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Boards: Pain > Pain Physiology > Flashcards

Pain Physiology Flashcards

1
Q

Noxious Stimulus

A

stimulus that actually is or is potentially damaging to tissue, one of intensity/quality to stimulate nociceptors

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2
Q

Nociception

A

neural process of encoding noxious stimuli
o Involves nociceptor stimulation, pain not implied
o Consequences may be anatomic or behavioral
o Ex: withdrawal reflex, increase in ABP with surgical stimulation

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3
Q

Pain

A

Unpleasant sensory, emotional experience assoc with or resembling that assoc with actual or potential tissue damage
o Nociceptor stimulation not required
o Requires conscious

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4
Q

Features of Pain Experience

A

o Experience defies precise anatomic, physiologic, pharmacologic definition
o Can be experienced in absence of obvious external noxious stimulus
o Modified by behavioral experiences
o Often consequence of nociceptive activity but not always
o Inability to communicate in no way negates possibility that individual is experiencing pain +/- in need of appropriate pain-relieving tx

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5
Q

Acute Pain

A

largely occurs IRT tissue damage, nociceptive/physiologic pain
o Usually assoc with tissue damage or threat of tissue damage
o Protective role: healing, tissue repair

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6
Q

Features of Acute Pain

A

Alters behavior to avoid/minimize damage, optimize healing conditions
o Localized, transient – ex healing post op from surgery
o Stimulus activates high-threshold sensory nerve fibers

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7
Q

Chronic Pain

A

pathologic pain, >3mo (LJ)
o Persists beyond expected course of healing – usually assoc with chronic inflammation, degenerative dz, following nerve injury/damage
o Little to no protective value, no biological valve

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8
Q

Consequences of Chronic Pain

A

o Typically intense, unrelenting
o Induces biochemical, phenotypical changes in nervous system (peripheral, central sensitization) that escalate, alter sensory inputs
 Results in physiologic, metabolic, immunologic alterations – threatens homeostasis
 Contributes to illness/death
o Difficult to treat, significant impact on QOL

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9
Q

Breakthrough Pain

A

o Acute exacerbations of chronic state

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10
Q

Acute on Chronic Pain

A

o Independent arrival of new pain states

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11
Q

Pownall et al 2021 (Vet Surg)

A

40% of dogs had a Helsinki Chronic Pain Index >12, consistent with chronic post surgical pain regardless of preemptive analgesia

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12
Q

Voscopoulos, Lema

A

transition from acute to chronic pain occurs in discrete steps, initiated by presence of persistent and intense stimuli

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13
Q

What is true about populations vulnerable to developing chronic pain conditions?

A

 Previous pain: predict future pain development
 Study in neonatal pigs: in utero stress  immediate behavioral responses to piglets at tail docking

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14
Q

Inflammatory Pain

A

o Normally contributes to acute postoperative pain
o Rapid onset
o Intensity, duration related to severity, duration of tissue damage
 Typically reversible
 Can persist if noxious insult was severe or focus of irritation ongoing

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15
Q

MOA Inflammatory Pain

A

Increases in substance P, calcitonin gene related peptide (CGRP), protein kinase (Cy), and substance P receptor reported in spinal cord

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16
Q

Neuropathic Pain

A

o Pain that develops following injury to peripheral nerves or CNS
o Causes many changes in spinal cord, brainstem and brain as damaged nerves fire spontaneously
 Develop hyper-responsiveness to both inflammatory, normally innocuous stimuli
 Ex: phantom limb pain

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17
Q

MOA Neuropathic Pain

A

Significant decreases in substance P, CGRP; increases in galanin, neuropeptide Y in primary afferent neurons, spinal cord

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18
Q

Cancer Pain

A

o Often displays inflammatory + neuropathic pain
o No detectable changes in markers that are changed in neuropathic/inflammatory pain

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19
Q

Adaptive Pain

A

o Biological function
o Nociceptive/inflammatory pain
 Pain from actual or threatened damage to non-neural tissue
 MOA: activation of nociceptors
o Same as physiologic pain?

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20
Q

Maladaptive Pain

A

o No biological function
o Neuropathic vs functional
 Neuropathic: caused by lesion or decrease of somatosensory NS
 Functional: physically normal NS

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21
Q

Four Physiological Processes of Pain

A
  1. Transduction
  2. Transmission
  3. Modulation
  4. Projection/Perception
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22
Q

Mediators of Transduction

A

 Sensory nerve endings, nociceptors
 Nociceptors encode intensity, duration, location, quality of stimulus

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23
Q

Generator Potential

A

membrane depolarization resulting from transduction event
* RMP: -50 to -75mV
* AP threshold: -35mV
* Passively propagated to AP initiation site with high concentrations of NaV channels
* Degree to which nociceptive stimulus propagated depends on balance btw excitatory, inhibitory signals

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24
Q

Transduction

A

 Activation of high-threshold transducers located in distal terminalis of afferent sensory nerve fibers by noxious stimulus – thermal, mechanical, chemical, or electrical

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25
Q

Transmission

A

Depolarizing electrical potentials (APs) transmitted along axons of primary afferent nerve fibers to synaptic sites in DH of SC

All afferents enter SC via dorsal roots of spinal nerves, separate to innervate second order neurons in different laminae of grey matter in SC DH

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26
Q

Synpatic Sites assoc with A delta fibers

A

Laminar I, II, V

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27
Q

Synpatic sites assoc with C fibers

A

laminae I, II (substania gelatinosa) or trigeminal ganglion

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28
Q

Synaptic sites assoc with A-beta fibers

A

Laminae II-V

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29
Q

WDR Neurons

A
  • Wide dynamic range (WDR) neurons: laminae V, respond to A-delta, A-beta, C fibers
    o Convergence of somatic, visceral input leads to referred pain
    o Gate Control Theory
    o Alternatively, referred pain DT branching of nociceptors in tissues
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30
Q

Modulation

A

 Centrally (spinal cord) or peripherally
* Peripheral via GPCRs (Gi/o): opioid, cannabinoid 1 and 2, a2A, somatostatin (SSTR), muscarinic (M2), GABAB, metabotropic glutamate R
o Different glutamate R than iontropic in DH
 Somatic sensory information relayed to SC for modulation before projected to brain for perception

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31
Q

MOA Modulation

A

 A-delta, C fiber inputs to DH release glutamate – binds to VG Na, Ca channels
* AMPA R
* Kainite R
* NMDA R
 Excitatory activity also modulated via variety of pre/post synaptic opioid (MOR, DOR, KOP), noradrenergic (a1, a2), muscarinic R in SC, brain

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32
Q

Role of NMDA R in Modulation

A

o For opening, Mg channel plug must be removed by intense mechanical/thermal stimulation
o Opening increases quantity of glutamate, substance P release from afferent sensory nerve terminals
o Activation of post-synaptic NK-1, metabotropic glutamate R – prolongs intracellular Ca release, postsynaptic membrane depolarization
o Leads to pain lasting long after stimulus removed, depending on magnitude of stimulus intensity

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33
Q

Projection, Perception

A

 Somatic sensory information projected to reticular formation of brain stem, surrounding nuclei via multiple parallel circuits/ascending pathways
* Converge in thalamus

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34
Q

Tracts responsible for projection?

A
  1. Spinothalamic
  2. Spinoreticular
  3. Spinomesencephalic
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35
Q

Role of spinothalmaic tract?

A

superficial pain, touch sensation
o Originates from lamina I, V
o Projects to thalamus, reticular formation

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36
Q

Role of spinoreticular tract

A

deep pain, visceral sensation

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37
Q

Role of spinomesencephalic tract

A

temperature sensation, pain
o Projects to midbrain: PAG, hypothalamus, limbic system

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38
Q

Role of post-synaptic dorsal column tracts

A

mediates pain transmission, projection

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39
Q

Trigeminal System

A

pain, touch sensation from head

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40
Q

Thalamus

A

integrates, relays info to somatosensory cortex –> projects to adjacent cortical assoc areas (limbic system) to evoke response, pain
* Cerebral cortex = seat of conscious experience of pain, top down control, modulates sensation of pain

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41
Q

Reticular Activating System (RAS)

A

brainstem
* Key role in integration of information
* Subjective responses to pain (projections to thalamus, limbic system)
* Autonomic, motor, endocrine responses

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42
Q

Supraspinal descending modulation controlled by:

A
  1. Periaqueductal grey (PAG)
  2. Medulla, pons of BS: rostroventral medulla
  3. Thalamocortical structures

Role: Release endorphins, enkephalins, dynorphins, serotonin, NE – regulate nociception at DH

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43
Q

How are nociceptor fibers classified?

A

Erlanger-Gasser System

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44
Q

Nociceptors

A

nonencapsulated (free) endings of specialized primary afferent neurons
o Parent neurons: nociceptive neurons, pseudounipolar structure
o Receptive fields: few mm2 to cm2, wide distribution
o Composed of glial cells (nourish, support), nerve cells (sense, conduct sensory info)
o Cell bodies: DRG for nerves in body, trigeminal ganglia for nerves in head
o Relatively high stimulus threshold

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45
Q

C Fibers

A

Non-myelinated
<2microns
0.5-2.0m/s - fastest
‘Slow Pain’
Burning Pain
Guarding
Diffuse
No background discharge
Broadly polymodal: respond to different stimuli modalities

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46
Q

What are the stimulation threshold for C fibers?

A

: higher than other sensory fibers (Thermal: >45*C)

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47
Q

Where do C fibers synapse?

A

Synapse: lamina II (substansia gelatinosa)

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48
Q

Are all C fibers nociceptive?

A

Not all C fibers are nociceptors (cooling, petting)

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49
Q

A-delta fibers

A

Lightly myelinated
2-5 microns
5-25m/sec
Transmit both non noxious and noxious info
Non noxious stimuli via myelinated
Conduct impulses more quickly
Rabid stab pain of acute pain response
Withdrawal, localizable

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50
Q

Where in the SC do A-delta synapse?

A

Synapse in lamina I, V of spinal cord

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51
Q

Type I A-delta fibers

A

polymodal, mechanically sensitive afferents (MSAs), also activated via chemical stimulation

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52
Q

Type II A-delta fibers

A

mechanical insensitive afferents, MIAs (silent nociceptors), heat activated

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53
Q

Silent Nociceptors

A

 Subset of C fibers (Zimmerman), type II A fibers (Boesch)
 Heat responsive but mechanically insensitive
 Can develop mechanical sensitivity when chemical mediators from inflammation, tissue damage released

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54
Q

A-beta fibers

A

transmit non-noxious sensory information, can transmit nociceptive information following tissue trauma/changes in properties of nociceptors
 Large myelinated fibers
 Low-threshold, rapidly conducting
 Usually transmit light touch, non-noxious stimuli via mechanoR

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55
Q

B fibers: diameter

A

1-3uM

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56
Q

B fibers: myelin, conduction velocity

A

Myelin: +
3-15m/s

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57
Q

Location, function and order of blockade of B fibers

A

Post-ganglionic: SNS
Function: autonomaic
Order of blockade: 1

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58
Q

C fiber diameter

A

0.4-1.5uM, smallest

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59
Q

C fibers: myelin, conjunction velocity

A

No myeline
0.5-1.3m/s - fastest conduction

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60
Q

C fiber location, function, and order of blockade

A

Post ganglionic in SNS - autonomic, slow pain, temp

Order of blockade: 2 (with a-delta fibers)

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61
Q

A-delta fiber diameter

A

2-5uM

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62
Q

A-delta fiber: myelin, conduction

A

Myelin: +
5-25m/s

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63
Q

A-delta location, function, order of block

A

-Afferent sensory
-Fast pain, temp, touch
-Order of blockade: 2

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64
Q

A-gamma diameter

A

2-6uM

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65
Q

A-gamma myelin, conduction velocity

A

Myelin: ++, conduction velocity 5-15m/s

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66
Q

A-gamma: location, function, order of block

A

Location: efferent to m spindle
Function: muscle tone
Order of block: 3

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67
Q

A-beta fibers: diameter

A

3-6microM

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68
Q

A-beta fibers: myelin, conduction velocity

A

Myelin: ++
Conduction velocity: 30-70m/s

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69
Q

A-beta fibers: location, function, order of blockade

A

Location: efferent to m, afferent sensory
Fun: motor, sensory (touch, pressure)
Order of blockade: 4

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70
Q

A-alpha fibers diameter

A

15-20microM - largest

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71
Q

A-alpha fibers myelin, conduction

A

Myelin: +++ (most)
conduction (m/s) 30-120 - slowest

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72
Q

A-alpha location, function, order of blockade

A

Location: afferent/efferent to m/joints
Fxn: motor/proprioception
Order of blockade: 5

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73
Q

Chemical Nociceptors

A

 Best understood
 Acid-sensing ion channels ASICs, chemical irritants: TRPA1
 Chemotransduction: tissue injury causes release of numerous chemicals

Also component of pathogenic organisms

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74
Q

Chemicals released during chemotransductinn

A
  • Arachidonic acid metabolites (prostaglandins, leukotrienes, thromboxanes)
  • Bradykinin
  • Protons
  • Serotonin (5-hydroxytryptamine, 5-HT)
  • Histamine
  • Cytokines IL-1beta, TNF-alpha, LIF
  • Excitatory amino acids eg glutamate
  • Neurotrophins eg NGF
  • Endothelians, ET-1
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75
Q

What cell types release chemical mediators during chemotransfuction

A

neurons, non-neuron cells including mast cells, macrophages/WBCs, platelets, Schwann cells, endothelial cells, keratinocytes, fibroblasts

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76
Q

Thermal Nociceptors

A

 Primarily via transient receptor protein (TRP) channels
 Heat: TRP vanilloid 1, TRPV1
 Cold: TRP menthol-8 , TRPM8

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77
Q

Mechanical Nociceptors

A

 Mechanotransduction: least understood, several different mechanoR involved
 Based on stimulus type (pressure vs stretch), tissue
 TRPA1, TRPV1, two pore potassium channels (TREK-1, TRAAK)

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78
Q

Peptidergic Nociceptors

A

C fibers release neuropeptides including substance P, CGRP

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79
Q

Nonpeptidergic Nociceptors

A

C fibers that express c-Ret neurotrophin R, targeted by glial-derived neurotrophic F

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80
Q

Ionotropic Transducers

A

 Most rapid, direct – microseconds
 LG: transducer has binding site
 Ion channel – cation selective (mono  divalent)
 May be activated directly or indirectly by activation of metabotropic

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81
Q

Main Examples of Ionotrophic R

A

TRPV1, 5-HT3, Glutamate
* TRPV1: thermal, chemical – heat hyperalgesia
* 5-HT3: chemical via serotonin – most prominent role in visceral analgesia
* Glutamate (GluR1-5, NR1-2): ampkine, kainite, NMDA R, chemical via glutamate, others – evidence for peripheral role, more important role at central terminals

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82
Q

Metabotrophic Transducer/R

A

 Slower: milliseconds to minutes
 Ligand binding induces conformational change in transducer  activation of intracellular signaling cascade
 GPCRs
 Sensitize ionotropics, homologues for many inotrophics

Two subtypes: metabotrophic, inflammatory mediator ligand

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83
Q

Main examples of Metabotrophic R

A

EP1-4 (grapriprant – EP4), B1/B2, H1, purinergic (P2Y2), endothelian A, protease-activated R (PAR-2)

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84
Q

Main examples of inflammatory mediator ligands

A

prostaglandins, bradykinin, histamine, ATP, endothelian-1, extracellular proteases

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85
Q

Neutrophin or Cytokine Transducers/R

A

 Functional R = dimers, trimers
 Activation of kinase pathway that affects gene transcription
 Elicit acute effects well
 Assoc protein kinases that catalyze phosphorylation of membrane proteins

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86
Q

Role of Cytokine R

A

recruit, separate protein kineases
o IL-1beta, TNF-alpha

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87
Q

Role of Neurotrophic R

A

receptor tyrosine kinase family (TRK), intrinsic protein catalytic site
o Nerve growth factor family: NGF, brain-derived neutrophic factor (BDNF), neurotropins 3, 4
o Glial cell line-derived family: glial cell-derived neutrophobic factor (GDNF), others

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88
Q

Neutrotrophins

A

regulate long-term survival, growth, function of neurons by altering transcription/translation of neuronal proteins
o Two families, infrequently co-expressed:
 NGF R: peptidergic neurons, release neuropeptides
 GDNF: nonpeptidergic

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89
Q

Nerve Growth Factors

A

o Released from numerous cells, binds trkA R
 Loss of trkA R: congenital insensitvity to pain
o Indirect effects: induce release of mediators from other cells (mast cells)
o Direct effects: DT binding to trkA R
 Early post-translational changes
 Delayed transcription-dependent changes, changes in gene expression

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90
Q

Axon Reflex, Neurogenic Signaling

A

o Caused by neuropeptide release:
 Substance P –> NK-1 R –> histamine release by mast cells, plasma extravasation, excitation of adjacent R
 Calcitonin gene-relayed peptide (CGRP)  vasodilation (flare)

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91
Q

Indirect Signaling

A

o Transducers present on non-neuronal cells
 Bladder endothelium
 GI epithelium
 Airway epithelium
 Keratinocytes

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92
Q

Indirect Signaling: Bladder Epithelium

A
  • ENaC – similar to ASIC on neurons
  • Release variety of inflammatory mediators
    o Bladder stretch –> ATP release –> binds P2X on adjacent neurons
    o Increased ATP in interstitial cystitis
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93
Q

3 components of pain

A
  1. Sensory-discrimination component
  2. Affective component
  3. Evaluative component
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94
Q

Sensory-Discrimination Component of Pain

A

 Temporal, spatial, thermal/mechanical
 Discrimination of stimuli by intensity, location, etc

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95
Q

Affective Component of Pain

A

 Subjective and emotional, describing associated fear, tension, autonomic responses)
 JB: Motivational affective, negative emotional aspects

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96
Q

Evaluative Component of Pain

A

 Magnitude of quality (ex: stabbing vs pounding; mild/severe)
 JB: cognitive evaluative – evaluation of pain in terms of past experiences, context

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97
Q

SC DH, trigeminal ganglia

A

sites of termination of all nociceptive afferents
o Cell bodies in DRG, trigeminal ganglion

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98
Q

Visceral Nociceptors

A

nociceptive neurons from viscera travel into DH with autonomic neurons
o Most pass through autonomic ganglia
o Nociceptive neurons sparser in viscera

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99
Q

Laminae of Rexed

A

grey matter divided into 10 distinct laminae based on neuron size, density

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100
Q

Laminae I, II

A

I: marginal layer
II: substantia gelatinosa

Constitute superficial DH
Main target of nociceptive primary afferent neurons

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101
Q

Peptidergic C neurons expressing TRPV1

A

lamina I, outer lamina II (oII)

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102
Q

Nonpeptidergic C neurons

A

inner lamina II (iII)

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103
Q

A-delta neurons - laminae of rexed

A

lamina I, II, V
 Overlap with projections of non-nociceptive mechanosensitive neurons in lamina III-V
 Allows integration of nociceptive, non-nociceptive input

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104
Q

Four DH Neuron Types

A

o Terminals of first order (primary afferent) neurons
o Cell bodies of second-order (projection) neurons
o Interneurons: majority in DH, remain within SC – inhibitory or excitatory
o Descending neurons: project caudally from brain, contact other neurons

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105
Q

Normal DH Transmission btw First, Second Order Neurons

A

o Virtually all first order neurons release glutamate, major excitatory NT
o Binda to AMPA, kainite R (ionotropic glutamatergic Glu R)
 Permits Na entry, depolarization of second order neurons
 Fast activation, inactivation kinetics
o Metabotropic glutamate R also present pre, post-synaptically – activated by glutamate but effect (excitatory vs inhibitory) depends on G protein coupling
o Neuropeptides: released as co-transmitters

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106
Q

Neuropeptides that are released as peptides during normal DH transmission

A

released as co-transmitters
 Substance P – binds NK-1 R
 Calcitonin Gene-Related Peptide (CGRP)
 Brain-derived neurotropic factor
* Internalization of trkA R-NGF in periphery
* Transport to nucleus, upregulation of BDNF = increased synaptic communication
 Somatostatin

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107
Q

First Order Neuron Terminals

A

o Many R/ion channels: opioid R, a2 R, cannabinoid R, serotonin/NE R, GABA/glycine R, VG Na, Ca channels, VG K channels

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108
Q

Opioid R

A

Opioids, ketamine

Agonism: inhibition of NT release, hyper polarization

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109
Q

a2 R

A

Alpha 2 agonists, methadone

Agonism: inhibition of NT release, hyperpolarization

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110
Q

Cannabinoid R (CB1)

A

Cannabidiol (CBD)

Agonism: inhibition of NT release, hyperpolarization

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111
Q

Serotonin, NE R

A

Opioids, tramadol, ketamine, antidepressants

Agonism: inhibition of NT release

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112
Q

VG K Channels

A

Opioids

Stimulation: hyperpolarization

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113
Q

VG Ca Channels

A

Opioids, Gabapentin, pregabalin, ziconotide

Inhibition: inhibition of NT release

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114
Q

Cell Bodies of Second Order Neurons

A

o Many R/ion channels: opioid, serotonin/NE, adenosine (A1), GABAB, glycine
o Drugs that target them hyperpolarize second order neurons

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115
Q

Excitatory IN

A

o Release glutamate as NT – many other NTs released as well
o Involved in nociceptive reflex arcs

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116
Q

Inhibitory IN, Gate Theory

A

o AKA gate cells: when stimulated by A neurons (‘closed gate’), inhibitory NT released
 GABA +/- glycine
 Wide variety of others
o Inhibit projection neurons preventing transmission of noxious signals, occurs at other sites as well

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117
Q

What are the two main ascending tracts?

A
  1. Spinothalamic
    - spine to thalamus
  2. Spinomedullary
    - spine to medulla
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118
Q

Spinothalamic Tract

A

 Cell body of first order neuron in DRG
* Ascends 1-2 segments in Lissaeur’s Tract (dorsolateral funiculus)
* Synapses in spinal cord DH
 Second order (projection) neuron decussates, projects to thalamus
* Synapses in thalamus

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119
Q

Spinomedullary Tract

A

 Comprised of neurons from lamina I, V, VII; spinal nucleus of V
 Terminates in four brainstem locations:
* Reticular formation
* Noradrenergic cell group (NACG, including LC)
* Parabrachial nucleus (PBN)
* Periaqueductal grey (PAG)

Three components: RAS, hypothalamus, limbic system

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120
Q

RAS

A

Reticular activating system
sends input from all afferent pathways to cortex
o Selective attention to stimuli, consciousness

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121
Q

Hypothalamus

A

o Input produces activity in SNS, pituitary gland

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122
Q

Limbic System

A

collection of structures in telencephalon, diencephaon (eg hippocampus, hypothalamus, amygdala)
o Responsible for motivation, emotion, learning, memory
o Ensures negative emotional reaction

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123
Q

Trigeminothalamic tract

A

equivalent to spinothalamic tract for head
 Cell bodies of first order neuron in trigeminal ganglion
* Synapse in spinal nucleus of V
 Second order neuron decussates, projects to thalamus
* Synapses in thalamus

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124
Q

Subcorticial way stations

A

Play Important role in:
–Autonomic functions
–Routing ascending signals to limbic (anterior cingulate cortex, amygdala, hippocampus), cortical regions

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125
Q

Spinocervicothalamic Tract

A

o Well-developed in carnivores, esp big cats
o Second order (projection) neuron projects cranially in ipsilateral Lissaeur’s Tract
o Synapses lateral cervical nucleus with third order neuron
 Third order neuron decussates, synapses in thalamus

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126
Q

Role: Thalamus

A

Key neuroanatomical structure linking ascending input from spinothalamic tract to cortex

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127
Q

Role: Posterior Ventral Medial Nucleus

A

Targeted by subset of lamina I neurons that also target lateral thalamic nuclei

Projects to insular cortex (insula)

Medial, lateral nuclei

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128
Q

Lateral Nuclei of Ventral Posterior Nuclei

A

Sensory Discriminative

Targeted by lamina V WDR

Projects to somatosensory cortex (SI, SII) and motor cortex

Sinals related to SI, SII remain organized somatotopically

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129
Q

Medial Nuclei of Posterior Ventral Medial Nuclei

A

–Motivational-effective

Targeted by lamina I neurons

Projects to anterior cingulate cortex, ventral lateral orbital cortex

130
Q

Somatosensory Cortex (SI)

A

Input from thalamus

Major structure underlying SD component of pain

Encodes location, time course, intensity, etc

131
Q

Somatosensory Cortex (SII) (I think)

A

Input from thalamus, reciprocal connections with IC

Role:
–Complements SI
–Integrates SD component with info rom limbic system (Anterior cingulate cortex, amygdala, hippocampus) via connections with IC

132
Q

Insular Cortex (IC) Connections

A

Input from brain regions modulating M-A component of pain
–Anterior cingulate cortex
–Temporal lobe (entorhinal cortex/hippocampus) - stores/receives sensory info

Output to PFC, limbic system

133
Q

Role of the Insular Cortex (IC)

A

Similar to SII

Connections btw IC, temporal lobe –> anticipation, elaboration of pain based on emotions, expectations, memory

134
Q

Prefrontal Cortex: connections

A

Input from basal ganglia

135
Q

Prefrontal Cortex - role

A

–Modulates attention to pain
–Implicated in placebo effect
–Produces reward-seeking, punishment aversive behaviors
–Adaptive strategies

136
Q

Anterior Cingulate Cortex (ACC) Connections

A

Connected to amygdala, IC, PFC, pre motor cortex, basal gangliga

137
Q

Anterior Cingulate Cortex Role

A

Modulates interconnected brain regions to mediate goal-directed/reward-based cognitive behaviors

Orchestration of motor responses

138
Q

Basal Ganglia

A

o Interconnected nuclei in white matter of both hemispheres
o Coordination of motor function
o Thought to be involved in pain processing
 Some clinical disorders feature movement disturbance, chronic pain (Parkinson’s dz, complex regional pain syndrome)
o Efferent output to ACC, PFC, amygdala, thalamus

139
Q

Descending Pathways

A

o Either attenuate or augment nociceptive or anti-nociceptive signaling dependent on biological needs
o Integrated with related alterations in autonomic, motor responses to noxious stimuli
o Inhibition dominant in absence of noxious stimuli
 Diffuse noxious inhibitor control: directs attention toward affected body site, away from distant body sites

140
Q

Descending Pathways Assoc with PAG, RVM

A

 Receives input from supraspinal structures
 Cognitive, emotional factors that modulate pain
 Disinhibits RVM, locus coeruleus (lateral floor of fourth ventricle in rostral pons) of NA cell group
 RVM, LC neurons project to DH
 PAG-RVM receive input from dorsal horn

141
Q

What are the two populations of neurons in the RVM?

A
  1. ON/facilitatory neurons
  2. OFF/inhibitory neurons

Balance btw off, on determines nociceptive response

142
Q

On/Facilitatory Neurons in RVM

A

o Pronociceptive
Express opioid R
o Inhibited directly by opioids/opioidergic neurons

143
Q

Off/Inhibitory Neurons in RVM

A

–Antinociceptive
–Excited by PAG output: serotonin, NE
–Stimulate opioidergic IN
–Tonically inhibited via GABAergic neurons

144
Q

What are the direct MOA in the DH?

A
  • Presynaptic inhibition
  • Postsynaptic inhibition
145
Q

What are the indirect MOA in the DH?

A
  • Inhibition or release of IN
  • Non-synaptic release of mediators (volume transmission, capable of releasing mediators that diffuse t/o DH)
146
Q

Hyperalgesia

A

Increase in responsiveness to painful stimuli, exaggerated and prolonged responses to noxious stimuli
 Leftward shift of stimulus-response function that relates magnitude of pain to stimulus intensity
* Consistent feature of somatic, visceral injury

147
Q

Primary Hyperalgesia

A

Hyperalgesia at site of original injury
* Injury, test site coincide – either inside or outside neuron’s receptive field (RF)
* Enhanced pain from heat, mechanical stimuli
* Periphery

148
Q

Secondary Hyperalgesia

A

hyperalgesia in surrounding, uninjured skin
* Enhanced pain from mechanical stimuli only
* CNS, precedes long-term central sensitization

149
Q

MOA Hyperalgesia

A

nociceptor sensitization –> lower threshold, increased threshold to suprathreshold stimuli, spontaneous activity, expansion of R field

150
Q

Allodynia

A

decreased pain threshold, non-painful stimuli now painful

151
Q

Some inflammatory mediators directly activate nociceptors, most change nociceptors

A

–Increases probability that given stimulus will activate R or generate AP
–Two MOA:
1) early post-translational changes
2) delayed transcription-dependent changes

152
Q

Early Post-Translational Changes in Pain Signaling/Development of Hyperalgesia

A
  • Phosphorylation of transducers or VG ion channels via second messenger pathways
  • Altered receptor trafficking eg increased TRPV1 density
153
Q

Delayed Transcription-dependent changes in Pain Signaling/Development of Hyperalgesia

A
  • Important effects of NGF: retrograde transport of internalized NGF-trkA to nucleus results in:
    o Increased expression of neuropeptides SP/CGRP
    o Upregulation of neurotropin BDNF
    o Increased expression of ion channels ie TRPV1, ASIC, NaV
154
Q

Peripheral Sensitization

A

Result of changes in environment bathing nociceptor terminals as a result of tissue injury or inflammation
o NT, chemical mediators either directly activate nociceptor or sensitize nerve terminals
o Long-lasting changes in functional properties of peripheral nociceptors
o Primary hyperalgesia

155
Q

Changes that Occur as a result of Primary Sensitization

A

Lowered threshold of high threshold nociceptors to mechanical, thermal or chemical stimuli
–Ex: TRVP1 threshold from 42C to 35C

Activation of silent nociceptors: increase hypersensitivity responses

Further release of inflammatory mediators, fluid, protein from SmM, inflammatory cells, endothelial cells, surrounding capillaries
–Contribute to hypersensitivity to nociceptors at/immediately adjacent to primary injury (primary hyperalgesia), sites not associated with site of injury (allodynia)

156
Q

Maladaptive changes in ion channels

A

hyperexcitability of afferent pain. signaling neurons, their axons  pain
o Electrical activity of primary afferent neurons from ion channels that define RMP, AP initiation, and transmitter release from terminals in DH
 VG Na, K, Ca channels; leak channels, LG ion channels
 NaV 1.7, 1.8; T type Ca channels

157
Q

Challenges with nonspecific Na channel blockers when used as analgesics

A

restricted in applicability to pain management because inhibit multiple channel isoforms including those expressed in brain, heart - induce AEs

158
Q

Which Nav channels are involved in inducing signals in peripheral nociceptors?

A

NaV 1.7, 1.8, 1.9: essential for inducing signals in peripheral nociceptors

not essential for function of CNS neurons or myocytes

159
Q

Role of NaV 1.8

A

linked to peripheral neuropathies in humans, neuropathic pain studies in rats

160
Q

Role of NaV 1.9

A

(NaN): in DRG, trigeminal ganglion – knockout mice display attenuated inflammatory pain behavior

161
Q

Central Sensitization

A

brief but intense period of nociceptor stimulation (ex: surgical incision)
o Process of development of hyper excitability state in CNS with decreased inhibition

Threshold of central neurons falls, responses to stimulation amplified

changes tissues response characteristics to thermal, mechanical, chemical stimuli

Receptive field enlarge to recruit additional previously “dormant” afferent fibers

162
Q

Consequences of Central Sensitization

A

o Manifestation of pain hypersensitivity: tactile allodynia, secondary hyperalgesia, enhanced temporal stimulation

163
Q

MOA Central Changes

A
  1. NMDA R-mediated sensitization
  2. Disinhibition
  3. Glial-neuronal interactions
164
Q

Disinhibition

A

 “Gate Control Theory”
 Uncontrolled, untreated tissue injury leads to loss of gate controlling inhibitory interneurons in substantia gelatinosa
* Increased projection of pain signals to brain

165
Q

MOA of NMDA-R Sensitization

A

Nociceptor activation via prolonged firing of C fibers – increased glutamate, substance P, CGRP, ATP release in DH

AMPA R, NDMA R, mGLuR activation (metabotropic GPCR)
* Glutamate from sensory afferents acts on AMPA if impulse short, acute
* Prolonged, repetitive stimuli –> glutamate acts on NMDA

166
Q

Details of NMDA R Activation

A

Repetitive, high frequency stimulus from C fibers –> increased glutamate release –> increased AMPA R binding –> Mg dislodges –> activation of normally silent NMDA R

167
Q

Windup

A
  • Zimmerman: Windup occurs when enough stimulation to remove Mg block on NMDA R: more available for activation of glutamate
  • LJ: Enhanced NMDA (wind-up) facilitated by co-release of substance P, CGRP from C fibers
    –Increase in co-transmitters: increase in GPCR activation
    –Activation, exacerbation of secondary hyperalgesia
168
Q

Where do NMDA R antagonists bind?

A

NR2B in DH (substantial gelatinosa)

Ketamine, dextromethorphan, memantine

Required for descending inhibitory pathway of CNS as well as ascending

169
Q

Translation changes in SC DH

A

Contribute to transition from persistent acute pain to chronic pain

170
Q

Glial Cells

A

Microglia, astrocytes
* Resident macrophages in CNS, central role in pain

Astrocytes: enhance maintenance of central sensitization

171
Q

Glial-Neuronal Interactions

A

 Activation by substances from primary afferent terminals, second-order transmission neurons leads to upregulation of COX2 in DRG
* Congregate at site of injured peripheral nerve terminal in dorsal or ventral horn – release cytokines/BDNF that enhance central sensitization/pain
* Produce PGE2, release additional neuroactive substances (cytokines)
* Increase excitability of DH neurons
* Also play role in axonal sprouting, altered connectivity, cell death

172
Q

Maintenance of Central Sensitization

A
  1. Increased intracellular calcium
  2. Changes in protein expression
173
Q

Maintenance of central sensitization: increased IC calcium

A
  • Phosphorylation of cytoplasmic AMPA R
    o More AMPA R inserted into post-synaptic membrane
  • Synapse to nucleus signaling via various molecules
    o Triggers activation of transcription factors that control protein expression
174
Q

Maintenance of Central Sensitization: changes in protein expression

A
  • Enhanced Na channel expression
    o Hyperexcitability
    o Ectopia: generation of impulses at abnormal sites
  • Changes involving Abeta R
  • ‘Sprout’ in DH to contact second order nociceptive neurons
  • Undergo phenotypic switching
  • Disinhibition of pre-existing pathways btw A, nociceptive neurons
175
Q

Neuroplasticity

A

caused by prolonged or intense nociceptive activity resulting in peripheral, central sensitization
o Alterations in phenotype of DH neurons, other neurons in CNS

176
Q

Targets of Transcriptional Changes in DH Neurons

A
  1. Induction of COX-2
  2. Endocannabinoids - derivatives of arachidonic acid
177
Q

Targets of Transcriptional Changes in DH Neurons: induction of COX-2

A

 Mediated by IL-1beta
 Upregulation of COX2, increased central sensitization and pain/hypersensitivity
 Downstream products of COX2 = CNS effects of PGE2
* Binds to prostaglandin E R
* EP1 or EP3 on sensory neurons: range of effects that reduce threshold for sensory neuron activation, increase neuronal excitability

178
Q

Endocannabinoids

A

derivatives of arachidonic acid
 Act on cannabinoid receptors (CB1 and CB2), expressed in all nociceptive neuroanatomic pathways of CNS, PNS

179
Q

Activation of Endocannabinoids

A

reduces release of neurotransmitters (glutamate)
* Involved in descending supraspinal inhibitory modulation via PAG, RVM

180
Q

Cannabinoids

A

antinociceptive properties for acute pain
* Antihyperalgesic, antiallodynic properties in models of neuropathic pain

181
Q

Endogenous Ligands that are Endocannabinoids

A
  1. anandamide
  2. 2-arachidonoylglycerol (2-AG)
  3. palmitoylthenolamdine
182
Q

Endogenous ligand anandamide

A

activates CB1 and CB2

183
Q

Endogenous ligand 2-arachidonoylglycerol (2-AG)

A

activates CB1, CB2

184
Q

Endogenous ligand palmitoylthenolamide

A

activates CB2 R

185
Q

Role of COX2 with endocannabinoids

A

 COX2 can biotransform anandamide, 2-AG to prostanoid compounds
* So inflammation = COX2 unregulated  antinociceptive effects of endocannabinoids can be lost, metabolites make pronociceptive effect

186
Q

Role of SNS

A

o Nociceptors normally unresponsive to sympathetic stimulation
o Inflammation may lead to catecholamine sensitization
 SNS stim, NE inj stimulate C neurons in chronically inflamed skin in rats
 Inhibited by a2 agonists

187
Q

Role of LA

A

Block transmission, transduction
Block modulation via inhibition of substance P binding
Inhibit GABA uptake
Block NMDA R
Others

188
Q

Role of Opioids

A

Centrally blunt pain perception in cortex, DH
Peripherally decrease NT release, decrease peripheral sensitization

189
Q

Role of NSAIDS

A

Block COX leading to decreased inflammatory mediators peripherally
Centrally block hyperalgesia induced by activation of substance P, etc

190
Q

Role of a2 agonists

A

centrally decrease AC –> decreased cAMP –> sedation, supra spinal analgesia

In DH: increase PLC, ITP, DAG, Ca leading to spinal analgesia

191
Q

Role of NMDA Agonists

A

Non competitively block central sensitization

192
Q

Medetomidine

A

racemic mixture of stereoisomers levomedetomidine, dexmedetomidine
o Levomedetomidine: inactive isomer

193
Q

Evidence for a2 analgesic properties: xylazine

A

analgesic effects on GI pain in horses, lower cortisol/improved behavior in calves vs ket alone for disbudding, antinociception in llamas with telazol

194
Q

a2 Site of Actions in CNS

A

peripherally, spinally, and supraspinally
o Agonist activity = antinociception
o Action on presynaptic terminal of primary afferent neurons, direct inhibition of SC neurons
o Local action suggests peripheral alpha2 can mediate analgesic activity

195
Q

a2a

A

voltage dependent, high concentration in dorsal horn of spinal cord

Synergism with a2a, a2c

196
Q

α2a, α2b, α2c

A

Analgesic MOA mediated by Gi-protein activation of K+ channels of α2a and α2c

197
Q

Cannabinoids + a2

A

o Inhibit transduction
o Alpha 2 may target cannabinergic receptors to produce antinociception
o Mice: synergism with MOR agonists, alpha 2 agonists, cannabinoid receptors

198
Q

Opioid R + a2

A

o Alpha 2 R agonists enhance opioid analgesia - Synergism
o Some mu opioids interact with 2 R with preferential affinity for certain R subtypes: 2b,c

199
Q

Local Anesthetics

A

Only analgesic drug that prevent nociceptive transmission, also inhibits transduction

200
Q

MOA Antinociceptive Effect of LA

A

reversible neuronal blockade, prevents transmission of noxious stimuli to SC, brain
o Dose dependent anti-inflammatory effects result of physical changes, direct effects on mediators of inflammation
o Inhibit proinflammatory mediator release, alter proinflammatory mediator activity
o Alter stages of leukocyte migration
o May reduce free radical formation

201
Q

MAC Reduction Effects of Lidocaine

A

o Conscious dogs, IV lidocaine = no change of nociceptive threshold with variety of dosages of systematically administered lidocaine
o Different results with intraocular sx
o Tsai et al: systemic admin of lidocaine comparable analgesia to meloxicam during OVH

202
Q

Anti-Inflammatory Effects of Lidocaine

A

o Inhibition of polymorphonuclear cell
o Suppression of histamine release from mast cells
o Inhibition of nuclear factor kappa B (transcription factor)
o Decrease in chemotactic factors, cytokines
o Decrease in albumin extravasation, microvascular permeability
o Decreased release of substance P from free nerve endings
o Decreased release of pro inflammatory lipoxygenase products
o Inhibition of release of toxic oxygen metabolites
o Decrease production of inducible nitric oxide synthase (iNOS)

203
Q

Na Channels

A

o Neuronal membrane resting potential = -60 to -90 mV
 Maintained by active Na+ transport out of cell, K+ into cell via Na/K ATPase pump
* K continually leaks from the membrane (K leak channels)
* Membrane relatively impermeable to Na
* Result: cell eventually becomes polarized
(high K inside, high Na outside)

204
Q

Role of LA on Na Channels

A

o Noxious stimulus opens voltage-gated channels: massive Na+ influx = depolarization. propagation of AP
 LAs penetrate nerve sheath, equilibrate, bind voltage gated Na channels to inhibit conformational change - do not allow passage of Na ions

205
Q

Alternative R for LAs

A

o May also block K+ channels, much lower affinity
o May also block Ca2+ channels, likely DT structural similarity btw Ca2+ channels, Na+ channels
o Modulation of NMDA R may also contribute to antinociceptive action of certain LAs

206
Q

Nodes of Ranvier

A

-Where Na channels concentrated
-To prevent transmission of stimuli, must block 3 consecutive nodes
–Block order of nerves DT proportional relationship btw conduction velocity, distance btw action sites

207
Q

Size of the Nerve and Block Order with LAs

A

Block order of nerves DT proportional relationship btw conduction velocity, distance btw action sites

Large fibers: greatest internodal distance, thus requiring less drug to provide blockade

Smaller myelinated fibers: smaller distance btw nodal distance, need more drug to block all sites
 Unmyelinated small nerves = highest drug concentration to block

208
Q

NMDS R Structure

A

Hetero-tetrameric R (5 subunits): two each of NR1, NR2 subunits

Cation channels: permeable to Na, K, Ca

209
Q

Role of Mg at NMDA R

A

Mg doesn’t allow ions to cross bc duration of depolarization too short
 Channel activated by glutamate+glycine
* Usually with persistent nociceptive input

Sites for multiple other endogenous, exogenous ligands: glutamate, ketamine, phencyclidine, Zn (voltage independent blocker), co-agonist modulators (glycine, polyamines)

210
Q

MOA NMDA R Antagonists

A

non-competitive binding phencyclidine site of NMDA R, antagonizing effects of excitatory NT
 Antagonism via result of inhibition of R activation, potentiation of GABA as inhibitory NT, decreasing presynaptic release of glutamate

211
Q

Ketamine: Somatic > Visceral Pain

A

Often utilized as adjunctive analgesic, success depends on type of pain patient is experiencing

Horses: ket (subanesthetic doses) + tramadol – analgesia to chronic laminitis

(S)-ketamine enantiomer = more analgesic than racemic mixture

212
Q

Other Benefits of Ketamine

A

As an NMDA antagonist, may counter opioid-induces hyperalgesia

213
Q

ROAs of Ketamine

A

Humans: IV regional ax improved with ketamine admin – reduced radiotherapy-induced pain with inclusion of topical ketamine on PO or skin mucosa

Epidural or SAS
 Epidural: rapid onset, short effect, intense effect (decrease in hyperalgesia may be longer)
 Not commercially available in PF form

214
Q

Ketamine Sites of Action

A

peripheral in DH of SC, supraspinally in limbic, thalamoneocortical systems
o NMDA R in secondary afferent neurons (postsynaptically)

215
Q

Ketamine at Opioid R

A

cannot exclude KOR effect

216
Q

Ketamine at Monoaminergic R

A

potential involvement of glutamate system in mechanism of antidepressant drug action
o Use of monoaminergic drugs common in treating depression in people
o Depression = common comorbidity when treating pain

217
Q

Ketamine at VG Na Channels, L-type Ca Channels

A

Na+, Ca2+ ion channels in DH of SC blocked with clinically relevant concentrations of ketamine when applied intrathecally

Decreases in neuronal excitability likely explains ketamine’s efficacy following epidural administration

218
Q

Ketamine and ATP-Sensitive K Channels

A

ATP-sensitive K+ channels (KATP) are activated through an increase in cyclic guanosine monophosphate (cGMP), via nitric oxide (NO)

Stimulation: one of mechanisms responsible for peripherally observed antinociception effects imparted by ketamine

219
Q

Ketamine and Neutrophil, Cytokine Expression

A

suppresses neutrophil production by inflammatory mediators
o Reduction in cytokine production
o Alteration of inflammatory cell recruitment

220
Q

Ketamine Metabolities

A

Rats: Norketamine = active metabolite with analgesic effects, not true in cattle

221
Q

Amantadine, Memantine

A

Amantadine: PO NMDA antagonist, dopamine agonist

222
Q

MOA Amantadaine

A

CNS stimulation mediated by amantadine’s dopaminergic activity, reduced neurotoxicity through its NMDA receptor antagonism
o Both have possible potential analgesic properties through NMDA receptor antagonism

Amantadine efficacy limited to cases of chronic pain where central sensitization may play a role

223
Q

Amandatine Excretion

A

o Primarily renal excretion

224
Q

AE Amandatine

A

o Overdose = CNS stimulation
o Be cautious with patients receiving other dopamine agonists (MOA) or agents inhibiting the reuptake of serotonin (ex: tricyclic antidepressants-fluoxetine) –> serotonin syndrome

225
Q

Serotonin Syndrome

A

Tachycardia, tachypnea, hypertension

Other signs: autonomic hyperactivity (diarrhea, mydriasis, and tachycardia), neuromuscular signs (hyperreflexia, myoclonus, tremors, and rigidity), altered mental status.

Systemic hypertension or hypotension, pulmonary hypertension, vomiting, anorexia, hyperthermia, restlessness, ataxia, seizures

226
Q

Drugs that Can Cause/Contribute to Serotonin Syndrome - antidepressants

A

Selective serotonin reuptake inhibitors, serotonin-NE reuptake inhibitors, tricyclic antidepressants

Monoamine oxidase inhibitors: selegiline (Anipryl [Zoetis], Eldepryl), tranylcypromine

Tricyclic antidepressants: trazodone, mirtazapine, amitriptyline

SSRIs: sertraline (Zoloft), fluoxetine (Prozac, Reconcile [PRN Pharmacal]), and citalopram (Celexa),

SSNRI: tramadol

227
Q

Examples of SSRIs used in veterinary medicine

A

sertraline (Zoloft), fluoxetine (Prozac, Reconcile [PRN Pharmacal]), and citalopram (Celexa),

228
Q

MOA Inhibitors Used in Veterinary Medicine

A

selegiline (Anipryl [Zoetis], Eldepryl), tranylcypromine, amitraz

229
Q

Examples of TCAs used in vet med

A

trazodone, mirtazapine, amitriptyline

230
Q

Opioids Known to Contribute to Serotonin Syndrome

A

-Buprenorphine
-Methadone
-Meperidine
-Tapentadol
-Tramadol
-Morphine (per Plumb’s)

231
Q

Antiemetics Known to Contribute to Serotonin Syndrome

A

-Ondansetron
-Granisetron
-Metoclopramidine

232
Q

Anticonvulsants Known to Contribute to Serotonin Syndrome

A

–Carbamazepine, Valproic Acid (3rd or 4th line of anticonvulsant therapy, supposedly increases CNS levels of GABA/increases K+ conductance)

233
Q

Tx Serotonine Sydrome

A

–decontamination
–Supportive Care: active cooling, BP support medications, anti seizure medications

234
Q

Amantadine Other Effects

A

= local anesthetic
 Mediated through sodium channel-blocking property with NMDA

Dogs with OA showed improvement with NSAID+amantidine use vs NSAID alone

235
Q

NSAIDS

A

Long acting, non controlled PO or injectable drugs for pain management
o Inhibit transduction

236
Q

NSAID MOA

A

Damage to cells phospholipid membrane initiates release / synthesis of inflammatory mediators that induce nociception
o NSAIDS inhibit COX production of proinflammatory molecules from arachidonic acid  decreasing prostaglandin formation, thromboxane production

237
Q

NSAID Use

A

somatic or integumentary pain where inflammation = major component
o NSAIDs produce analgesia by decrease in peripheral inflammatory COX enzyme conversion of arachidonic acid
o Some extent reduce central pain transmission

238
Q

NSAIDS in Practice

A

flunixin in horses particularly effective for visceral pain

Topical application of 1% diclofenac: reduce inflammation in horses undergoing RLP

Salicylates in cattle water: reduced cortisol levels, increased average daily weight gain following dehorning and castration vs no

Pigeons: quantifiable analgesia

239
Q

COX 1 MOA

A

o MOA for acute antinociceptive effects at level of brain is part by COX-1 isoenzymes
o PGs in neuronal tissues structures alter C fiber vs A- 𝛿 mediated spinal nociception
o Expression of COX1 mRNA upregulated in spinal cord in post-op pain models
o More AEs

240
Q

Leukotrienes, 5-Lopoxygenase (5-LOX)

A

Leukotrienes liberated by lipoxygenases (a proinflammatory mediator)
 Suggested that blockade of 5-LOX inhibition suppresses mechanical allodynia
 Leukotrienes play role at level of spinal cord in neuropathic pain

Dogs with osteosarcoma or OA in joints = expression of 5-LOX
 Suggests dual inhibitor of 5-LOX/cyclooxygenase (Tepoxalin) may have therapeutic effect in addition to providing analgesia

241
Q

Contraindications for NSAIDS

A

o Concurrent administration of any type of systemic steroid
o Patients already receiving an NSAID
o Documented renal or hepatic insufficiency or dysfunction
o Clinical syndrome that creates a decrease in circulating blood volume ie shock, dehydration, hypotension, ascites
o Active GI disease
o Trauma patients with known or suspected active hemorrhage or blood loss
o Pregnant patients or females intended for breeding
o Patients with significant pulmonary disease
 May be less important with COX-2
o Any type of confirmed or suspected coagulopathy
 May be less important with COX-2

242
Q

AEs NSAIDS

A

o Most common problems associated with NSAID administration: GIT
 Vomiting diarrhea, hematemesis, melanoma, silent ulcer - results in perforation
 Overall incidence of GI toxicity with NSAIDs unknown
o Effect of aging or disease on individual patient’s ability to metabolize NSAID unknown
o Hepatotoxicosis caused by NSAIDS generally considered to be idiosyncratic
 generally recover with cessation of treatment, supportive care
o Renal dysfunction DT prostaglandin inhibition
 Renal prostaglandin synthesis low under normovolemic conditions
 In face of hypovolemia synthesis is increased, important for maintaining renal perfusion

243
Q

Opioids

A

Mimic action of endogenous opioids (enkephalins, endorphins, and dynorphins), bind their receptors where pain modulation occurs

244
Q

Opioids MOA

A

utilize G- protein inhibition of cyclic AMP to achieve analgesic effect
o Inhibition –> increased K+ conductance (more K+ leaves), hyperpolarization of second-order neuron
o Inhibition of Ca VG channels, decreased NT release from first order neuron
o Result in decreased neurotransmission of painful stimuli within sensory afferent nervous system

245
Q

Other Roles of Opioids

A

Inhibition of release of other excitatory NT (substance P)
o May occur through activation of peripheral opioid receptors

246
Q

Opioids and Actual Analgesic Effects

A
  • Opioids do NOT alter conduction of impulses or response of nerve ending to noxious stimuli
  • Primarily MODULATE pain by raising paid threshold
    o Do not prevent generation of noxious stimuli
247
Q

Cellular Level MOA of Opioids

A
  • Agonist binding leads to conformational change, exchange of ADP for ATP – dissociation of G protein
    o Gi/o: decreased AC, cAMP, PKA  inotropic R inhibition
    o Gbeta/gamma: Inhibits CaV, TRPM3 channels –> inhibition of neuropeptide release, stimulation of hyperpolarizing (inwardly rectifying) K channels
     Also increases PLC –> IP3 –> Ca –> endogenous opioid peptide release, increased in inflamed tissue
    o Opioid R synthesis (DRG), transport to periphery – upregulated during inflammatory pain states
248
Q

Opioid AEs

A

o AEs: hyperthermia in cats, dysphoria
 Many AEs of opioids diminished when animal in pain
 High safety margin, reversible if necessary

249
Q

Opioids and Hypoalgesia

A

as a result of opioid use not equally efficacious for all types of pain
 Horses: morphine effective clinically when admin epidurally, maintained responses to thermal/electrical noxious stimuli
 Remifentanil: no MAC-sparing in ax’d cats, induce hypoalgesia effect in conscious cars
 Torb, nalbupine: effective visceral analgesia in cats, not as effective vs electrical stimulus

250
Q

Opioid Sites of Action

A

o Peripherally, spinally, supraspinally at stereospecific opioid receptors
o Receptors: pre, post synaptic

251
Q

Opioid R in Synovium

A

–Generated by dogs, horses
–Benefit to IA morphine
–Peripheral action of opioids more profound after inflammatory event in articular or periarticular tissue
* Suggests activation or upregulation of opioid receptors on primary afferent neurons locally

252
Q

Other Tissues than Can Generate Opioid R

A

 Corneal tissue generates opioid receptors in several species
* Topically applied tramadol, morphine provide analgesia to cornea

253
Q

Epidural Opioids

A

Produce postsynaptic inhibition of second-order neurons transmitting nociception info in DH of SC

Opioid R in substantia gelatinosa accounts for analgesia from opioids in epidural working

MOA: Epidural opioids diffuse across dura into CSF which bathes spinal cord

Drugs with low lipophilicity (morphine) = longer DOA DT longer residence time

Epidural morphine particularly beneficial/effective in horses

254
Q

Supraspinal Effects of Morphine

A

wide distribution of opioid R in frontal cortex, amygdala, somatosensory cortex, colliculus, cerebellum
 Species variation in distribution
 Species with opioid excitement (horses, cats): lower concentration of R in amygdala, frontal cortex

255
Q

Opioid R in Birds

A

more KOR expression
 Few studies: MOR (hydro) may also be effective, increase thermal threshold in some species

256
Q

Opioid R Classification

A

o International Union of Basic and Clinical Pharmacology (IUPHAR): δ, κ, μ, nociception/orphanin FQ (NOP)
o MOR, KOR = main in nociceptive modulation
o DOR does not appear to play role in acute analgesia
 DOR agonist activity beneficial in some chronic pain states

257
Q

MOR Subtypes

A

M1, M2

258
Q

DOR Subtypes

A

delta 1, delta 2

259
Q

KOR Subtypes

A

Kappa 1, Kappa 2, Kappa 3

260
Q

Opioids and Monoaminergic R

A

 Ex: tramadol, tapentadols
 Tramadol (and metabolites) = weak mu agonists
* Tramadol: NE and serotonin uptake inhibition
 Tapentadols mu activity > tramadol
* Greater opioid effect in humans vs tramadol DT better CNS penetration
* Prominent NE reuptake inhibition
* Minimal serotonin effect

261
Q

Opioids and Muscarinic R

A

Opioids can cause inhibition of ACh release from nerve endings (explains pupil changes / GI stasis)

262
Q

Opioids and NMDA R

A

 Opioid R may be uncoupled from downstream signaling pathways following protein kinase C activity as result of excitatory amino acids binding to NMDA R
 Prolonged opioid administration  tolerance
* Use of ketamine or methadone (NMDA) may lessen onset of tolerance

263
Q

Nerve Growth Factor - mAB

A

o Elevates with noxious stimuli, injury, dz
 Released by damaged cells, including synovial cells, chondrocytes
 Elevated NGF levels found in synovial fluid, synovium, osteochondral junction/articular cartilage in humans
 One of main factors in nerve sprouting
o Increase in substance P, gene-related peptide, calcitonin, histamine, serotonin, more NGF –> peripheral sensitization

Also important player in central sensitization

264
Q

Role of anti-NGF monoclonal antibodies (mABs)

A

o Bind to NGF, prevents interaction with R (TrkA)
o Interrupts NGF/TrkA signaling
o Decreases hyperalgesic response with OA

265
Q

Corral et al 2021 (VAA)

A

tx success significantly greater in BED group vs placebo from day 7 through all assessed time points
 Day 28: 44%
 Day 56: 51%
 Day 84: 48.2%
 Placebo: <25% treatment success
 AEs at similar frequencies btw groups, typical for population of dogs with OA – not related to study tx
 BED = significant effect on all three components of canine brief pain inventory (CBPI): pain interference, pain severity, QOL

266
Q

Which mABs are used in dogs?

A

ranevetmab, bedinvetmab (Librela)

267
Q

mAB Therapy in Cats

A

(frunevetmab inj)
o Zoetis, 7mg/mL solution in single use 1mL vial
 1mg/kg; 1 vial <7kg, 2 vials >7kg
o Indicated for q28 SQ admin for feline OA
o MOA: binds NGF to block effect
 Biologic product – mABs = anti-NGF mABs

268
Q

AEs of Fruevetmab

A

 Immunogenicity (therapeutic protein), poor/decreased efficacy seen (not anaphylactic)
 Most commonly alopecia, dermatitis
 GI signs (V, D)
 Do not administer concurrently/in same location as vax
 Do not allow administration by pregnant women

269
Q

Corticosteroids

A

Inhibit transduction

Anti-inflammatory drugs that reduce pain of inflammatory origin

270
Q

Site of Action of Corticosteroids

A

 Peripheral anti-inflamm effects
 Some role of hypothalamic-pituitary-adrenocortical axis in pain modulation

271
Q

AE Corticosteroids

A

 Systemic AEs with long term high dose exogenous steroid administration
 polyuria, polydipsia, GI ulceration, iatrogenic Cushing’s disease

272
Q

Gabapentin, Pregabalin

A

o Most common for neuropathic pain
o Neuro-pharmaceutical compounds, structural analogs of GABA
o MOA does not appear from GABAergic

273
Q

Gabapentin, Pregabalin Site of Action

A

 Analgesic occurs at spinal and supraspinal sites of action
 Alpha2- delta receptors associate with specific voltage-dependent calcium channel blockade for supraspinal action, higher CNS, inhibition of sensory afferent neurons within peripheral nervous system

274
Q

NK-1 R Antagonists

A

o NK-1 activated by substance P
o Diffusely distributed in CNS, PNS
o Maropitant = antiemetic with action on NK-1 with some analgesic properties
 MAC reduction, decreased noxious stimulus to ovarian manipulation

275
Q

NK1 R Antagonists Analgesic/MAC Sparing Effects

A

infusion of maropitant can effect ~15-25% MAC reduction, confounding factor in pain studies is elimination of nausea/vomiting (unpleasant in themselves) – higher pains scores in human med with nausea, vomiting
 Not appropriate as solo analgesic

276
Q

Transient R Potential Vanilloid Type 1 Antagonists

A

TRPV 1 upregulated in inflammation
o Antagonists initially cause excitation (may result in neuronal damage, pain) followed by analgesia
o Example of antagonist = ABT-116

277
Q

AEs of TRPV 1 Antagonists

A

Diarrhea, hyperthermia

278
Q

Site of Action of TRPV 1 Antagonists

A

LG nonselective cation channel that contributes to regulation of intracellular calcium concentrations

279
Q

Panoquell CA1 (Fluzapladib sodium)

A

o Canine acute pancreatitis: inflammatory condition, potentially life threatening with recurrence/chronicity
o Inj intended for in hospital use – targets pathophysiology of dz process, decreases hospitalization time
o Available in Japan since 2018, conditional FDA approval in April 2023

280
Q

SE of Panoquell CA1 (Fluzapladib sodium)

A

loss of appetite, digestive/resp tract disorders, liver dz/jaundice

281
Q

Panoquell CA 1 MOA

A

leukocyte-function assoc antigen-1 (LFA-1) inhibitor

282
Q

Amitriptyline, Nortripyline

A

o Humans: depression, anxiety DO, certain types of chronic, neuropathic pain
o Active reuptake inhibition on serotonin R relative to NE R
 Tricyclic antidepressant (TCA)
 Strong anticholinergic, antihistamine, a1 adrenergic, analgesic properties

283
Q

MOA TCAs/SSRIs

A

increases synaptic levels of serotonin, NE

Other proposed MOAs for analgesia:
* Na channel blockade
* NMDA R antagonism
* Antihistamine activity
* NO OPIOID R ACTIVITY

284
Q

Nortriptyline

A

active metabolite, available as Pamelor ®

285
Q

Metabolism, Excretion of Ami/Nortriptyline

A

 Hepatic metabolism in dogs, humans to produce active metabolite
 Both are excreted unchanged in urine, caution in animals with renal insufficiency

286
Q

Use of Ami/Notripyline in Animals

A

behavioral calming, augment behavioral tx program
 Dogs: separation anxiety, repetitive self-trauma
* Time for max effect = 2-4 weeks
 Cats: psychogenic alopecia
 Other uses:
* Idiopathic feline LUTD
* Neuropathic pain states

287
Q

Most Common Use in Cats for Amitripyline

A

urinary DO –> urinary marking, inappropriate urination secondary to idiopathic interstitial cystitis
 Stimulates beta adrenergic R in smooth muscle including urinary bladder –> decrease in smooth muscle excitability, increased bladder capacity

288
Q

SE of Amitripyline in Cats

A

 SID PM dosing recommended to avoid excessive daytime sedation (10mg/cat)
 Dose: 1-2mg/kg/day
 For FLUTD, tx periods >7d to observe improvements in CS

289
Q

Amitripyline and Treatment of Pain Syndromes

A

 Cashmore et al case series: 3 dogs with neuropathic pain in dogs, two of which responded to amitriptyline when gabapentin failed (1.1-1.3mg/kg PO BID)
* One dog: pain restarted when amitriptyline discontinued
 Cats: ~2mg/kg BID for neuropathic pain

290
Q

ROA for Amitripyline

A

PO, transdermal application not effective at increasing plasma drug levels
 Intrathecal admin –> marked spinal cord pathology

291
Q

AE Amitripyline

A

tachycardia mediated via anticholinergic effect, potential fatal vtach from overdose at 15mg/kg
 Preceded by prolonged QRS complex
 No ECG changes appreciated in dogs receiving appropriate dose
 Other SE: weight gain, sedation, hypersalivation, vomiting

Theoretical risk of trigging serotonin syndrome with concurrent use of TCAs and MOIs, risk (in humans) believed to be low with amitriptyline

292
Q

Analgesic Effects of Cold

A

 Decreases pain signaling peripherally and spinally
 Decreases migration of inflammatory cells to injured tissues
 VC reduces pain cascades, reduces edema formation, decreases inflammation
 Decreases tissue metabolism and O2 demand
 Reduces tissue distensibility

293
Q

Effects of Heat

A

may inactivate, suppress TRP channels
 Central heat provides competitive inhibition to nociceptive signals
 Releases antinociceptive NT at level of thalamus, cerebral cortex, spinal cord
 Heat increases tissue distensibility, tissue blood flow, metabolism
* Increased blood flow = promotes edema to injured tissue
* Increasing venous dilation relative to arterial dilation reduces previously established edema
* Heat reduces muscle spasm
* Facilitates DO2 – shifts oxyhemoglobin dissociation curve right, restores BF to hypoxic regions

294
Q

Shock Wave Therapy

A
  • tissue deformation to promote healing by use of sound waves to distort deep tissues
  • Promotes healing and joints deep tendon injuries deep wounds nerve injuries and non healing fractures
  • Demonstration of protective effects on cartilage and a cruise sheet injury model in rodents when used early in the degenerative process
295
Q

Peripheral Neuromodulation

A

 Acupuncture needle applied, fibroblasts are wound around tip –> mechano-transduction occurs
 Mast cells release peptides, NTs (opioid peptides, bradykinin, serotonin, adenosine
 R populations altered to increase cannabinoid, opioid R populations on peripheral nerve endings, transient receptor potential (TRP) undergo subtype changes
 Interleukins, prostaglandins altered at location of needle entry
* Promotes anti-inflammatory, analgesic activities

296
Q

Spinal Neuromodulation

A

 Can occur from altering a milieu of NT including endogenous opioids, serotonin, NE, glutamate, cytokines; suppression of glial inflammation
 Inhibitors of opioid transmission reduce efficacy of acupuncture-induced analgesia
 Add electrical impulses  alters type of opioids released from SC segments
* Low frequency (2-4 Hz) releases endorphins, enkephalins
* High frequency (100-200 Hz) releases dynorphins
 Serotonin, NE releasing neurons project to SC – also implicated in neuromodulation
 Glutamate, its receptors = major excitatory inputs at level of spinal cord
* Phosphorylation of glutamate receptors decreased with acupuncture
* Inhibition of NMDA receptor activity

297
Q

Indirect Effect of Nutritional Support - omega 3s

A

EPA, DHA, a-linolenic acid (ALA)
o EPA, DHA: Precursors for anti-inflammatory lipid mediators

298
Q

Indirect Effect of Nutritional Support - omega 6s

A
  • Omega 6s: linolenic acid, arachidonic acid (AA)
    o AA: precursor for pro inflammatory lipid mediators
299
Q

Indirect Effect of Diets with High Polyunsaturated FAs

A
  • Increased consumption of omega-3 PUFA lowers AA concentration in body, concurrently increases concentrations of EPA, DHA
    o Functional significance: eicosanoids = less potent mediators of inflammation
    o Increased consumption of EPA, DHA: increased production of these FAs, inflammatory cells
     Dose response fashion, at expense of AA
    o Result = formation of fewer inflammatory eicosanoids, less substrate available for formation of AA-derived eicosanoids
300
Q

Direct Effect of Diets high in PUFA

A
  • Cartilage cell cultures treated with omega-3 PUFAs inhibit transcription of major enzymes, cytokines tied to matrix degradation
301
Q

Pulsed Signal Therapy

A

application of pulsed electromagnetic fields on joint, surrounding tissue
 One study: subjective outcome measurements improved in OA dogs

302
Q

Laser Therapy

A

contributes to neuromodulation, neuroprotection
 Stimulates metabolism, cellular respiration via light energy

303
Q

Muscle Spasm

A
  • Muscle spasm = contributor to both acute, chronic pain
  • Significant percentage of acupuncture point locations associated with regions that generate muscle dysfunction and pain
    o Ex: Myofascial trigger points, musculotendinous junctions, muscle motor points
304
Q

Myofascial Tension

A

can result from stimuli arising in other locations such as joints, spine, tendons
o Amplifies pain sensation, can damage local and regional tissues by creating excessive and persistent traction across joints and disk spaces
o Actions may contribute to DJD (?) and rupture, OA, tendinopathies, ligament rupture

305
Q

Methocarbamol

A

Centrally acting muscle relaxant: selectively inhibits spinal, supraspinal polysynaptic reflexes through action on interneurons without direct effects on skeletal m

306
Q

Methocarb use in Vet Med

A

tetanus, metaldehyde and pyrethrin/permethrin toxicities, exertional rhadbo, management of acute muscle strain with NSAIDS
 Will see sedation at higher doses, esp if combined with other sedatives

307
Q

Methocarb Metabolism and Excretion

A

Extensive hepatic metabolism
 Dealkylation, hydroxylation followed by conjugation
 Urinary excretion of metabolites
 Horses: guaifenesin = metabolite produced in low concentrations

308
Q

Dosing Methocarb

A

o Doses cats, dogs: 40-60mgkg PO or IV TID x 1d followed by 20-40mgkg PO or IV TID until symptoms resolve
 Can also give per rectum: 55-200mg/kg, up to 330mg/kg Q6-8hr, few SE
o No CP changes when admin at therapeutic doses
o Overdose: sedation, excessive m weakness  effects = short-lived
o Formulations: 500mg, 750mg tablets; 100mg/mL injectable solution

309
Q

Chronic Pain QOL Assessment

A

o Chronic Pain in dogs and cats: composite oral pain scale
o Chronic pain in dogs: canine brief pain inventory (OA, bone cancer)
o Chronic pain in cats: feline MSK pain index (DJD)
o QOL: VetMerica Health-Related QOL Tool

310
Q

Acute Pain in Dogs

A

o Glasgow Composite Measure Pain Scale – Dogs
o Glasgow Composite Measure Pain Scale – Short Form, Dogs
o Colorado State University (CSU) Pain Scale, not validated

311
Q

Acute Pain in Cats

A

o Glasgow Composite Measure Pain Scale – Cats
o UNESP – Botucatu
o Feline Grimace Scale
o Colorado State University Feline Acute Pain Scale
 Showed moderate to good interrater reliability when used by veterinarians to assess pain level or need to reassess analgesic plan after OH and cats
 validity fell short of current guidelines for correlation coefficients, further refinement slash testing warranted to improve performance

312
Q

OA

A
  • Articular cartilage damage, inflammation, synovitis, subchondral bone/periarticular tissue changes
  • Slow, progressive often insidious problem
    o ~20% of canine population
     OA, DJD synonymous
    o 24-90% of feline population
     Joint pathology may have different etiology with onset, CS, pathophys differing from dogs
     64-90% radiographic effective, 45% clinically affected
313
Q

OA as a Disease

A

dz manifested by morphological, biochemical, molecular/biomechanical changes of both cells, matrix
o Softening, fibrillation, ulceration, articular cartilage loss, sclerosis, subchondral bone hibernation, osteophyte production
o Joint pain, tenderness, limitation of mobility, crepitus, occasional effusion, variable degrees of inflammation without systemic effects

314
Q

Definition of OA via American Academy of Orthopedic Surgeons

A

OA dz result of both mechanical, biological events that destabilize the normal coupling of degradation and synthesis of articular cartilage chondrocytes, extracellular matrix (primarily collagen and aggrecan), subchondral bone

May be initiated by multiple factors including genetic, developmental, metabolic, and traumatic factors; involve all of tissues of diarthrodial joint

315
Q

Pathophysiology of OA

A

o Characterized by articular cartilage degeneration, changes in periarticular soft tissue (synovium, joint capsule), subchondral bone
o Comparable to end stage organ failure
o hypertrophic bone changes with osteophyte formation, subchondral bone plate thickening
o Failure to repair damage affecting surface cartilage, inability of chondrocytes in articular cartilage to restore a functional matrix despite high metabolic activity

316
Q

Why OA Painful

A

o Painful mechanical stimuli detected by nociceptor afferent nerve fibers located in joint capsule, associated ligaments, periosteum, subchondral bone
 Joint movement induces mechano gated ion channels to open – nerve firing
 When joint movement exceeds normal limits, nerve firing dramatically increases
* Higher centers in CNS interpret signals as pain
 Mechano sensory fibers become sensitized, resulting in increased afferent firing even in response to normal physiologic joint motion

317
Q

Mainstays of OA Tx

A

WEDDS

Weight management, exercise/PT, diet modification, drugs, sx

318
Q

Radiosynoviorthesis

A

homogeneous Tin (117mSn) colloid
* Tin(117mSn) stannic colloid in ammonium salt
* Label use: 2-4mCi (74-148 Mbq)/mL suspension for IA inj
* MOA: radioactive isotype taken up by macrophages, long-lasting reduction of IFM, pain assoc with elbow OA
* 1yr DOA, ok to repeat tx after 12mo

319
Q

Use/SE of Synovetin

A
  • SE: joint soreness post inj up to 3d
    o Radiation exposure is minimal: avoid co-sleeping at home for 2-6 weeks, 1dog/household/yr
  • Needs sedation for IA inj by DVM, otherwise OP
320
Q

Other Requirements of Synovetin

A

o Federal or state license to use internal radiation-based medical therapies
 Non-beta radiation emitter, synovetin = gamma
o Start up costs: equipment, radiation (RAM) license, safety officer, approx $13K
o Authorized veterinarian, online modules 6-8h
o Cost to vet office: 2 inj = $1600, vials not shared btw patients

321
Q

Benefits of Synovetin

A
  • Pilot study: significant reduction in pain, lameness, no AEs
  • Most efficacious with grade 1, 2 elbow dysplasia

Boards: Pain (2 decks)

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