What is pain?: An unpleasant sensation. What is an unpleasant sensation?: Pain. - Aristotle.

What is pain?: An unpleasant sensation. What is an unpleasant sensation?: Pain. - Aristotle.

Nociception The detection of tissue damage or impending tissue damage, but There can be tissue damage without pain. Pain Unpleasant sensory experience normally associated with tissue damage, but There can be pain without tissue damage (psychogenic, psycho-social, headaches, migranes)

Three Types of Pain 1. Physiological (related to tissue damage) 2. Inflammatory (immunological) 3. Neuropathic (+/- associated with 1 & 2) Two dimensions of pain Sensation Unpleasantness

How do you study pain, from an experimental perspective?

Common Experimental Procedures to Induce Pain 1. Mechanical (e.g. rat tail pinch) 2. Thermal (hot water immersion) 3. Inflammation (injection of formalin, capsacin, Freund s adjuvant) A) Acute induction B) Chronic induction Note: Pain in a clinical situation has to be reported. So clinical pain is associated with the ability to verbally communicate.

When pain is induced experimentally, or with natural experiments, there is not a standard perceptual response for a given stimulus. Rather there is a spectrum of pain awareness, independent of nociception per se. Allodynia Hyperalgesia Pain response to a normally non-painful stimulus Excessive response to a normally painful stimulus

Topics of Discussion

Is pain due to the activation of specific fibers or to the over-activity of sensory fibers normally associated with other sensory modalities? Common experience seems to favor overactivity of normal sensory fibers, but in most cases pain is due to the activation of dedicated nerve fibers.

Nociceptors have broad specificities, but may prefer particular modalities of force/pressure, temperature, chemicals. Under normal circumstances nociceptors have much higher thresholds than other sensory receptors for the equivalent modality. No morphological specializations associated with nociceptors. Receptors on dendritic arbors.

Afferent Nerve Fibers Associated with Nociception A-α (A-β: non-pain) Conduction velocity - 36-120m/sec A- pain impulses due to heat/mechanical pressure Large diameter, myelinated, conduction velocity 4-30m/sec Short duration, sharp, prickling, localized C pain impulses due to chemicals, heat or mechanical Small diameter, unmyelinated, conduction velocity -.5-2m/sec Delayed onset, diffuse, aching, throbbing

Afferent Nerve Fibers Associated with Nociception The A- and C fibers: utilize different sets of neurotransmitters have different pathways/ CNS terminations result in different types of pain reported group according to sensitivity and specificity High threshold (narrow dynamic range) or wide dynamic range Noxious stimuli only or polymodal (noxious + nonnoxious)

Physiological response differences between HT and WDR type nociceptors. Why high threshold is high threshold Note polymodal

Polymodal WDRs are common. -- Associated with C-type afferents and respond to at least two types of stimulation: Mechanical: mechanical-gated ion flow Thermal: Chemical: Vanilloid receptor (noxious heat activated ion channel) Acid sensing proteins (Drasic ASIC = acidsensing ion channel ; proton-gated), (+ ATP receptors (P2x3) )

Vanilloid receptors part of the TRP family VR-1 (= TRPV1) only responds to temperatures above 43 C (110 F) gated on by capsaicin VRL-1 (= TRPV2) only responds to temperatures above 53 C (127 F) Channels permeable to Ca 2+ and Mg 2+

Water Temperature Effects on Adult Skin Moritz and Henriques, Harvard Medical School in the 1940s) Temp ( F) Time to 1 st degree burn Time to 2 nd degree burn 111 270 minutes 300 minutes 113 120 minutes 180 minutes 116 20 minutes 45 minutes 118 15 minutes 20 minutes 120 8 minutes 10 minutes 124 2 minutes 4.2 minutes 131 17 seconds 30 seconds 140 3 seconds 5 seconds 151 instant 2 seconds VR-1 (= TRPV1) only responds to temperatures above 43 C (110 F) VRL-1 (=TRPV2) only responds to temperatures above 53 C (127 F) From -- http://www.hgexperts.com/article.asp?id=5135

Some DRG cells have large response to high temperatures Response due to presence of vanilloid receptor Responses measured in disassociated DRG cells so DRG intrinsic response.

DRG cell morphology. Cell body In the ganglion Multiple afferent axon branches synapse on 2 nd order cells in the spinal cord.

Pain pathways in the CNS

Pain Transmission Overview Acute Pain Noxious Stimulus travel Via A-Delta and C-delta Fibers to Dorsal Horn (spinal Cord) Limbic system & Cortex: perception, sensibility A-delta, C-delta Thalamus and Cortex: location and discrimination Doral Horn (via DRG) STT (Spinal thalamic Tract) transmission to Higher Brain Centers Descending motor control (avoidance, scratching, etc) plus opiate release Reticular Formation & Periaqueductal Gray (PAG) area: Motor, sensory and autonomic responses

Peripheral and central pain modulation circuits characterized by changeable set points in how much stimulus is needed to induce pain. local effects descending central effects

Example: Poor modulation of human infant pain perception. Due to incomplete pathway for establishing proper set-point. If gating (off) of pain pathways is incomplete allodynia.

Mechanico- Thermo- (-) (-) allodynia Stimuli that should not cause pain, but do. Incomplete gating off

Mechanico- Thermo- (- - -) (- - -) Reduced allodynia Stimuli that should not cause pain, but do. Opioid release Non-opioid release Oro-gustatory stimulation: suckling+sweet+fat taste Oro-tactile (suckling) + whole body tactile (hugging)

Fight/flight pain modulation Ascending pain signal Stress Neuron 4 releases enkephalin when active. Neuron 4 normally silent: inhibited by N3. N2 tonic activity, excites N3 inhibit N4. Nociceptive input N1 detects stress, releases opiates inhibit N2. N2 blocked N3 silent remove N4 inhibition. N4 active, release enkephalin block N5.

A more accurate diagram of the sketch from the previous slide.

Neurotransmitters/ receptors found in spinal cord and associated with pain transmission: Substance P Glutamate Calcitonin gene related peptide Somatostatin Neuropeptide Y GABA Serotonin Var. Opioid Dopamine Vasoactive intestinal peptide Met-enkephalin and at any one neuron or pathway, a number of neurotransmitters may be expressed

Two principle ascending pathways

What animals have nociceptors? What animals experience pain? There is evidence for nociception even in relatively simple animals, including invertebrates.

Alplysia californica- the marine snail Byrne et al. identified VC, LE cells Hiriudo medicinalis- the medicinal leech Nicholas and Baylor identified N cells... with similar properties as mammalian nociceptors: i.e. selective responsive to noxious stimuli.

Comparison of neural responses for a mammal and two invertebrates

Since it is such a powerful model for everything else, more than a small amount of effort has gone into searching for nociceptors in Caenorhabditis elegans (the nematode). Zang and Kahn Identified polymodal ASH neurons similar to mammalian polymodal nociceptors Determined that they were unambiguously nociceptive in function, and dependent on the TRPV channel family that is prominent in vertebrate nociception.

One popular non-mammalian vertebrate model for nociception is the rainbow trout (Oncorhynchus mykiss).

Sneddon et al. Likely nociceptors (A-delta, C fibers) are present in trigeminal nerve of the trout. But central reception of sensory input is unclear. Clinical signs of acute and chronic stress can be observed when exposed to noxious stimuli ( cortisol levels, changes in other health and behavior parameters). Avoidance of adverse stimuli (reflex manner). Substance P has been found in the CNS of fish; highest levels in the hypothalamus & forebrain (Kestin 1994)

Polymodal nociceptors: mechano-thermal receptors and mechano-chemical receptors.

Chronic and Abnormal Pain Not all chronic pain is abnormal. With repeated tissue damage expect a chronic pain condition. Chronic and Abnormal pain are usually associated with adaptive changes. receptive fields Sensitivity Various phenomena lead to these phenotypes.

Chronic Pain Rat Model: Continued injection of inflammatory substance. Six phenomena 1. A, B, and C fibers start expressing substance P in greater amounts allodynia 2. Sprouting of primary sensory axon branches Synapses onto dorsal horn neurons and also to caudal spinal cord neurons that ordinarily do not receive nociceptor input! allodynia and hyperalgesia Continued

Chronic Pain Rat Model cont d 3. Secondary Hyperalgesia primary nociceptors increase gain a) Skin Injury C-fibers become extra sensitive to temperature (but not pressure) b) Deep tissue injury C-fibers become extra sensitive to pressure (but not Temperature) Continued

4. Silent nociceptors become active. Probably high threshold receptors that are now low threshold or functionally WDR 5. Neurogenic inflammation: inject toxin in right foot (repeated) Swelling in right foot, but also swelling in left foot Efferent signal causes contralateral inflammation crank up immune system via increased vascular permeability. Pain perception without tissue injury

6. Inflammatory agent causes nerve damage itself (direct neuronal tissue damage) Sprouting of neural processes (de novo innervation) - larger receptive fields - increased sensitivity - innervation by wrong sensory afferent - innervation of wrong tissue

Mechanism of de-novo innervation

Sprouting of New Neuronal processes Nerve sprouting effect can appear in some terminal cancer patients. E.g., Pancreatic cancer -- the first sign is lower back pain due to poorly focused nociceptor receptive fields. If the patient is terminally ill the pain can be stopped by cutting Lissauer s tract.

Phantom Limb Pain Afferent dendrites re-grow after the limb is severed, but cannot make previous connections. Dendrites invade other Tissues Get spontaneous or irrelevant stimulation Brain interprets as coming from lost limb.

Phantom Limb Pain The amount of phantom pain is a function of the injury history: 1. With a quick amputation little phantom pain 2. Crush hand Partial recovery later have to amputate Much more phantom pain!

Sensitization With repeated pain signals the neurons become sensitized (this occurs with phantom limb pain). Surgical procedures now avoid sensitization. For example during and after knee surgery ice is used to block the pain afferent signal to the spinal cord. General anesthetic does not work since it only blocks pain processing in the CNS!

Sensitization

Reflex Sympathetic Dystrophy A neurological disorder with unknown cause! Real pain/injury Perceived pain/injury Regional change in circulation, increase temperature in damaged area to accelerate healing. Increased nociceptor activity Sweating to cool region C-type nociceptors can be NE - sensitive Activation of sympathetic afferents Sympathetic feedback to correct NE release

Selected References: Sneddon, L.U. 2002 Anatomical and electrophysiological analysis of the trigeminal nerve in the rainbow trout, Oncorhynchus mykiss. Neurosci. Lett. 319, 167-171. Belmonte and Cerero, Neurobiology of nociceptors, Oxford Press, 1996. Torebjörk, H.E. & Hallin, R.G. 1974 Identification of afferent C units in intact human skin nerves. Brain Res. 67, 387-403. Chal.e M, Sulston JE, White JG, Southgate E, Thomson JN, Brenner S. 1985. The neural circuit for touch sensitivity in Caenorhabditis elegans. J Neurosci 5:956 964.