The Pathophysiology of Nociception and Pain.txt

  1. The Pathophysiology of Nociception and Pain
    • Peripheral receptors for pain are naked nerve endings of the primary neuron
    • Nociceptors contain specialized ion channels that are activated by noxious stimuli
    • 3 categories:
    • mechanical: excess deformation
    • thermal: temperature >45 or <5 activate TRPV1, TRPV2 channels; some also activated by capsaicin
    • Polymodal: noxious mechanical, thermal stimuli, and chemicals; also activated by capsaicin
  2. Noxious stimulus information is encoded by
    • action potential frequency: for stimulus intensity
    • and duration of activity: for period of stimulation on the body
  3. Receptive Fields
    of nociceptors as well as second order and 3rd order neurons are larger: more convergence!
  4. Noxious stimuli directly activate specific ion channels on nociceptor terminals
    Noxious mechanical, thermal, and chemical stimuli activate specific ion channels on nociceptor terminals in the skin
  5. Damaged tissue releases inflammatory molecules that activate nociceptor terminals
    • Some molecules: K+, ATP, H+ are released from damaged cells into the extracellular environment
    • some molecules such as serotonin, histamine, NGF are secreted by cells upon stimulation
    • Some molecules such as bradykinin and prostaglandin's (PGE2, PGD2) are enzymatic byproducts or receptor-stimulated products
  6. Nociceptor terminals contain receptors for H+, ATP, serotonin, histamine, bradykinin, prostaglandin, NGF, and other molecules: have 2 effects
    • 1) they depolarize nociceptor terminals by directly activating ion channels/receptors: histamine serotonin, bradykinin, ATP, H+, K+
    • 2) they lower the threshold for nociceptor action potentials by phosphorylating ion channels in the terminal (serotonin, bradykinin, prostaglandin, NGF)
  7. Bradykinin synthesis
    • by enzymatic cleavage of HMW kininogen in plasma
    • Prostaglandin synthesis: is initiated by the binding of molecules such as bradykinin to membrane receptors
    • This activates phospholipases that cleave phospholipids to produce arachidonic acid, which is enzymatically modified to prostaglandins in mast cells
    • and important enzyme in this sequence is CYCLOOXYGENASE
  8. 3,4 Peripheral nociceptor terminals release inflammatory molecules that affect blood vessels and mast cells (neurogenic inflammation)
    • Dendrites can release molecules in addition to receiving signals
    • Electrical activity in one branch of a peripheral nociceptor terminal evokes simultaneous release of molecules from that branch as well as other branches as the depolarization spreads electronically
  9. Nociceptor terminals are both
    • sensory/receptive and secretory
    • mediated by C fiber nociceptors
    • Substance P and CGRP are neuropeptides, but here they act on non-neural cells: they are potent vasodilators
  10. Lowering threshold for nociceptor action potentials and release of inflammatory molecules by peripheral nociceptors contributes to the INFLAMMATORY RESPONSE
    • 1) vasodilation
    • 2) increased vascular permeability
    • 3) increased pain - due to increased nociceptor excitability
  11. Released molecules have multiple and combinatorial effects:
    • Histamine, serotonin, bradykinin, prostaglandin, substance P and CGRP: cause vasodilation and increased vascular permeability
    • Substance P, serotonin: cause histamine release from mast cells
  12. Inflammatory response leads to sensitization
    • vasodilation, increased vascular permeability and pain: part of healing process
    • GOAL: to increase blood flow and prevent further damage by making the area painful to ensure protection
  13. Sensitization is characterized by
    • Allodynia: generation of pain by stimuli that previously were not painful (touching sunburnt skin)
    • Hyperalgesia: perceiving an increased sensitivity to pain - noxious stimuli evoke significantly more intense pain than normal
    • Sensitization - has both peripheral and central causes
  14. Peripheral sensitization due to
    • changes at nociceptor terminals in the skin, which become more sensitive as a result of the inflammatory response
    • the molecules released into the injured area: can
    • 1) cause depolarization by binding to receptors on nociceptor terminals (histamine, bradykinin, ATP, H+)
    • 2) cause receptor-mediated changes in nociceptor channel phosphorylation that facilitate channel activity (serotonin, bradykinin, prostaglandin, NGF)
    • **These changes make nociceptors more sensitive and responsive by decreasing the threshold for evoking action potentials, increasing the frequency of action potential activity in response to noxious stimuli, or inducing spontaneous activity in nociceptors! which are normally quiescent
    • ***can be reduced by application of COX inhibitors, which reduce prostaglandin synthesis and thus their effects on blood vessels and channel phosphorylation
  15. Central Sensitization
    Stimuli that were normally subthreshold in the spinal cord/CNS will evoke activity
  16. Central Sensitization Caused by:
    • increased excitability of Second-order neurons and interneurons in the dorsal horn
    • Physiological causes: enhanced efficacy of postsynaptic potentials in dorsal horn neurons
    • decreased threshold for evoking action potentials in dorsal horn neurons
  17. Glutamate and Substance P released together produce
    • an increased depolarization that activates NMDA receptors on spinothalamic neurons to cause Ca2+ influx.
    • The increased Ca2+ can activate numerous molecules including phospholipas A2, which can lead to prostaglandin synthesis with subsequent effects on channel activity
  18. Steps that occur at nociceptor ending in body
    • 1. Molecules bind to their receptors causing depolarization
    • 2. Molecules bind to other receptors and modulate their activity
    • 3/4. bradykinin, prostaglandin, histamine binding causes phosphorylation of channels and receptors
    • 5. secreted molecules bind to receptors, become internalized, are transported to nucleus where they affect gene expression
  19. Clinical conditions cause by central sensitization
    • Windup: an acute condition in which repeated nociceptor activation causes a progressive increase in action potential frequency of spinothalamic neurons --> perceived as more intense
    • Allodynia: light touch to an inflamed area causes pain; Due to some convergence in pathways, tactile mechanoreceptor axons make synaptic concoctions with spinothalamic neurons in the dorsal horn. Normally, these connections are not sufficient to evoke action potentials in the spinothalamic neurons. After Central Sensitization though, tactile stimuli can evoke action potentials in the pain fibers
  20. Clinical Implications of Sensitization
    usually declines as tissue heals, but with nerve injury sensitization is often sustained, resulting in neuropathic pain
  21. neuropathic pain
    is due to central sensitization, a prolonged increase in excitability of central neurons. it cannot be reduced by decreasing activity in first order nociceptors
  22. Growth factors like NGF released during inflammation are transported to
    the DRG cell bodies where they cause long-term changes in gene expression that alter levels of neuropeptides, ion channels, and receptors: results in long-lasting pain syndromes
  23. Postsurgical pain
    the single most common reason for patient readmission following outpatient surgery
  24. Intrinsic Circuits Modulate Pain
    • the regions that modulate pain are in three locations:
    • 1) midbrain: periaquiductal grey
    • 2) dorsal lateral pons: locus ceruleus
    • 3) medulla: raphia and other nuclei of the reticular formation
  25. how do Intrinsic Circuits Modulate Pain
    • these brainstem regions send axons to the spinal cord where they modulate the transmission of nociceptive signals from first and second order nociceptive neurons
    • two important neurotransmitters used by the descending brainstem axons: serotonin from raphia nuclei in the medulla and NOREPINEPHRINE from locus ceruleus neurons in pons
    • These transmitters excite opiate interneurons in the spinal cord to inhibit nociceptive signals
    • Opiate interneurons: 1) presynaptically inhibit NT release from first order nociceptors and to 2) postsynaptically inhibit spinothalamic neurons
  26. The CNS naturally uses the modulatory pathways to
    • modulate pain
    • the PAG is activated by the hypothalamus and cortex in response to stressful and emotional situations
    • Descending brainstem axons have both inhibitory and excitatory effects on nociceptive signals
    • These different possibilities make it very difficult to understand and develop pharmacological strategies to treat pain
  27. Clinical treatment of pain
    • reduce pain by stopping the transmission of nociceptive signals in the spinal cord through
    • Electrical Stimulation
    • Pharmacological treatments
    • Surgical Treatment
    • Placebo Effect
  28. Electrical Stimulation
    • stimulation of descending brainstem axons arising in the PAG causes a long-lasting reduction in pain
    • first order tactile axons make inhibitory connections onto spinothalamic neurons: stimulation of the dorsal column axons sends action potentials back into the dorsal horn to inhibit nociceptors
  29. Transcutaneous Electrical Nerve Stimulation (TENS):
    • a patch containing electrodes is placed on the skin over a peripheral nerve associated with an injured area
    • the stimulus is adjusted to excite large diameter (tactile) first order axons, which will inhibit nociceptive transmission in the spinal cord
  30. Drugs that increase inhibition of the pain pathway
    • Opiates
    • NE
    • Antidepressants
  31. Opiates
    have long-lasting inhibitory effects on pain transmission
  32. Norepinephrine
    • descending NA axons arise from pontine locus ceruleus
    • these axons inhibit first order nociceptive terminals in spinal cord via alpha2-ARs and excite inhibitory interneurons via alpha1-ARs
    • thus alpha2 and alpha1 agonists both can reduce pain
  33. Antidepressants
    5-HT reuptake inhibitors potentiate the effects of serotonin, a pain modulator in the spinal cord
  34. antiseizure drugs
    increase GABA activity
  35. Glutamate antagonists
    • glutamate is a transmitter for first order pain fibers
    • excessive stimulation activates NMDA receptors, leading to central sensitization
    • However, NMDAR antagonists cannot be used because they would cause severe cognitive deficits!
  36. Capsaisin creams
    • capsaisin: binds to first order peripheral terminals of heat and polymodal nociceptors
    • continued presence of it can desensitize these receptors to prevent their activation by inflammatory molecules in the injured area
  37. Surgical Treatment
    • Tacotomy or Chordotomy: the lateral location of the ALS in the spinal cord makes it possible to sever these axons without damaging deeper areas
    • this results in immediate cessation of pain
    • However, this is transient and pain often returns after several months probably for several reasons involving sensitization at higher levels induced by the injury
  38. Placebo Effect
    the psychological expectation of an effect is enough stimulus to activate pain modulatory pathways
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The Pathophysiology of Nociception and Pain.txt