chronic alcohol use
  27. Opioid Analgesics
    • *Overview of Analgesic Use
    • –For severe pain :Acts on CNS opioid receptors
    • –Duration of action = 4-5 hr
    • IV: Not very active if given orally

    *Nonselective Opioid Agonist: Mu (u), delta (d), kappa (k) receptors

    • *Other Beneficial Actions
    • –Anti-tussive
    • –Applications in Anesthesia
    • –Anti-diarrhea
  28. Opioid Analgesics
    Morphine – Adverse Effects
    • Tolerance can develop: Require larger doses for same Response (or get a weakening response).
    • Most common cause of fatal overdose with drug
    • is respiratory depression.

    • Addiction (Euphoric effect)*
    • Respiratory Depression*
    • Nausea and Vomiting*
    • Constipation
    • Decreased Renal Function
    • Reduced Immune Function
    • Constriction of Pupils (Myosis)

    *=tolerance develops
  29. Opioid Analgesics
    • –Mild to moderate pain :12 times less potent than
    • morphine
    • –Anti-tussive
    • –Orally Active
    • –Tylenol #2 and #3: Acetaminophen and codeine
  30. Opiod Analgesics:

    • –Rapidly crosses the BBB
    • Metabolized to morphine
    • 3 times as potent as morphine
    • –No accepted medical use
  31. Opioid Analgesics
    • *Meperidine (Demerol)
    • –Potent analgesic

    • *Fentanyl (Sublimaze)
    • –Potent analgesic; often used in surgical anesthesia

    • *Methadone (Dolophine)
    • –Used to detoxify addicts
    • –Longer duration of action; reduced withdrawal symptoms
    • –Potent analgesic; less euphoria

    • *Propoxyphene (Darvon)
    • or Oxycodone (Percocet)
    • –Low analgesic activity; combined with acetaminophen
  32. opioid receptor antagonists
    Naloxone and Naltrexone
  33. Other “Cool” Analgesics
    Topical OTC Agents
    • Capsaicin
    • –Plant product such as hot peppers
    • –Binds nociceptors on Vanilloid receptors
    • –Found in OTC topical analgesic cremes

    Capzasin®, Zostrix®

    • –Mechanism of Action
    • Initial mild pain and irritation
    • With prolonged use --> desensitization of nociceptor
    • Reduces release of substance P in Type C receptor

    • –Uses: mainly arthritis, mild muscle
    • aches and pains
  34. Nonpharmacological Pain Management

    • Electrical Stimulation
    • Cold / Heat Application
    • Massage
    • Diet
    • Exercise
    • Yoga
    • Meditation
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