What is this thing called PAIN?! Edvard Munch, The Scream 1910, Munch Museet, Oslo!
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1 What is this thing called PAIN?! Edvard Munch, The Scream 1910, Munch Museet, Oslo!
2 How do we describe pain?! Aversive sensation! Various classes of pain! pricking, stabbing, pinching (mechanical )! burning, freezing (thermal )! aching, stinging, soreness (chemical )! visceral (mechanical, chemical )! Intensity ranges from unpleasant to horrible! Emotional component (pain tolerance)! Protective function! Warn of injury that should be avoided or treated!
3 Painful stimuli activate specific nociceptors!
4 Pain and temperature sensed by free nerve endings!
5 Fiber diameter profile of peripheral nerves!
6 Four classes of noxious (painful) sensations! Heat pain! Chemical! Mechanical! Cold pain!
7 Mechanical nociceptors respond to prick and pinch!
8 Mechanical Nociceptors! Receptors specialized for painful mechanical stimuli (Nociceptive Specific)! A-δ 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)!
9 Temperature Sense! Normal skin temperature: T = 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!
10 Thermal Receptors! Cold Receptors (TRPM8)! A-δ 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!
11 Cold fibers signal rapid skin cooling!
12 Dynamic Response to Temperature!
13 Warm Receptors Code T > 35 C!
14 Warm receptors saturate at high temperatures!
15 Heat and cold stimulate pain receptors (nociceptors)!
16 Thermo-TRPs respond to specific temperature ranges! TRP = Transient receptor potential!
17 Heat Nociceptors and Burning Pain! A-δ fibers (NS)! Express TRPV1 and/or TRPV2 receptors! Firing rate signals heat intensity at T > 45 C! Response outlasts heat stimulus! Sensitize to repeated heat stimuli!
18 Nociceptors activate second messengers!
19 Polymodal nociceptors (CPNs)! 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 C-nociceptors (CPNs) respond to painful stimuli! Ma C, Donnelly CF, LaMotte RH J Neurosci Meth 2010!
21 C-nociceptors respond to pressure, heat and capsaicin!
22 Polymodal nociceptors express multiple receptors!
23 Noxious Cold (T < 10 C)! Cold Fibers (TRPM8)! A-δ 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!
24 Heat and cold stimulate specific groups of receptors!
25 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!
26 Tissue damage stimulates nociceptors!
27 Irritant chemicals activate TRP receptors!
28 Noxious stimuli are spread by axon reflexes!
29 Hyperalgesia!
30 Inflammation sensitizes nociceptors!
31 Pain inputs to the dorsal horn!
32 Lamina I cells respond to pain! Mechanical and Heat (NS)! Cold! Polymodal (Heat, Pinch, Cold)! Irritant Chemicals (Histamine, Capsaicin, Mustard Oil)
33 Touch and pain fibers project to distinct spinal laminae!
34 Lamina V neurons: Wide Dynamic Range!
35 Gate Control of Pain!
36 Spinothalamic tract fibers originate in laminae I and V!
37 Touch and pain ascend in separate tracts!
38 Multiple pain pathways to thalamus and cortex!
39 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!
40 Pain Centers in the Brain! Apkarian et al. Eur J Pain 9: , 2005!
41 Cold activates the insula!
42 Pain Perception Involves Multiple Processes!
43 Descending pathways modulate pain transmission!
44 Emotions modulate pain sensations! (nucleus cuneiformis)! (periaqueductal gray)! (dorsolateral pontine tegmentum)!
45 Endogenous pain inhibition!
46 Endogenous Opioid Peptides! Leucine-enkephalin! Tyr-Gly-Gly-Phe-Leu-OH! Methionine-enkephalin! Tyr-Gly-Gly-Phe-Met-OH! β-endorphin! Tyr-Gly-Gly-Phe-[26 amino acids]-oh! Dynorphin! Tyr-Gly-Gly-Phe-[13 amino acids]-oh!
47 Opiates & Opioids Modulate Pain!
48
49 Pain begets pain (Pro-nociception pathways)!
50 Nocebo and placebo pathways in the brain! Tracey I. Nature Medicine 2010!
51 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 bodyʼs own pain control system!
52 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!
53 Nociceptive Pain: Somatosensory response!
54 Inflammatory pain: trauma or disease!
55 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!
56 Neuropathic pain: Nerve injury or CNS lesion!
57 Peripheral nerve injury!
58 Injured Schwann cells sensitize nociceptors!
59 DRG neurons respond to cytokines and ATP!
60 Peripheral sensitization: Presynaptic fibers!
61 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)!
62 Glutamate receptor mechanisms!
63 Central sensitization (postsynaptic) mechanisms!
64 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!
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