Download Lecture 10 Wednesday, October 27, 2010 1:03 PM Physiology of

Lecture 10
Wednesday, October 27, 2010
1:03 PM

Physiology of Pain
o Sensory Transduction
 The five sense
 Seeing
 Hearing
 Tasting
 Smelling
 Touching
 Other
 Temperature - Termoception
 Pain - Nociception
 Pruritus - Itch
 Balance and acceleration
 Body awareness
 Sensory Receptors
 Mechanoreceptors
 Chemoreceptors (Photoreceptors)
 Thermoreceptors
o Organization of the NErvous System
 Peripheral Nervous System
 Cranial nerves
 Spinal nerves
 Four main functions

Somatic - external
 Autonomic - internal
 Central Nervous System
Somatosensory System
 Primary sensory neuron
 Many neurons come form the dorsal root ganglia or the
brain stem (cranial nerve) (primary sensory)
 Thermoreceptors and chemoreceptors
 Causes terminals to depolarize and fire action
potentials to send to the secondary sensory neuron

o

o
o
o
Secondary sensory neuron
 In brain stem or spinal chord
 Send to thalamus then cortex
 Only when information reaches cortex, this is when
we "feel" the stimulation
Posterior Column Sensory Pathway
 Sensory stimulation is carried by these neurons
 Vibration/Light tough
 Send neurons all the way to the brain stem to the thalamus
then cortex
 Pain
 Axon terminal in spinal chord in the dorsal horn
 Location of secondary sensory neurons in the dorsal horn
of the spin
Visceral Afferent
 Nociceptic (pain)(sympathetic)
 Sympathetic
 Both output and input neurons
 Mechanical
 Chemical
 Temperature
Pain Transduction
 TRP
 Most common receptors
 Most are channels, some are g-coupled receptors (use
ATP)
 Different types
 All cause depolarization of terminals to fire an action
potential to activate the secondary neurons in the spinal
chord to send information to the thalamus to the cortex
 Thermal
 TRPV1
 Temperature and capsaicin
 TRPv2 > 50OC
 TRPm8
 Cold, menthol
 TRPA1

o
o
Intense cold, mustard oil
 Mechanical
 TRPA1
 ENaC
 Degenerin epithelial sodium channels
 Chemical
 Chemical activators
 Protons: TRPv1, Acid sensitive ion channels including
ENaC
 ATP: P2X (channels), P2Y (GPCR)
 Kinins: Bradykinin B1 and B2 (GPCR-Gq)
 Sensitizing agents
 Porstaglandin E2
 Hypothesis
 Able to block these channels can reduce pain in theory
 No drugs available
Pain Pathway
 From the Periphery to the Spinal Cord
 Aɑ
 Muscle spindle, golgi tendon organ
 A[delta]
 C
 slow conducting - dull, burning pain
 Polymodal nociceptors: heat, warmth, intense
mechanical stimuli, or chemical irritants
 Some are silent, but become responsive during
inflammation
Dorsal Horn of the Spinal Cord
 Glutamate
 Released by primary sensory neuron
 Binds to many other receptors, NMA, AMPA, etc
 Causes depolarization of the secondary neuron, thus
relaying informatino to the thalamus then the cortex
 Reduction of the release of glutamate should reduce pain
 Block Ca channels
 [omega]-conotoxin blocks channels
 Co-transmitters
Tachykinins such as substance P
 Calcitonin gene-relegated peptide
 Brain-derived neurotropic factor
 Can contribute to the pain sensation transmission
 If blocked may reduce pain sensation
 Secondary projection neurons
Descending Modulation
 Secondary sends information to the thalamus to the cortex
 Brain is not passive and waiting for information
 Controls how information is received
 Can reduce pain such as being angry or cursing
 Increasing the pain threshold
 Also love can reduce pain as well
Inhibitory Regulation in the Spinal Cord
 Opiods
 Morphine, codeine
 Some are endogenous
 Mostly mediated by [mu] receptors
 ↑ K channels, ↓ Ca channels, ↓ cAMP
 Decrease release of glutamate
 Brain
 Alter mood, produce sedation, and reduce the
emotional reaction to pain
 Brainstem
 Increase descending inhibitory influence; also produce
nausea and respiratory depression
 Why overdose of morphine can cause death
 Spinal cord
 Inhibit release from primary afferent and
hyperpolarize postsynaptic neurons
 Peripheral
 Reduce the activation of primary afferents
 NE
 ɑ2 agonist clonidine, NET or NET/5-HTT blockers
amitriptyline, duloxetine
 ɑ2 - ↑ K channels, ↓ Ca channels, ↓ cAMP

o
o


5-HT
Selective 5-HTT blockers not effective and cannot reduce
pain
 Cannabinoids
 Receptors that are activated by cannabinoids are found in
the periphery, spinal cord, brainstem
 CB1 and CB2
 Marijuana
 Can reduce pain
Sensitization
 Peripheral Sensitization
 Allodynia
 Innocuous stimuli are perceived as painful
 Hyperalgesia
 Increased sensitivity to pain
 Dramatically exaggerated
 Inflammatory mediators
 Bradykinin, protons, histamine, prostaglandin E2, and
NGF
 Can lead to activation of various kinases and
activated sodium channels on the primary nerve
terminals or other sensory neurons
 Prostaglandin E2 is most important
 Number of drugs are available to decrease
synthesis
 PKA → Nav1.8; PKC → TRPV1
 Neuropepetides
 Substance P and CGRP
 Vasodilation, ↑ capillary permeability, ↑ release of
histamine and TNF-ɑ (tumor necrosis factor cytokine)
 AA Signaling Pathways
 COX leads to production of prostoglandin
 One is prostaglandin E2

o
Decrease in glutamate release and increase in
hyperpolarization
 Reduces primary to secondary neuron transmission

o
An inflammatory mediator
 Found in both peripheral and central nervous system
 Central Sensitization
 Secondary hyperalgesia and/or allodynia
 Dorsal horn of the spinal cord
 Enhanced response to the same stimuli following
repetitive, high intensity sitmulation
 Primary neurons fire repeatedly to induce high stimuli
 NMDA receptor blockade prevents the induction and
maintenance of central sensitization
 Ketamine
 Used in anesthesia
 Not used because of unwanted side affects such
as schizophrenia
 An analog of "angel drug"
 Block NMDA receptors to reduce transmission from
primary to secondary
 Hallucination
 Neuropathic Pain
 Patient can still really feel pain though there are
no signs of pain
 Can be caused by changes in the periheral and
central nervous systems
 Persistent pain following nerve injury
 Treatment
 Tricyclics, SNRIs, anticonvulsants, lidocaine,
opiod analgesics
Analgesics
 Channel Blockers
 Effective because it prevents depolarization to reach the
threshold to fire action potentials
 Can be used to reduce pain
 Lidocaine
 Lamotrigine (anticonvulsant)
 Carbamazepine (anticonvulsant)
 Gabapentin (anticonvulsant)
 Pregabalin (anticonvulsant)




NSAIDS
 Inhibit COX enzyme
 Thus reducing synthesis of prostaglandins (E2)
 Leads to reduced sensitization
Acetaminophen
 Not an anti-inflammatory drug
 No clear evidence
 Hypothesis is that it acts primarily in the central
nervous system (inhibits COX in CNS)
 Inhibits COX enzyme
 Metabolized to AM404
 Inhibit uptake of anandamide (endogenous
Canninbinoid)
 Inhibits Na channels
 Both contribute to the reduction of pain
Glucocorticoids
 Cortisol (steroid)
 Most potent anti-inflammatory
 Not an analgesic
 ↑ Lipocortin-1 (annexin-1) synthesis
 ↓ PLA2
 ↓ release of inflammatory mediators
 ↓ pro-inflammatory genes
Triptans
 Migraine
 Sumatriptan
 5-HT1b and 5-HT1D agonists
 Theories on why it reduces migraines
 ↓ sensory transduction
 ↓ sensitization - trigeminal nucleus
 Located in the brain stem
 Sensory nuclei
 Receives many different sensory neurons