1. 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

2. Pain and temperature sensed by free nerve endings

3. Fiber diameter profile of peripheral nerves

4. Heat and cold stimulate pain receptors (nociceptors)

5. 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

6. Thermal Receptors Cold Receptors (TRPM8) Warm Receptors (TRPV3)
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

7. Cold fibers signal rapid skin cooling

8. Dynamic Response to Temperature

9. Warm Receptors Code T > 35 °C

10. Warm Receptors Saturate at High T

11. Thermo-TRPs respond to specific temperature ranges
TRP = Transient receptor potential

12. 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

13. 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 pain

14. Heat and cold stimulate specific groups of receptors

15. 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

16. Four classes of noxious (painful) sensations
Heat pain
Chemical
Mechanical
Cold pain

17. 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)

18. Mechanical nociceptors respond to prick and pinch

19. 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

20. Polymodal nociceptors express multiple receptors

21. 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

22. Tissue Damage Stimulates Nociceptors

23. TRP receptors respond to pungent chemicals
Garlic, radishes, mustard oil
Menthol
Camphor
Capsaicin

24. Irritant chemicals activate TRP receptors

25. Inflammation sensitizes nociceptors

26. Noxious stimuli are spread by axon reflexes

27. Hyperalgesia

28. Touch and pain fibers project to distinct spinal laminae

29. Pain Inputs to Spinal Cord

30. Lamina I Cells Respond Only to Pain
Mechanical and Heat (NS)
Cold
Polymodal (Heat, Pinch, Cold)
Irritant Chemicals (Histamine, Capsaicin, Mustard Oil)

31. Small Fiber Inputs to Spinal Cord

32. Touch and pain fibers project to distinct spinal laminae

33. Referred Pain: Wide Dynamic Range Neurons

34. Touch and Pain Ascend in Separate Tracts

35. Visceral pain transmitted in the dorsal columns
Central gray matter
Willis WD, et al. PNAS 96: , 1999

36. Pain Pathways to Thalamus and Cortex II

37. 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

38. Pain Centers in the Brain
Apkarian et al. Eur J Pain 9: , 2005

39. 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

40. Gate Control of Pain

41. Emotions Modulate Pain Transmission
(nucleus cuneiformis)
(periaqueductal gray)
(dorsolateral pontine tegmentum)

42. Endogenous Pain Inhibition

43. 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

44. Opiates & Opioids Modulate Pain

46. 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

47. Pain Perception Involves Multiple Processes

48. Nociceptive Pain: Somatosensory response

49. Inflammatory pain: trauma or disease

50. 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

51. Neuropathic Pain
Elicited by prolonged strong activation of nociceptors
Result of major injury
Trauma
Severe burns
Major surgery
Limb amputation
Peripheral nerve injury or neuroma
Postherpetic neuralgia

52. Neuropathic pain: Nerve injury or CNS lesion

53. Peripheral Sensitization

54. Peripheral nerve injury

55. Injured Schwann cells sensitize nociceptors

56. DRG neurons respond to cytokines and ATP

57. 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)

58. Glutamate receptor mechanisms

59. Silent synapses and LTP

60. Central Sensitization Mechanisms

61. Pain begets pain (Pro-nociception pathways)

62. Dysfunctional Pain: unknown cause

63. 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: , 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: , 2005
Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron 55: , 2007
Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neuroscience 25: , 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

64. Pain vocabulary Hyperalgesia Allodynia Analgesia
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