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What is Pain?
• “An unpleasant sensory and emotional
experience associated with actual or
potential tissue damage, or described in
terms of such damage.”
– International Association for the Study of Pain
Pain and temperature sensed by free nerve endings
Fiber diameter profile of peripheral nerves
Heat and cold stimulate pain receptors (nociceptors)
Temperature Sense
• Normal skin temperature: T = 30-32 °C
• Thermal sensations span four ranges:
1. Cold (T < 15 °C)
2. Cool (T > 15 °C and < 30 °C)
3. Warm (T > 35 °C and < 45 °C)
4. Hot (T > 45 °C)
• Specific temperature-sensitive receptors
code each range
Thermal Receptors
• Cold Receptors (TRPM8)
– A-d fibers (thinly myelinated)
– Stimulus: Cooling between T = 8 °C and 40 °C
– Most sensitive at T = 25 °C
– Saturate at T < 8 °C
• Warm Receptors (TRPV3)
– C fibers (unmyelinated)
– Stimulus: Warming between T = 35 °C and 45 °C
– Most sensitive at T = ~42 °C
– Saturate at T > 45 °C
Cold fibers signal rapid skin cooling
Dynamic Response to Temperature
Warm Receptors Code T > 35 °C
Warm Receptors Saturate at High T
Thermo-TRPs respond to specific temperature ranges
TRP = Transient receptor potential
Heat Nociceptors … and Burning Pain
• A-d fibers (NS) or C fibers (HPC)
Express TRPV1 and/or TRPV2 receptors
Firing rate signals heat intensity at T > 45 °C
Response outlasts heat stimulus
Sensitize to repeated heat stimuli
Noxious Cold (T < 10 °C)
• Cold Fibers (TRPM8)
– A-d fibers (thinly myelinated)
– Saturate at T < 8 °C
• Polymodal Nociceptors (HeatPinchCold)
C fibers (unmyelinated)
Firing rate signals degree of cooling at T < 25 °C
Fire at highest rates at T < 0 °C
Express TRPA1, TRPV1 and TRPM8 receptors
Paradoxical Cold: Freezing temperatures are perceived as burning
Heat and cold stimulate specific groups of receptors
What is Pain?
• Aversive sensation
• Intensity ranges from unpleasant to horrible
• Various classes of pain
pricking, stabbing, pinching (mechanical )
burning, freezing (thermal )
aching, stinging, soreness (chemical )
visceral (mechanical, chemical )
• Emotional component (pain tolerance)
• Protective function
– Warn of injury that should be avoided or treated
Four classes of noxious (painful) sensations
Heat pain
Cold pain
Mechanical Nociceptors
• Receptors specialized for painful mechanical
stimuli (Nociceptive Specific)
– A-d fibers (thinly myelinated)
– Do not respond to light touch (high threshold)
– Excited by strong pressure, pinch or squeezing
– Mediate pain from skeletal muscle or viscera due
to excessive stretch or contractile force
– Most respond to noxious heat (T > 45 °C)
Mechanical nociceptors respond to prick and pinch
Polymodal nociceptors
C fibers (unmyelinated free nerve endings)
Respond to heat, pinch and cold (HPC receptors)
Express TRPV1, TRPA1 and other TRP receptors
Respond to irritant chemicals
Capsaicin (chili peppers): TRPV1 receptors
Mustard oil, garlic, horseradish: TRPA1 receptor
Low pH (acids)
Endogenous peptides: Bradykinin, NGF
Environmental irritants and pollutants
Polymodal nociceptors express multiple receptors
Nociceptors Respond to Chemicals
• Exogenous chemicals that penetrate skin
– Acids, alkalis, organic molecules
– Capsaicin, Mustard oil
• Intracellular molecules released by cell injury
– Cations [K+, H+]
– Peptides, neurotransmitters
– Prostaglandins, histamine
• Toxins [micro-organisms, insect bites, venom]
• Pathological substances released by
diseased tissue
Tissue Damage Stimulates Nociceptors
TRP receptors respond to pungent chemicals
Garlic, radishes,
mustard oil
Irritant chemicals activate TRP receptors
Inflammation sensitizes nociceptors
Noxious stimuli are spread by axon reflexes
Touch and pain fibers project to distinct spinal laminae
Pain Inputs to Spinal Cord
Lamina I Cells Respond Only to Pain
• Mechanical and Heat (NS)
• Cold
• Polymodal (Heat, Pinch,
• Irritant Chemicals
(Histamine, Capsaicin,
Mustard Oil)
Small Fiber Inputs to Spinal Cord
Touch and pain fibers project to distinct spinal laminae
Referred Pain: Wide Dynamic Range Neurons
Touch and Pain Ascend in Separate Tracts
Visceral pain transmitted in the dorsal columns
Willis WD, et al. PNAS 96: 7675-7679, 1999
Central gray matter
Pain Pathways to Thalamus and Cortex II
Parallel Processing of Pain in Cortex
• VPL/VPM —> SI Cortex
– Pain localization to particular body site
• VMpo —> Dorsal Insular Cortex
– Pain sensation experienced (cold, heat, stab)
• MDvc —> Anterior Cingulate Cortex
– Pain emotional reaction
• Hypothalamus and Limbic Cortex
– Body physical response to pain
– Subjective memory of pain
Pain Centers in the Brain
Apkarian et al. Eur J Pain 9: 463-484, 2005
How Can We Reduce Pain?
• Remove the painful stimulus
– Flexion reflex (hard-wired circuit to avoid pain)
– Treat injury or pathology
– Analgesics and/or antihistamines
• Block impulse conduction in peripheral nerve
– Local anesthetics, epidural anesthesia
• Block synaptic transmission in CNS
– General anesthesia
– Narcotic analgesics (e.g. morphine)
• Activate body’s own pain control system
Gate Control of Pain
Emotions Modulate Pain Transmission
(nucleus cuneiformis)
(periaqueductal gray)
(dorsolateral pontine tegmentum)
Endogenous Pain Inhibition
Endogenous Opioid Peptides
• Leucine-enkephalin
– Tyr-Gly-Gly-Phe-Leu-OH
• Methionine-enkephalin
– Tyr-Gly-Gly-Phe-Met-OH
• b-endorphin
– Tyr-Gly-Gly-Phe-[26 amino acids]-OH
• Dynorphin
– Tyr-Gly-Gly-Phe-[13 amino acids]-OH
Opiates & Opioids Modulate Pain
Pain Prevention
• Local anesthetics as supplements or
alternatives to general anesthesia
Intrathecal morphine intraoperatively
Postoperative pain relief
Physical therapy to stimulate large fibers
Psychotherapy to optimize use of
descending pain control pathways and
improve pain tolerance
Pain Perception Involves Multiple Processes
Nociceptive Pain: Somatosensory response
Inflammatory pain: trauma or disease
Two Classes of Pain
• Nociceptive or Inflammatory Pain (Acute)
– Sensation transmitted by free nerve endings
– Stimulus provided by noxious (harmful)
mechanical, thermal or chemical input
– Protective function
• Neuropathic Pain (Chronic)
– Abnormal firing pattern in PNS or CNS
– Caused by lesion or trauma to nerve or CNS
– Sensitization of central pathways due to
excessive painful input
Neuropathic Pain
• Elicited by prolonged strong activation of
• Result of major injury
– Trauma
– Severe burns
– Major surgery
– Limb amputation
– Peripheral nerve injury or neuroma
– Postherpetic neuralgia
Neuropathic pain: Nerve injury or CNS lesion
Peripheral Sensitization
Peripheral nerve injury
Injured Schwann cells sensitize nociceptors
DRG neurons respond to cytokines and ATP
Central Sensitization … and Neuropathic Pain
• Nociceptor synapses are glutaminergic
• Strong stimulation activates NMDA receptors
• LTP-like process increases synaptic efficacy
through protein synthesis
• Spinal synapses become more responsive to
pain (hyperalgesia) and touch (allodynia)
Glutamate receptor mechanisms
Silent synapses and LTP
Central Sensitization Mechanisms
Pain begets pain (Pro-nociception pathways)
Dysfunctional Pain: unknown cause
Recommended additional readings (optional)
Patapoutian A, Tate S, Woolf CJ. Transient receptor potential channels:
targeting pain at the source. Nature Reviews: Drug Discovery 8: 55-68, 2009
Craig AD. How do you feel? Intero-ception: the sense of the physiological
condition of the body. Nature Reviews Neuroscience 3: 655-666, 2002
Apkarian AV, Bushnell MC, Treede R-D, Zubieta J-K. Human brain
mechanisms of pain perception and regulation in health and disease. Eur J
Pain 9: 463-484, 2005
Tracey I, Mantyh PW. The cerebral signature for pain perception and its
modulation. Neuron 55: 377-391, 2007
Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending
facilitation. Trends Neuroscience 25: 319-325, 2002
Costigan M, Scholz J, Woolf CJ. Neuropathic pain: A maladaptive response of
the nervous system to damage. Annu Rev Neurosci 32: 1-32, 2009
Pain vocabulary
• Hyperalgesia
– Sensitization: enhanced sensation to noxious
stimuli following injury
– Stimulus provided by noxious mechanical,
thermal or chemical input
• Allodynia
– Sensitization: abnormal response to touch
– Caused by lesion or trauma to nerve or CNS
• Analgesia
– Pain relief and/or attenuation