Physiology 1.05 - Somatosensory-Pain

1.05

PHYSIOLOGY SOMATOSENSORY: PAIN PHYSIOLOGY Katherine Munarriz, M.D. PAIN PHYSIOLOGY PAIN RECEPTORS -Free Nerve Endings -widespread in superficial layer of the skin -also found in certain internal tissues (eg. Periosteum, arterial walls, joint surfaces, falx, tentorium) -most other deep tissues are only sparsely supplied with pain endings -nonadapting: excitation of pain fibers becomes progressively greater, especially so for slowingaching-nauseous pain -increase sensitivity: hyperalgesia STIMULUS FOR PAIN RECEPTORS 1. Mechanical --> inflammation, heat and radiation 2. Pain from Nerves --> Neuropathic—chronic pain -pain occurring in the absence of nociceptor stimulation -likely to occur after damage to peripheral nerves or to parts of the CNS that are involved in transmitting nociceptive info (peripheral and central neuropathic pain) eg. - Of pain secondary to damage to a peripheral nerve --> causalgia (severe burning pain) and phantom limb pain - hyperpathia is also charactestic of neuropathic pain - complains with the very lightest moving stimuli evoke exquisite pain (allodynia) 3. Thermal --> TRP (Transient Receptor Potential) —protein family that are currently the most likely candidates for being the transducers of thermal sensations 4. Chemical -some chemicals that excite chemical type of pain: bradykinin, serotonin, histamine, potassium ion, acids, acetylcholine and proteolytic enzymes -prostaglandins and substance P (aka. tachykininsan 11-aa peptide; potent vasodilator; degranulates mast cells; chemoattractant for leukocytes) enhance the sensitivity of pain endings but do not directly excite them -important in stimulating slow, suffering type of pain in tissue injury -bradykinin: more painful than other chemicals intensity of the pain felt correlates with the local increase in [K+] or increase in proteolytic enzymes directly attacking nerve endings

JULY 16, 2013

-CGRP (calcitonin gene related peptide)- increase substance P release and prolongs action by inhibiting enzyme degrading it RATE OF TISSUE DAMAGE AS STIMULUS NOCICEPTORS - non-adapting - pass through A-delta and C fibers - stimulus  Tissue damage → Nociceptive pain  Tissue inflammation, chemical damage → pain of inflammation  Nerve damage → Neuropathic pain -begins to perceive pain when skin is heated above 45°C --> tissues begin to be damaged -pain resulting from heat --> rate at which damage to tissues is occurring (not with the total damage that has already occurred) -intensity of pain --> rate of tissue damage (bacterial infection, tissue ischemia, tissue contusion) *Tissue Ischemia- greater the rate of metabolism of tissue blocked, more rapidly the pain appears -accumulation of large amounts of lactic acid in the tissues, formed as a consequence of anaerobic metabolism -bradykinin and proteolytic enzymes are formed in the tissues because of cell damage *Muscle Spasm- direct effect of muscle spasm in stimulating mechanoreceptors; indirect effect of muscle spasm to compress blood vessels and cause ischemia -increases the rate of metabolism in the muscle tissue PATHWAYS FOR TRANSMISSION OF PAIN SIGNALS SPINOTHALAMIC PATHWAY Nociceptors ↓ Pain fibers (A-delta, C fibers) ↓ Dorsal roots ascend/descend 1-2 segments in tract of Lissauer ↓ Release glutamate or substance P ↓ nd 2 order neuron from spinal cord to thalamus ↓

TRANSCRIBERS: Maja, Von, Catie, Kenan, Eli, Rissa, Trisha, Eunika

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SOMATOSENSORY: PAIN PHYSIOLOGY

PHYSIOLOGY rd

3 order neuron from thalamus to cortex TWO PATHWAYS - peripheral nerves to the spinal cord by fast and slow fibers - ―DOUBLE” pain sensation: a fast-sharp pain that is transmitted to the brain by the A followed by a slow pain that is transmitted by type C - slow pain tends to become greater over time - terminate on relay neurons in the dorsal horns 1. Fast or Pricking Pain Pathway - felt within about 0.1 second after a pain stimulus is applied - acute and mechanical pain - not felt in most deeper tissues of the body - can be localized much more exactly in the different parts of the body, however, w/o simultaneous stimulation of tactile receptors --> may be poorly localized - type Afibers at velocities b/w 6-30 m/sec - glutamate: NT believed to be secreted in the spinal cord; fast receptor activating AMPA (aminohydroxy-methyl-isoxazolepropionic acid) receptors - terminate in lamina I (marginalis) of dorsal horns 

Excite 2nd order neuron 

Long fibers cross immediately to opposite side of the cord—ANTERIOR COMMISURE 

ANTEROLATERAL PATHWAY 

Few fibers reticular areas or posterior nuclear group of thalamus other basal areas of brain (somatosensory cortex) *VPL with projections to:  somatic sensory cortex  cingulate gyrus

Most fibers thalamus w/o interruption VENTROBASAL COMPLEX (along with the dorsal column-medial lemniscal tract) 2. Burning Pain Pathway - begins only after 1 second or more and then increases slowly over many seconds and sometimes even minutes - usually associated with tissue destruction - can occur both in skin and in almost any deep tissue or organ - in general, elicited by all 3 types of stimulus - type C fibers at velocities b/w 0.5 and 2 m/sec

- secrete both glutamate and substance P (glutamate-instantaneously; substance P-slowly building up in concentration) - ―double‖ pain sensation - pain impulses entering the brain stem reticular formation, thalamus, and other lower brain centers --> conscious perception of pain - cortex plays an especially important role in interpreting pain quality - poor localization: keeping w/ the multisynaptic, diffuse connectivity of this pathway - electrical stimulation in reticular areas of brain stem and intralaminar nuclei of thalamus --> strong arousal effect on nervous activity throughout the entire brain (BRAIN’S PRINCIPAL ―AROUSAL SYSTEM‖) - terminates in RAS, midbrain tectum, PAQ and in thalamic intralaminar nuclei terminate in lamina II and III (substantia gelatinosa); addt’l short fiber neurons in lamina V  Excite 2nd order neuron  Long axons that mostly join fibers from the fast pain pathway—ANTERIOR COMMISURE  ANTEROLATERAL PATHWAY  1/10-1/4 fibers --> thalamus w/o interruption Most fibers  (1) reticular nuclei of medulla, pons, and mesencephalon; (2) tectal area of mesencephalon deep to superior and inferior colliculi; (3) periaqueductal gray region surrounding the Sylvius aqueduct  From brain stem, multiple short-fiber neurons intralaminar and ventrolateral nuclei of thalamus and certain portions of hypothalamus and other basal regions of brain TRIGEMINAL PATHWAY Nociceptors ↓ Pain fibers (A-delta, C fibers of CN V) ↓ Trigeminal ganglion ↓ Release glutamate or substance P ↓ nd 2 order neurons in pons (spinal nerve ↓ Thalamic VPM ↓ Sensory cortex, limbic lobe

TRANSCRIBERS: Maja, Von, Catie, Kenan, Eli, Rissa, Trisha, Eunika

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PHYSIOLOGY

SOMATOSENSORY: PAIN PHYSIOLOGY ↓ ↑ impulses thru 2° PF ↓ Central sensitization ↓ Chronic Pain

MECHANISMS OF PAIN Peripheral Pain 1. At the level of 1° pain fibers - tissue damage due to several mechanisms: thermal, chemical stress - pain producing substances (histamine, serotonin, bradykinin, proteolytic enzymes, lt, potassium) that affect pain receptors directly → Pain of inflammation of Nociceptive pain → Substance P (neurotransmitter of nociceptive) 2. Senzitization of Pain receptors - lowering of threshold for pain perception due to repeatedapplication of stimuli - HIST, 5HT, BK, PG → activate and sensitize other nociceptors → ↑↑ pain Repeated or sustained stimulus ↓ ↓ threshold of firing nociceptors ↓ ↑ impulses thru 1° pain fibers ↓ SP stimulation of mast cells, platelets, to release HIST, BK, PG, etc. ↓ Peripheral sensitization NEUROTRANSMITTERS THAT MODULATE PAIN (by first order neuron) 1. Glutamate - fast NT that binds to AMPA 2. Substance P - NM → NK → produces sustained increase in responses of ST neurons (chronic pain) 3. CGRP (Calcitonin gene-related protein) - ↑ SP release and prolongs action of SP by inhibiting its enzymatic degradation CENTRAL PAIN MECHANISMS - Ability of 2° neurons to transmit pain impulses 1. ↑ Synaptic efficiency between 1° and 2° fibers → ↑ pain transmission Repeated or prolonged impulses thru 1° pain fibers ↓ Prolonged SP release from 1° neurons (PF) → stimulation of 2° pain fibers ↓ ↓ threshold of firing of 2° pain fibers Ectopic discharges → ↑ Na channel opening

ACUTE PAIN - less transmission among 1°, 2°, and 3° PF - not enough to open NMDA CHRONIC PAIN 1. glutamate 2. substance P, CGRP → sustained activity of 2° order neuron → central sensitization *AMPA – sustained opening causes sustained depolarization by Na channels which will subsequently cause conformational change in NMDA → Ca influx [↑ conversion of IP3 → DAC (↑ PKC)] ↑ Ca2+ → ↑ PKC - gene alteration - phosphorylation of AMPA - ↑ NO synthesis = sustained depolarization = ↑ Glu release  will stimulate guanyl synthase to close K+ channels = ↓ K+ efflux = ↑ depolarization  ↑ release of substance P NEUROPATHIC PAIN 1. Lesions of peripheral or CNS pathways for pain fibers → ↓ pain sensation 2. Damage to Peripheral nerves (DM) or 1° afferents [HZ](-) nociceptor stimulation of 2° fibers → spontaneous abnormal excitability to chemical, thermal, mechanical stimuli → ↑ Na channel opening → ↑ transmission of pain 3. Abnormal sensation =dysesthesias or paresthesias (pins and needles, burning, tingling), hyperalgesia CAUSES OF SOMATIC PAIN - somatic pain: musculoskeletal pain 1. Mechanical 2. Ischemia 3. Chemical Noxious stimuli 4. Spasms of BV CAUSES OF VISCERAL PAIN 1. Ischemia - formation of acidic metabolic end products or tissue degenerative products 2. Chemical - damaging substances leak from the GIT into the peritoneal cavity 3. Spasm of hollow viscus - mechanical stimulation of pain nerve endings or diminished blood flow to the

TRANSCRIBERS: Maja, Von, Catie, Kenan, Eli, Rissa, Trisha, Eunika

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PHYSIOLOGY

SOMATOSENSORY: PAIN PHYSIOLOGY

muscle (cramps—periods of contraction of smooth muscle) 4. Overdistention of hollow viscus - extreme overfilling, overstretch; can collapse the blood vessels 5. Insensitive viscera- parenchyma of liver and alveoli of lungs (yet liver capsule, bile ducts, bronchi and parietal pleura are very sensitive to pain) REFERRED PAIN - pain felt that is considerably removed from tissues causing pain -cells in dorsal horn receive noxious sensations from nociceptors in viscera also receive input from nd afferents in skin → convergent impulses on ST 2 order neuron relay impulses from viscera perceives as if coming from skin PAIN SUPPRESSION (ANALGESIA) - consist of 3 major components: 1. PERIAQUEDUCTAL GRAY and PERIVENTRICULAR AREAS of mesencephalon and upper pons  2. RAPHE MAGNUS NUCLEUS, thin midline nucleus in lower pons and upper medulla, and NUCLEUS RETICULARIS PARAGIGANTOCELLULARIS, located laterally in the medulla  2nd order signals to dorsolateral columns of SC  3. PAIN INHIBITORY COMPLEX located in dorsal horns of SC - stimulation at still higher levels of brain that excite PAG can also suppress pain: 1. PERIVENTRICULAR NUCLEI in hypothalamus lying adjacent to 3rd ventricle 2. MEDIAL FOREBRAIN BUNDLE (lesser extent), also in hypothalamus ENDOGENOUS PAIN INHIBITING SYSTEM 1. Hypothalamic Responses Hypothalamus ↓ β-endorphins ↓ periaquedectal gray ↓ Raphe nuclei 2. Reticular formation responses Median raphe ↓ Release 5HT (and NE)

↓ Spinal interneurons release ENKEPHALINS ↓ Hyperpolarization of 2° order neurons by closing Ca2+ channels and ↓ glutamate release ↓ ↓ pain *Enkephalins - 1° neuron  Close Ca channels  ↓ glutamate - 2° neuron  Close K channels  hyperpolarization ENDOGENOUS OPIOIDS 1. Enkephalins - Met and Leu - ENK, found in substantia gelatinosa, amygdala, hypothalamus, thalamus 2. Endorphins - products of POMC OPIATE RECEPTORS 1. Mu (μ) 2. Delta (δ) 3. Kappa (κ) *μ and δ receptors activation → ↑Potassium nd Conductace (gK) (2 order) * κ receptor activation → inactivates Ca channels *morphine – received by opiate receptor CLINICAL ABNORMALITIES OF PAIN HYPERALGESIA -hypersensitivity to pain -possible causes: 1. Excessive sensitivity of the pain receptors --> PRIMARY HYPERALGESIA (eg. Sunburned skin— histamine or prostaglandins) 2. Facilitation of sensory transmission --> SECONDARY HYPERALGESIA (results from lesions in the spinal cord or the thalamus) PRIMARY SECONDARY Mechanical, thermal Mechanical On site Beyond the site Peripheral sensitization Central sensitization Inflammation/sunburned Neuropathic/chronic *SENSITIZATION (axon reflex) -intense, repeated or prolonged stimuli are applied to damage or inflamed tissues, the threshold for activation primary afferent nociceptors is lowered and frequency of firing is higher for all stimulus intensities

TRANSCRIBERS: Maja, Von, Catie, Kenan, Eli, Rissa, Trisha, Eunika

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PHYSIOLOGY

SOMATOSENSORY: PAIN PHYSIOLOGY

-contributes to tenderness, soreness and hyperalgesia *SILENT NOCICEPTORS- large proportion of A and C afferents innervating viscera are completely insensitive in normal noninjured, noninflammed tissue --> presence of inflammatory mediators --> these afferents become sensitive to mechanical stimuli DYSESTESIAS/PARESTHESIAS -abnormal sensation *ALLODYNIA- pain after touching; pain states in which the activation of mechanoreceptor causes pain THERMAL SENSATIONS

-from freezing cold cold cool indifferent warm hot burning hot -3 types of receptors: cold receptors, warmth receptors, and pain receptors -located immediately under the skin at discrete separated spots (cold and warmth receptors) -presumed to be free nerve endings: warmth signals type C nerve fibers; cold receptor type Abranching number of times, protrude into the bottom surface of basal epidermal cells

Signals travel in the TRACT OF LISSAUER  Terminate mainly in laminae I, II and III of dorsal horns  Enter long, ascending thermal fibers that cross to the opposite anterolateral sensory tract  Terminate in both (1) reticular areas of the brain stem and (2) Ventrobasal complex of the thalamus  Cerebral somatic sensory cortex from Ventrobasal GATE CONTROL THEORY OF MELZACK AND WALL 1967 The spinal cord contains a neurological ―gate‖ that either blocks pain signals or allows them to continue on to the brain. Unlike an actual gate, which opens and closes to allow things to pass through, the "gate" in the spinal cord operates by differentiating between the types of fibers carrying pain signals (ADelta and C). Pain signals traveling via small nerve fibers (A-Delta, Fast) are allowed to pass through, while signals sent by large nerve fibers (C, Slow) are blocked.

-at around 45°C, heat-pain fibers begin to be stimulated by heat and, paradoxically, some of the cold fibers begin to be stimulated again (because of damage to the cold endings caused by excessive heat) -thermal senses respond markedly to changes in temp -cold and warmth receptors are stimulated by changes in their metabolic rates --> temp alters the rate of intracellular chemical reactions more than 2fold for each 10°C change -thermal signals from entire area summate (spatial summation)

TRANSCRIBERS: Maja, Von, Catie, Kenan, Eli, Rissa, Trisha, Eunika

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