Scientific Basic of Pain RM Clemmons DVM Ph

Scientific Basic of Pain RM Clemmons, DVM, Ph. D, CVA. CVFT University of Florida

PAIN • Unpleasant sensory and emotional experience associated with actual or potential tissue damage • Functions: Stop Signal • Warning of a threat • Basis of learning • Forces a person to rest

Terminology • Noxious – harmful, injurious • Noxious stimuli – stimuli that activate nociceptors (pressure, cold/heat extremes, chemicals) • Hyperesthesia – abnormal acuteness of sensitivity to touch, pain, or other sensory stimuli • Nociceptor – nerve receptors • Paresthesia – abnormal • Pain Threshold – level of • Analgesic – a neurologic or that transmits pain impulses noxious stimulus required to alert an individual of a potential threat to tissue • Pain Tolerance – amount of pain a person is willing or able to tolerate sensation, such as burning, pricking, tingling pharmacologic state in which painful stimuli are no longer painful

Overview of Neural Integration Figure 15. 1

Neural pathways • Afferent pathways • Sensory information coming from the sensory receptors through peripheral nerves to the spinal cord and on to the brain • Efferent pathways • Motor commands coming from the brain and spinal cord, through peripheral nerves to effecter organs

Types of Nerves • Afferent (Ascending) – transmit impulses from the periphery to the brain • First Order neuron • Second Order neuron • Third Order neuron • Efferent (Descending) – transmit impulses from the brain to the periphery

Sensory receptor • Specialized cell or cell process that monitors specific conditions • Arriving information is a sensation • Awareness of a sensation is a perception

Senses • General senses • • Pain Temperature Physical distortion Chemical detection • Receptors for general senses scattered throughout the body • Special senses • Located in specific sense organs • Structurally complex

Sensory receptors • Each receptor cell monitors a specific receptive field • Transduction • A large enough stimulus changes the receptor potential, reaching generator potential

Figure 15. 2

Three types of nociceptor • Provide information on pain as related to extremes of temperature • Provide information on pain as related to extremes of mechanical damage • Provide information on pain as related to extremes of dissolved chemicals • Myelinated type A fibers carry fast pain • Slower type C fibers carry slow pain

Thermoceptors and mechaniceptors • Found in the dermis • Mechaniceptors • Sensitive to distortion of their membrane • Tactile receptors (six types) • Baroreceptors • Proprioceptors (three groups)

Skin Tactile Receptors Figure 15. 3 a-f

Sensory Receptors • Mechanoreceptors – touch, light or deep pressure • Meissner’s corpuscles (light touch), Pacinian corpuscles (deep pressure), Merkel’s corpuscles (deep pressure) • Thermoreceptors - heat, cold • Krause’s end bulbs ( temp & touch), Ruffini corpuscles (in the skin) – touch, tension, heat; (in joint capsules & ligaments – change of position) • Proprioceptors – change in length or tension • Muscle Spindles, Golgi Tendon Organs • Nociceptors – painful stimuli • mechanosensitive • chemosensitive

Nerve Endings • “A nerve ending is the termination of a nerve fiber in a peripheral structure. ” • Nerve endings may be sensory (receptor) or motor (effector). • Nerve endings may: • Respond to phasic activity - produce an impulse when the stimulus is or , but not during sustained stimulus; adapt to a constant stimulus (Meissner’s corpuscles & Pacinian corpuscles) • Respond to tonic receptors produce impulses as long as the stimulus is present. (muscle spindles, free n. endings, Krause’s end bulbs)

Nerve Endings • Merkel’s corpuscles/disks • • Sensitive to light touch & vibrations Rapid adapting Superficial location Pacinian corpuscles • • • Sensitive to deep pressure & vibrations Rapid adapting Deep subcutaneous tissue location Krause’s end bulbs – • • • Thermoreceptor Ruffini corpuscles/endings • • • Meissner’s corpuscles – • • Sensitive to touch & vibration Slow adapting Superficial location Most sensitive • Thermoreceptor Sensitive to touch & tension Slow adapting Free nerve endings • • Afferent Detects pain, touch, temperature, mechanical stimuli

Nociceptors • Sensitive to repeated or prolonged stimulation • Mechanosensitive – excited by stress & tissue damage • Chemosensitive – excited by the release of chemical mediators • Bradykinin, Histamine, Prostaglandins, Arachadonic Acid • Hyperalgesia • Primary Hyperalgesia – due to injury • Secondary Hyperalgesia – due to spreading of chemical mediators

First Order Neurons • Stimulated by sensory receptors • End in the dorsal horn of the spinal cord • Types • A-alpha – non-pain impulses • A-beta – non-pain impulses • Large, myelinated • Low threshold mechanoreceptor; respond to light touch & lowintensity mechanical info • A-delta – pain impulses due to mechanical pressure • Large diameter, thinly myelinated • Short duration, sharp, fast, bright, localized sensation (prickling, stinging, burning) • C – pain impulses due to chemicals or mechanical • Small diameter, unmyelinated • Delayed onset, diffuse nagging sensation (aching, throbbing)

Second Order Neurons • Receive impulses from the FON in the dorsal horn • Lamina II, Substantia Gelatinosa (SG) - determines the input sent to T cells from peripheral nerve • T Cells (transmission cells): transmission cell that connects sensory n. to CNS; neurons that organize stimulus input & transmit stimulus to the brain • Travel along the spinothalmic tract • Pass through Reticular Formation • Types • Wide range specific • Receive impulses from A-beta, A-delta, & C • Nociceptive specific • Receive impulses from A-delta & C • Ends in thalamus

Third Order Neurons • Begins in thalamus • Ends in specific brain centers (cerebral cortex) • Perceive location, quality, intensity • Allows to feel pain, integrate past experiences & emotions and determine reaction to stimulus

Descending Neurons • Descending Pain Modulation (Descending Pain Control Mechanism) • Transmit impulses from the brain (corticospinal tract in the cortex) to the spinal cord (lamina) • Periaquaductal Gray Area (PGA) – release enkephalins • Nucleus Raphe Magnus (NRM) – release serotonin • The release of these neurotransmitters inhibit ascending neurons • Stimulation of the PGA in the midbrain & NRM in the pons & medulla causes analgesia. • Endogenous opioid peptides - endorphins & enkephalins

Neurotransmitters • Chemical substances that allow nerve impulses to move from one neuron to another • Found in synapses • Substance P • thought to be responsible for the transmission of pain-producing impulses • Acetylcholine • responsible for transmitting motor nerve impulses • Enkephalins • reduces pain perception by bonding to pain receptor sites • Norepinephrine • causes vasoconstriction • 2 types of chemical neurotransmitters that mediate pain • Endorphins • morphine-like neurohormone; thought to pain threshold by binding to receptor sites • Serotonin • substance that causes local vasodilation & permeability of capillaries • Both are generated by noxious stimuli, which activate the inhibition of pain transmission • Can be either excitatory or inhibitory

Somatic Sensory Pathways • Three major pathways carry sensory information • Posterior (Dorsal) column pathway • Anterolateral pathway • Spinocerebellar pathway

Ascending Tracts in the Spinal Cord Figure 15. 6

Posterior column pathway • Carries fine touch, pressure and proprioceptive sensations • Axons ascend within the fasciculus gracilis and fasciculus cuneatus • Relay information to the thalamus via the medial lemniscus

Dorsal Columns & Spinothalamic Tracts Figure 15. 8 a, b

Spinothalamic pathway • Carries poorly localized sensations of touch, pressure, pain, and temperature • Axons decussate in the spinal cord and ascend within the anterior and lateral spinothalamic tracts • Headed toward the ventral nuclei of the thalamus

Role of Thalamus • Second order neurons transmit pain and temperature signals to thalamus contralateral to stimulated receptor • VPM processes pain and temperature signals from trigeminal (CNV) analog of spinothalamic system for head and neck • VPL processes pain and temperature signals from peripheral regions of the body such as viscera, trunk and limbs • Medial (intralaminar) thalamic nuclei process pain and temperature signals from reticular formation (spinoreticular fibers) such as raphe nuclei and locus coruleus • Central (thalamic) pain signals cannot be localized (e. g. , metastatic cancer) and central (thalamic) pain syndrome is relieved by producing electrical lesions in a thalamotomy procedure

Role of Cerebral Cortex • Pain and temperature signals transmitted from VPL and VPM (specific thalamic nuclei) to somatosensory cortices SI and SII for localization • Pain and temperature signals transmitted from medial intralaminar (nonspecific) nuclei to all regions of cerebral cortex for “alerting” response, which induce wakefulness and inhibit sleep • Pain and temperature signals also transmitted from intralaminar nonspecific nuclei to limbic system, hypothalamus and associated structures for emotional, endocrine, stress and autonomic responses which produce fear, suffering, cardiovascular, respiratory, gastrointestinal, urogenital and stress-related hormonal responses

Where Does Pain Come From? • Cutaneous Pain • sharp, bright, burning; can have a fast or slow onset • Deep Somatic Pain • stems from tendons, muscles, joints, periosteum, & b. vessels • Visceral Pain • originates from internal organs; diffused @ 1 st & later may be localized (i. e. appendicitis) • Psychogenic Pain • individual feels pain but cause is emotional rather than physical

Types of Pain: Classification by Duration Acute vs chronic 1 Acute pain Chronic pain • An unpleasant experience with emotional, cognitive, and sensory features, resulting from tissue trauma • • Usually associated with significant, observable tissue pathology • • Resolves with healing of causative injury • Protective biological function to protect against further injury; protective reflexes include withdrawal, muscle spasm, and autonomic reactions • Pain lasting beyond expected recovery period and identifiable pathology insufficient to explain the pain state Disrupts sleep and normal activities of living Does not serve a protective, adaptive function

Types of Pain: Classification by Etiology Nociceptive vs neuropathic 1 Nociceptive pain Neuropathic pain • Results from normal function of the nervous system • • Caused when a noxious stimulus (eg, trauma, inflammation, infection) activates A-delta and C nociceptors • — Visceral pain: originates in internal organs — Somatic pain: originates in skin, muscle, skeletal structures • Abnormal nociceptive signaling caused by an impairment of the nervous system Serves no functional or adaptive purpose Causes and examples — Metabolic: diabetic neuropathy — Infectious: herpes zoster — Trauma: nerve entrapment

The Neurophysiology of Pain • Nociception: process by which information about tissue damage reaches the central nervous system • Transduction • Transmission • Perception • Modulation

Pain Transduction • Nociceptor = pain receptor: specialized receptor for detecting tissue injury/damage • Two classes of nociceptive afferent fibers A-delta axon C axon A-delta C Caliber Small diameter, thinly myelinated Small diameter, unmyelinated Stimuli Thermal & high-threshold mechanical Polymodal: high-intensity mechanical, chemical, heat, cold 5 -30 0. 5 -2 Short, sharp, prickling pain More prolonged sensation of dull pain Type Conduction velocity (meters/sec) Effect of activation

Pain Transduction • Nociceptors do not spontaneously depolarize: they send impulses (action potentials) only when stimulated • No specialized pain “receptors” • The receptor region of the nociceptor is the free terminal of the axon • Ion channels in nerve terminal open in response to noxious stimuli, initiating an action potential, the “pain signal” • Peripheral sensitization: local tissue injury with release of inflammatory mediators can enhance nociceptor response

Small Diameter Afferent Fibers • Cutaneous mechanoreceptors • Respond to nondiscriminative tactile stimuli • Pinch, rub, stretch, squeeze • A-delta and C fiber, high-threshold • Cutaneous thermoreceptors • Respond to transient change in temperature • Innocuous ward and cool stimuli

Small Diameter Afferent Fibers • Cutaneous nociceptors – cutaneous pain • A-delta mechanoreceptors • Mechanical tissue damage • C-polymodal nociceptors • Mechanical tissue damage, noxious thermal stimuli, endogenous algesic chemicals • C-fiber mechanonociceptors • A-delta heat thermonociceptors • A-delta, C-fiber cold thermonociceptors • C-fiber chemonociceptors – algesic chemicals

Pain Transmission • Nociceptors (primary sensory afferents) have cell body in dorsal root ganglia; synapse to second-order neurons in dorsal horn of spinal cord • Pain impulses can trigger a withdrawal reflex via connections to motor neurons in the spinal cord • Impulses ascend to brain via various ascending tracts

CNS Neurotransmitters of A-delta and C-fibers • Substance P (Neuropeptide) • Calcitonin Gene Related Peptide (CGRP) • Excitatory amino acids – e. g. , glutamate • Release in ischemia/hypoxia - neurotoxicity

Pain Perception • Perception of and reaction to pain are influenced by social and environmental cues, as well as by cultural norms and personal experience • Both cortical and limbic systems are involved in conscious awareness (perception) of pain • Recognition of location, intensity, and quality of pain is mediated by processing of signals from the spinothalamic tract > thalamus > somatosensory cortex • Pain information processing in the brainstem, midbrain, and limbic system appear to mediate affective, motivational, and behavioral responses to painful stimuli

Pain Modulation • Gate control theory advanced by Melzack and Wall in 1965 focused on descending pathways from the brain to the spinal cord that inhibit pain signaling • • Current view: signals originating in the brain can both inhibit and facilitate pain signal transmission • Neurotransmitters involved in these pathways include • Endogenous opiates (enkephalins, dynorphins, betaendorphins) • Serotonin • Norepinephrine

Pain Control Theories • Gate Control Theory • Central Biasing Theory • Endogenous Opiates Theory

Gate Control Theory • Melzack & Wall, 1965 • Substantia Gelatinosa (SG) in dorsal horn of spinal cord acts as a ‘gate’ – only allows one type of impulses to connect with the SON • Transmission Cell (T-cell) – distal end of the SON • If A-beta neurons are stimulated – SG is activated which closes the gate to A-delta & C neurons • If A-delta & C neurons are stimulated – SG is blocked which closes the gate to A-beta neurons

Gate Control Theory • Gate - located in the dorsal horn of the spinal cord • Smaller, slower n. carry pain impulses • Larger, faster n. fibers carry other sensations • Impulses from faster fibers arriving @ gate 1 st inhibit pain impulses (acupuncture/pressure, cold, heat, chem. skin irritation). Brain Gate (T cells/ SG) Pain Heat, Cold, Mechanical

Central Biasing Theory • Descending neurons are activated by: stimulation of A-delta & C neurons, cognitive processes, anxiety, depression, previous experiences, expectations • Cause release of enkephalins (PAG) and serotonin (NRM) • Enkephalin interneuron in area of the SG blocks A-delta & C neurons

Endogenous Opiates Theory • Least understood of all theories • Stimulation of A-delta & C fibers causes release of Bendorphins from the PAG & NRM Or • ACTH/B-lipotropin is released from the anterior pituitary in response to pain – broken down into Bendorphins and corticosteroids • Mechanism of action – similar to enkephalins to block ascending nerve impulses • Examples: TENS (low freq. & long pulse duration)

Goals in Managing Pain • Reduce pain! • Control acute pain! • Protect the patient from further injury while encouraging progressive exercise

Other ways to control pain • Encourage central biasing – motivation, relaxation, positive thinking • Minimize tissue damage • Maintain communication • If possible, allow exercise • Medications

Opportunities for Pain Control Systemic AP effects Local AP effects Segmental Local & AP effects Segmental AP effects

Romance • 10 month old Golden Retriever • 2 weeks history of lip twitches & abnormal behavior • Mild CP deficit in R rear leg S

Romance • Localization of Lesion Cerebral (Forebrain) O • • • D A M N N I I I T T V Genetic Liver Disease Brain Tumor Encephalitis GME Epilepsy

Romance • Problem List 1. Facial Twiches • Differential Dx • ? 2. Ataxia 3. Behavioral Change 1. 2. 3. 4. 5. Inf/Inflam Neoplasia Inborn Error Liver Epilepsy • Diagnostic Approach • ? • Treatment P • ?

Romance- -Diagnostic Approach • MDB • • CBC Chemistry Profile UA Chest & Abdominal Radiographs Abdominal Ultrasound Bile Acids Cholinesterase Ammonia level • Neurologic Tests • EEG • CSF Analysis • Cisternal • Titers • MRI P • Client Education

Romance- -CBC O

Romance- -Chemistry O

Romance- -UA O

Romance- -MRI L O L

Romance- -CSF Analysis • SPECIMEN: CSF – AO • • Color/Transparency: Protein mg/d. L RBC/μL WBC/μL • A 32 cell differential count yielded the following: • • • colorless/clear 16 46 14 13 Neutrophils 5 Lymphocytes 14 Mononuclear phagocytes • Two cytospin preparations are stained and microscopically examined. The slides are of adequate staining and preservation of cellular detail with scant hemodilution present against a colorless background that contains occasional squamous epithelial contaminants. Approximately equal numbers of mature, nondegenerate neutrophils and variably reactive mononuclear phagocytes are the predominant cell types. Small, well-differentiated lymphocytes are infrequently identified. • No infectious agents or neoplastic cells are identified. • Interpretation: Mild, mixed pleocytosis. O

Romance- -Titers (Serum) • 3 DX - Negative for Dirofilaria immitis antigen, Borrelia burgdorferi and Ehrlichia canis antibody. • RMS - Negative for Rickettsia rickettsii Ig. G AB by IFA: Titer <64 • BLM - Negative for Blastomyces by AGID. • DIS - CDV Ig. G AB: 50 Ig. M AB: Negative • CRC - Negative for Cryptococcus antigen by latex agglutination test • TO 1 – Toxoplasma O • Ig. G AB: Negative Ig. M AB: Negative NEO - Negative for Neospora caninurn Ig. G AB by IFA: Titer <50

Romance- -Final Diagnosis Seizures Secondary to GME A

Romance- -Client Education • The prognosis is guarded to poor • May continue to progress over 3 -6 months • Treat • phenobarbital • anti-inflammatory and anti-cancer drugs P • Consider CAVM & TCVM approaches to augment or instead of Western therapy

Romance- -TCVM exam • Tongue • TCVM Diagnosis • Red/purple • Pulse • Superficial • Slippery • Fast • Sensitivity • BL 15 • Nao Shu • Damp Heat with Internal Wind

Romance- -TCVM Therapy • AP • Herbal • Cranial points • • • GV 20 GV 21 An Shen Meng Men (staple) GB 20 • Cancer points • • • LI 4 PC 6 GV 14 SP 9 ST 40 LIV 3 • Mind Damp Heat Formula • Jing Tang • Di Tang • Jing Tang

Mansion of Mind Damp-Heat Encephalitis, SRME, GME Lonicera Jin Yin Hua Forsynthia Lian Qiao Isatidis Ban Lan Gen Astragalus Huang Qi Akebia Mu Tong Platycodon Jie Geng Licorice Gan Cao Clear heat, Expel wind Clear heat, Detoxify Clear heat, Cool blood Move Qi (stimulate immune system) Drain Damp-Heat Transporter Harmonizer 20 gm 10 gm 15 gm 10 gm

Cody • History of brainstem tumor • leading to secondary hydrocephalus • ~2. 5 cm mass • Probable meningioma • TCVM Dx • Blood Stagnation

Cody (13 months) • Western Rx • Phenobarbital • Prednisone • TCVM • Stasis in Mansion of Mind formula • Di Tang • Max formula

Electro-acupuncture techniques History • After electro-acupuncture (EA) analgesia was found effectively to perform a surgery in China in the early 1970's, EA has been widely used in TCM practice.

Advantage: • • More effective Less treatments Less acupoints Save labor to manipulate the needles (Classically, the needles should be manipulated every 2 to 3 minutes). • Objective control of frequency and amplitude • Amplitude (intensity of stimulation): a tolerance level • Frequency: • Low level: pain ----> beta endorphin mediated • High level: internal medicine� > serotonin mediated

Methods: Acupuncture Points: 6 to 10 points Frequency: 20 Hz Or 80 to 120 Hz Electrical intensity: gradually goes to the points the patient can tolerate. Indications: • Pain management • Bi syndromes (arthritis) • Soft tissue injuries • Disc problems • Colic/abdominal pain • Peripheral nerve paralysis • Facial • Radial • Others • Gastrointestinal conditions: vomiting, diarrhea, constipation, indigestion • Muscle atrophy •

Contraindications: • • 1) Weak/deficient patients 2) Heart problems 3) Seizure/epilepsy 4) Tumor

How to Use EA 1. Dial the AMPLITUDE and FREQUENCY to zero; 2. Plug the wire leads into sockets 1 to 7 and fasten the clips to the handles of needles; 3. Set the desirable frequencies and wave forms Frequency: • Low frequency (F 1 = 20 -30 Hz) • Indication: pain conditions---Endorphin & Enkephalin release • Moderate frequency (F 1=80 to 120 Hz) • Indications: internal medical conditions (diarrhea etc)- -Dynorphin release • High frequency (F 1=200 Hz) • Indication: pain conditions- -Serotonin release Dynorphins

How to Use EA Wave Form: depends on how F 1 and F 2 is set up • Continuing Wave: F 1=20 -200; F 2=0 • Indications: pain conditions • Intermittent wave: F 1=0; F 2=40 • Indications: muscular atrophy • Dense and Disperse (DD) wave: F 1=80; F 2 =120 • Indications: nerve paralysis and internal medical conditions

How to Use EA 4. Turn on the power 3 5. Gradually increase AMPLITUDE buttons until the patient can tolerate. a) Can increase amplitude a little bit every 5 minutes. 6. The duration of a treatment session: 10 to 30 minutes. 4. Turn off power to terminate the acupuncture treatment.

EA: how to pair the points The general rules: The same lead to pair 2 points • 1) Bilateral connection • • • a. Pair BL-54 on left side to right BL 54 for hip dysplasia; b. Hua-tuo-jia-ji on the left to right side for disk diseases c. BL-21 on the left to right BL-21 for vomiting d. KID-1 on the left to right KID-1 for rear weakness e. Left Ding-chuan + right Ding-chuan for cough • 2) Same Channel connection. • a. GV-14 + Bai-hui for disk disease • b. LI-10 + LI-15 on the same side for shoulder pain • c. Tip of tail + GV-20 for vestibular dx, disk disease • 3) Local connection • a. TH-14 + LI-15 on the same side for shoulder pain • b. GB-34 + ST-35 on the same side for stifle pain • 4) Same energetic connection • ST-36 + GB-34 on the same side for vomiting, rear weakness • ST-36 + BL-20 on the same side for SP Qi deficiency

EA: how to pair the points • 5) From the top to bottoms for paralysis • a. BL-54 + KID-1 for rear limb paralysis • b. PC-8 + GV-14 for front limb paralysis • c. GB-21 + HT-3 for front limb paralysis • 6) Cover large areas • a. BL-20 on the left + right BL 28 for T-L-S IVDD • 7) Normal area to sick area • a. BL-21 to KID-1 for no deep pain caudal to BL-22 • b. ST-5 left to right for right facial paralysis

EA: how to pair the points • But, we must pay attention to the following: • 1) The wire (lead) should NOT be connected around the abdominal areas for pregnant moms. • 2) The wire (lead) should NOT be connected through the chest if the patient has a pacemaker. • 3) The wire (lead) should NOT be connected through the tumor mass. • 4) Caution for seizure dogs when using EA

GOD cures, Doctors send the bill! -Mark Twain