Neurobiology of Pain

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created 3 years ago by Stephen_Clark
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What is Pain

  • series of chemical responses to noxious or damaging stimuli.
  • a sensory experience incurred when nociceptive pathways to central pain centers are stimulated.
  • primitive adaptive response that ensures that animals exhibit escape behaviors in response to injurious or life threatening circumstances
  • perceptual experience; it is an “unpleasant sensory and emotional experience associated with actual or potential tissue damage.

Fast Pain

  • Sharp, pricking, acute, electric
  • Mediated primarily by Aδ (Type III) fibers ( neospinothalamic tract)
  • Easy to localize; found mostly in Periphery
  • Release glutamate at dorsal horn

Slow Pain

  • difficult to localize, persistent and emotional; peripheral and deep tissue pain
  • Burning, aching, throbbing, nauseous
  • Mediated primarily by C (Type IV) fibers (paleospinothalamic tract)
  • release substance P at dorsal horn

Skin Mechanorecptors

  • Meissner's corpuscles
  • Pacinian Corpuscles
  • Merkel Recptors
  • Ruffini endings
  • Free nerve endings

Meissners Corpuscles

Fine Touch


Pacinian Corpuscles



Ruffini Endings

Skin Stretch


Free Nerve Endings

Hair follicles, Nociceptors, Thermoreceptors



  • Free nerve endings
    • Widespread in superficial layers of the skin, periosteum/cranium, arterial walls, joints
    • Sparse innervation of most deep tissues; No innervation of central neural tissue
  • Receptor properties vary
    • Adequate stimulus depends on modality
    • Receptive field size varies between different pain modalities. 100 μm for mechanical
  • Little to no sensory adaptation

Nociceptors: Responsive to multiple stimuli

  • Mechanical stimuli lack of specialized endings raises threshold may be somatic or visceral
  • Chemical stimuli exogenous and endogenous algesic factors may be somatic or visceral
  • Thermal stimuli heat : > 43ºC (113ºF) ; cold: < 15ºC (59ºF) usually somatic
  • Itch and Tickle associated with nociceptors travel in spinothalamic pathway

Thermal Receptors

  • More cold receptors (cool spots) than warmth receptors.
  • Warmth transmitted mainly by C fibers
    • Noxious heat transmitted by Aδ fibers Cool transmitted mainly by Aδ fibers
  • Slow and incomplete sensory adaptation
  • Conveyed through anterolateral (spinothalamic) system

Pain and temperature sensation: Lissauer's tract

  • Axons from some first order neurons conveying pain and temperature synapse immediately onto second order neurons, but many ascend or descend 1-2 levels in Lissauer’s tract before synapsing
  • Some pain and temperature sensation is therefore spared when a spinal hemisection is discrete.
  • Sensory sparing reflects branching of afferent pain fibers (Lissaur’s tract)

Visceral Afferent Pathways

Visceral reflexes, Afferent visceral sensory information, Visceral Pain


Visceral Reflexes

Afferent visceral sensory neurons synapse with second order neurons that send branches to autonomic efferents.


Afferent Visceral sensory information

Afferent visceral sensory neurons synapse with second order neurons that project ipsilaterally to the solitary nucleus, which conveys the information to homeostatic centers in the brain.


Visceral Pain

Afferent visceral sensory neurons synapse with second order neurons that project contralaterally in the spinothalamic tract. Pain is usually referred to the surface of the body.


Subcortical Pain Responses

  • Collateral branching in the slow pain pathway allows subcortical response
  • Reticular formation= arousal center; limbic system =emotional responses
  • thalamus= slows pain perception

Subcortical Pain Perception Evidence

  • Removal of somatic sensory cortex does not prevent pain perception
  • Stimulation of somatosensory cortex induces mild pain only
  • Cortical awareness relates mostly to perception of the quality of pain

Deep pain

  • Slow pain – conveyed mainly by C fibers. Few Aδ fibers in deep structures
  • Frequently associated with nausea, sweating, changes in blood pressure
  • Often induces reflex muscle contraction.
  • Extended muscle contraction exacerbates deep pain

Visceral Pain

  • Usually doesn’t convey small discrete stimuli. Requires diffuse stimulation of nociceptors throughout
  • mechanical or chemical stimuli
  • Variety of etiological factors
    • Ischemia: formation of acids, bradykinins, proteolytic enzymes.
      Chemical stimuli: gastric juices
      Smooth muscle spasm of hollow viscus (cramps and ischemia)
      Overdistention of a hollow viscus (stretch and ischemia

Referred Pain: Predicting Visceral injury site

  • Site of referral is consistent for each organ
  • Referral of visceral pain confounds localization but assists diagnosis.
  • Not necessarily close to the adult anatomical location
  • Pain refers to dermatomes that are associated embryologically

Referred Pain: Mechanism

  • Interactions between somatosensory and visceral pain pathways
  • Dorsal Horn Interaction : Shared synapses onto second order neurons that form the spinothalamic tract
  • Dorsal Column Interaction : Branching of visceral nociceptive afferents into the DCML pathway

Parietal Pain

  • Somatic innervation of pleura - GSA
  • Travel with spinal nerves
  • Fast pain – mainly Aδ fibers; easily localized
  • Conveyed by neospinothalamic tract

Visceral Pain

  • Visceral innervation of organs
  • Travel with autonomic fibers
  • Slow achy pain – C fibers only; referred pain
  • Conveyed by paleospinothalamic tract

Appendicitis-pain: Visceral Component

  • originates from appendix
  • travels with sympathetic nerves
  • enters spinal cord at T10
  • pain referred to umbilicus
  • slow achy crampy pain

Appendicitis pain: Parietal Component

  • originates from abdominal wall
  • travels with lumbar spinal nerves
  • enters spinal cord at L1
  • pain felt in lower right abdomen
  • sharp intense immediate pain

Neuropathic Pain

  • pain arising as a direct consequence of a lesion or disease affecting the somatosensory system
  • Neuropathies from diabetes, cancer, HIV
  • Thalamic pain, Spinal cord stenosis or injury
  • Herpes zoster infection of dorsal root ganglion (shingles)
  • Causalgia (peripheral nerve damage)
  • Phantom limb pain
  • Often accompanied by hyperalgesia and allodynia

Neuropathic Pain: Trigeminal Neuroglia

  • Age related (50 and over)
  • Brief episodes of intense stabbing pain ; Usually triggered by ‘fine touch’ mechanical stimulus
  • Seizure-like hyperactivity of the spinal trigeminal nucleus
  • Usually results from impingement of a blood vessel compressing trigeminal entry zone
  • Associated with cluster headaches (primarily in men)
  • Primary treatment approach is anticonvulsant drugs (carbamazepine)

Phantom Pain

  • Most common after limb amputation ;Mastectomy, tooth extraction, etc.
  • Intense acutely, made diminish with time
  • Central somatosensory reorganization
  • Prominent cause of chronic pain

Thalamic Pain: Dejerine-Roussy Syndrome

  • Primary cause is thalamic stroke
  • Initial presentation is contralateral numbness and tingling
  • Recovery of function associated with burning and tingling pain
  • Pain worsens over time, chronic and unrelenting
  • Hyperalgesia, allodynia, dysesthesia

Thalamic Pain: Teatment

  • Unresponsive to basic analgesic
  • Some success with opiates, anti-depressants, anticonvulsants, alternative approaches (NICAM)
  • Intralaminar (VPI) thalamic lesions
    • Only for severe, intractable pain
      Spare VPM and VPL functions
  • Electrical Stimulation
  • Unreliable and short-lived effects of existing treatments.


  • Most common neurological complaint
  • No nociceptors in neural tissues. Pain comes from other tissues of the head
    • Skin, Connective tissue, Muscles (tension headache), Bone (blunt trauma headache), Sinuses, Meninges (meningitis),Vasculature (aneurism)
  • Pain conveyed primarily via trigeminal nerve
  • Primary vs. secondary headache

Primary Headache

  • Not attributable to pathology
  • Three main types: Migraine (w/ or w/o aura), Tension-type, Trigeminal autonomic cephalalgia, Cluster headaches

Secondary Headache

  • Directly attributable to cause (injury, infection, disease)
  • Many different causes
  • Treatment approach must address cause

Nociceptive Mechanisms

  • Mechanical Pain
  • Thermal Pain-hot
  • Thermal pain- Cold
  • Chemical Pain

Mechanical Pain

Physical disruption of the nerve ending membrane opens ion channels and depolarizes neuron.


Thermal Pain: Cold

CMR1: Cold and Menthol Sensitive Receptor


Thermal Pain: Hot

  • TRP Receptors
  • Vanilloid receptors: heat and capsaicin
    TRPV1: noxious heat (> 43ºC) and capsaicin
    potentiated by PKC*
    TRPV2: noxious heat (> 50ºC) only

Chemical Pain

  • TRP Receptors (V1 and others)
  • Exogenous compounds such as capsaicin, acrolein, neurotoxins
  • Endogenous compounds from damaged tissue such as histamine, bradykinins, H+ ions, inflammatory cytokines: *activate PKC
  • Contribute to hyperalgesia from inflammation

Nociceptive Mechanism: Axon Reflex

  • C-Fiber interactions with damaged tissue
  • Substance P from C-fiber stimulates histamine release from mast cells
  • Role for C-fiber in initiating inflammatory responses, ATP release, H+
  • Substance P from C-fibers causes vasodilation
  • Locally released factors stimulate C-fibers
  • “Vicious circle” of hyperalgesia

Nociceptive Mechanisms: Purinergic Receptors

  • Present on nociceptive nerve endings
  • P2X (ionotropic) and P2Y (metabotropic)
  • Signal pain at nanomolar concentrations of ATP: Adequate stimulus
  • Activation of P2X (nonselective cation) channels results from release of ATP by metabolically hyperactive and injured tissues
  • Activation of P2Y receptors by the released ATP stimulates Gi and Gq proteins for Ca++ channel opening and Ca++ induced Ca++ release.

Pain modulation Algesic sensation

Peripheral sensation, Central sensitization


Peripheral sensitization

  • Response to inflammatory mediators
  • cytokines, histamines, serotonin
  • Upregulation of voltage-gated ion channels
  • Increased membrane excitability
  • Mechanical and thermal thresholds reduced with peripheral nerve lesions (neuropathic sensitization)

Central sensitization

  • Activity dependent synaptic facilitation
  • May involve synapses at dorsal horn , thalamus, or cortex
  • Long term potentiation

Pain modulation Algesic factors

  • Factors related to injury
    • Cytokines – IL6, TNFα, TNFβ
      Hydrogen ions
  • neurotransmitters
    • Serotonin in the periphery
    • Glutamate and Substance P in the spinal cord
  • irritants
    • Capsaicin
      Allergens/Plant oils
  • Effects of mood disorders
    • Low levels of brainstem monoamines

Analgesic factors: Gate control Theory

  • Melzack and Wall, 1965
  • Inhibitory neuron to second order pain neurons in substantia gelatinosa
  • Modulated by fine touch primary afferents
  • “Gates” the efficacy of transmission of pain signal
  • Possible mechanism for acupuncture

Pain modulation Endogenous Analgesic Factors

  • Stimulation of periaqueductal gray leads to endorphin release
  • Stimulation of periaqueductal gray facilitates serotonin release
  • Descending serotonin pathways cause release of enkephalins in the dorsal horn that inhibit pain neurotransmission
  • Ascending serotonin pathways act positively in mood control centers and raise the pain threshold centrally
  • Norepinephrine also inhibits pain through both descending and ascending pathways

Pain Modulation: Exogenous Analgesic Factors

  • Lidocaine/Novocaine
    • Short lived, topical use
      Sodium channel blocker
      Prevents action potential in nerve
  • Aspirin (acetylsalicylic acid) and NSAIDS
    • Inhibit prostaglandinsInhibit NOReduce inflammation
  • Acetaminophen
    • Similar actions to aspirin
      Limited anti-inflammatory actions
  • Opiods
    • Act through endogenous opioid receptors.
      Central inhibition of pain perception.
      Highly addictive – **last resort**

Local Anesthesia Ancient Plant Medinals

  • Used by ancient civilizations including Incas, Egyptians and Chinese
    • Coca leaves – numbing effects when chewed
    • Henbane leaves – atropine, scopolamine analgesic, sedative, anti-spasmodic
    • Mandrake bark/root – sleep inducing
    • Opium (poppy) – narcotic, analgesic effects
  • All of these are toxic plants with risks and side effects

Local Modern Anethetics

Cocaine, Procaine(Novocaine), Lidocaine



  • Precursor to modern dental anesthetics
  • Observed to cause a numbing effect on the tongue
  • Studied by Freud and others in 1860’s
  • Introduced for eye and oral surgeries in 1884
  • Toxic and highly addictive


  • Developed in 1904
  • Non-addictive alternative to cocaine
  • Allergic reactions (Procaine or PABA)
  • Use started to decline in 1960’s
  • Almost no use in USA after 1980’s


  • Approved for use in USA in 1948
  • Most commonly used dental anesthetic
  • Low incidence of allergies and adverse
    side effects
  • Topical anesthetic used before injection
  • Alternatives available
    • Mepivacaine (1960)
      Prilocaine (1965)
      Bupivacaine (1983)
      Articaine (2000)
  • Typically contains epinephrine
    • Vasoconstrictive properties
    • Decreases systemic absorption
    • Lower doses, longer lasting

Local Anethesia Failure

  • Patient variability
    • Reduced dose for children
  • Site of injection
    • Should be near bone and tooth apex
    • Vascular injection – drug loss
    • Muscular injection – poor diffusion
  • Psychogenic drug resistance
    • Fear and anxiety
    • Influence of existing pain
  • Biological propensity for drug resistance

Alternative Pain Managment

Physical Therapy, Targeted exercises, Acupuncture, Acupressure, Massage, Meditation, Yoga/Tai Chi, Biofeedback