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 PainPain and temperature sensed by free nerve endingsFiber diameter profle of peripheral nervesHeat and cold stimulate pain receptors (nociceptors)Temperature SenseNormal skin temperature: T = 30-32 CThermal 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) Specifc temperature-sensitive receptors code each rangeThermal ReceptorsCold Receptors (TRPM8)A- fbers (thinly myelinated)Stimulus: Cooling between T = 8 C and 40 C Most sensitive at T = 25 CSaturate at T < 8 C Warm Receptors (TRPV3)C fbers (unmyelinated)Stimulus: Warming between T = 35 C and 45 C Most sensitive at T = ~42 CSaturate at T > 45 C Cold fbers signal rapid skin coolingDynamic Response to TemperatureWarm Receptors Code T > 35 CWarm Receptors Saturate at High TThermo-TRPs respond to specifc temperature rangesTRP = Transient receptor potentialHeat Nociceptors and Burning PainA- fbers (NS) or C fbers (HPC)Express TRPV1 and/or TRPV2 receptorsFiring rate signals heat intensity at T > 45 CResponse outlasts heat stimulusSensitize to repeated heat stimuliNoxious Cold (T < 10 C)Cold Fibers (TRPM8)A- fbers (thinly myelinated)Saturate at T < 8 CPolymodal Nociceptors (HeatPinchCold)C fbers (unmyelinated)Firing rate signals degree of cooling at T < 25 CFire at highest rates at T < 0 CExpress TRPA1, TRPV1 and TRPM8 receptorsParadoxical Cold: Freezing temperatures are perceived as burning painHeat and cold stimulate specifc groups of receptorsWhat is Pain?Aversive sensationIntensity ranges from unpleasant to horribleVarious classes of painpricking, stabbing, pinching (mechanical )burning, freezing (thermal )aching, stinging, soreness (chemical )visceral (mechanical, chemical )Emotional component (pain tolerance)Protective functionWarn of injury that should be avoided or treatedFour classes of noxious (painful) sensationsHeat painCold painChemicalMechanicalMechanical NociceptorsReceptors specialized for painful mechanical stimuli (Nociceptive Specifc)A- fbers (thinly myelinated)Do not respond to light touch (high threshold)Excited by strong pressure, pinch or squeezingMediate pain from skeletal muscle or viscera due to excessive stretch or contractile forceMost respond to noxious heat (T > 45 C)Mechanical nociceptors respond to prick and pinchPolymodal nociceptorsC fbers (unmyelinated free nerve endings) Respond to heat, pinch and cold (HPC receptors)Express TRPV1, TRPA1 and other TRP receptorsRespond to irritant chemicalsCapsaicin (chili peppers): TRPV1 receptorsMustard oil, garlic, horseradish: TRPA1 receptorLow pH (acids)Endogenous peptides: Bradykinin, NGFEnvironmental irritants and pollutants Polymodal nociceptors express multiple receptorsNociceptors Respond to ChemicalsExogenous chemicals that penetrate skinAcids, alkalis, organic moleculesCapsaicin, Mustard oilIntracellular molecules released by cell injuryCations [K+, H+]Peptides, neurotransmittersProstaglandins, histamine Toxins [micro-organisms, insect bites, venom]Pathological substances released by diseased tissueTissue Damage Stimulates NociceptorsTRP receptors respond to pungent chemicalsGarlic, radishes, mustard oilMentholCamphor CapsaicinIrritant chemicals activate TRP receptorsInfammation sensitizes nociceptorsNoxious stimuli are spread by axon refexesHyperalgesiaTouch and pain fbers project to distinct spinal laminaePain Inputs to Spinal CordLamina I Cells Respond Only to Pain Mechanical and Heat (NS) Cold Polymodal (Heat, Pinch, Cold) Irritant Chemicals (Histamine, Capsaicin, Mustard Oil)Small Fiber Inputs to Spinal CordTouch and pain fbers project to distinct spinal laminaeReferred Pain: Wide Dynamic Range NeuronsTouch and Pain Ascend in Separate TractsVisceral pain transmitted in the dorsal columnsWillis WD, et al. PNAS 96: 7675-7679, 1999Central gray matterT10Pain Pathways to Thalamus and Cortex IIParallel Processing of Pain in CortexVPL/VPM > SI Cortex Pain localization to particular body siteVMpo > Dorsal Insular Cortex Pain sensation experienced (cold, heat, stab)MDvc > Anterior Cingulate Cortex Pain emotional reactionHypothalamus and Limbic Cortex Body physical response to painSubjective memory of painPain Centers in the BrainApkarian et al. Eur J Pain 9: 463-484, 2005How Can We Reduce Pain?Remove the painful stimulusFlexion refex (hard-wired circuit to avoid pain)Treat injury or pathologyAnalgesics and/or antihistaminesBlock impulse conduction in peripheral nerveLocal anesthetics, epidural anesthesiaBlock synaptic transmission in CNSGeneral anesthesiaNarcotic analgesics (e.g. morphine)Activate bodys own pain control systemGate Control of PainEmotions Modulate Pain Transmission(nucleus cuneiformis)(dorsolateral pontine tegmentum)(periaqueductal gray)Endogenous Pain InhibitionEndogenous Opioid Peptides Leucine-enkephalinTyr-Gly-Gly-Phe-Leu-OHMethionine-enkephalinTyr-Gly-Gly-Phe-Met-OH-endorphinTyr-Gly-Gly-Phe-[26 amino acids]-OHDynorphinTyr-Gly-Gly-Phe-[13 amino acids]-OHOpiates & Opioids Modulate PainPain Prevention Local anesthetics as supplements or alternatives to general anesthesiaIntrathecal morphine intraoperatively Postoperative pain reliefPhysical therapy to stimulate large fbersPsychotherapy to optimize use of descending pain control pathways and improve pain tolerancePain Perception Involves Multiple ProcessesNociceptive Pain: Somatosensory responseInfammatory pain: trauma or diseaseTwo Classes of PainNociceptive or Infammatory Pain (Acute)Sensation transmitted by free nerve endingsStimulus provided by noxious (harmful) mechanical, thermal or chemical inputProtective functionNeuropathic Pain (Chronic)Abnormal fring pattern in PNS or CNSCaused by lesion or trauma to nerve or CNSSensitization of central pathways due to excessive painful inputNeuropathic Pain Elicited by prolonged strong activation of nociceptorsResult of major injuryTraumaSevere burnsMajor surgeryLimb amputationPeripheral nerve injury or neuromaPostherpetic neuralgiaNeuropathic pain: Nerve injury or CNS lesionPeripheral SensitizationPeripheral nerve injuryInjured Schwann cells sensitize nociceptorsDRG neurons respond to cytokines and ATPCentral Sensitization and Neuropathic Pain Nociceptor synapses are glutaminergicStrong stimulation activates NMDA receptorsLTP-like process increases synaptic efcacy through protein synthesisSpinal synapses become more responsive to pain (hyperalgesia) and touch (allodynia)Glutamate receptor mechanismsSilent synapses and LTPCentral Sensitization MechanismsPain begets pain (Pro-nociception pathways)Dysfunctional Pain: unknown causeRecommended 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, 2009Craig AD. How do you feel? Intero-ception: the sense of the physiological condition of the body. Nature Reviews Neuroscience 3: 655-666, 2002Apkarian 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, 2005Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron 55: 377-391, 2007Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neuroscience 25: 319-325, 2002Costigan M, Scholz J, Woolf CJ. Neuropathic pain: A maladaptive response of the nervous system to damage. Annu Rev Neurosci 32: 1-32, 2009Pain vocabularyHyperalgesiaSensitization: enhanced sensation to noxious stimuli following injuryStimulus provided by noxious mechanical, thermal or chemical inputAllodyniaSensitization: abnormal response to touchCaused by lesion or trauma to nerve or CNSAnalgesiaPain relief and/or attenuation