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
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
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
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
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
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
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
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
9
Q
Breakthrough Pain
A
o Acute exacerbations of chronic state
10
Q
Acute on Chronic Pain
A
o Independent arrival of new pain states
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
12
Q
Voscopoulos, Lema
A
transition from acute to chronic pain occurs in discrete steps, initiated by presence of persistent and intense stimuli
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
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
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
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
17
Q
MOA Neuropathic Pain
A
Significant decreases in substance P, CGRP; increases in galanin, neuropeptide Y in primary afferent neurons, spinal cord
18
Q
Cancer Pain
A
o Often displays inflammatory + neuropathic pain
o No detectable changes in markers that are changed in neuropathic/inflammatory pain
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?
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
21
Q
Four Physiological Processes of Pain
A
- Transduction
- Transmission
- Modulation
- Projection/Perception
22
Q
Mediators of Transduction
A
Sensory nerve endings, nociceptors
Nociceptors encode intensity, duration, location, quality of stimulus
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
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
25
Transmission
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
26
Synpatic Sites assoc with A delta fibers
Laminar I, II, V
27
Synpatic sites assoc with C fibers
laminae I, II (substania gelatinosa) or trigeminal ganglion
28
Synaptic sites assoc with A-beta fibers
Laminae II-V
29
WDR Neurons
* 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
30
Modulation
Centrally (spinal cord) or peripherally
* Peripheral via GPCRs (Gi/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
31
MOA Modulation
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
32
Role of NMDA R in Modulation
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
33
Projection, Perception
Somatic sensory information projected to reticular formation of brain stem, surrounding nuclei via multiple parallel circuits/ascending pathways
* Converge in thalamus
34
Tracts responsible for projection?
1. Spinothalamic
2. Spinoreticular
3. Spinomesencephalic
35
Role of spinothalmaic tract?
superficial pain, touch sensation
o Originates from lamina I, V
o Projects to thalamus, reticular formation
36
Role of spinoreticular tract
deep pain, visceral sensation
37
Role of spinomesencephalic tract
temperature sensation, pain
o Projects to midbrain: PAG, hypothalamus, limbic system
38
Role of post-synaptic dorsal column tracts
mediates pain transmission, projection
39
Trigeminal System
pain, touch sensation from head
40
Thalamus
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
41
Reticular Activating System (RAS)
brainstem
* Key role in integration of information
* Subjective responses to pain (projections to thalamus, limbic system)
* Autonomic, motor, endocrine responses
42
Supraspinal descending modulation controlled by:
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
43
How are nociceptor fibers classified?
Erlanger-Gasser System
44
Nociceptors
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**
45
C Fibers
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
46
What are the stimulation threshold for C fibers?
: higher than other sensory fibers (Thermal: >45*C)
47
Where do C fibers synapse?
Synapse: lamina II (substansia gelatinosa)
48
Are all C fibers nociceptive?
Not all C fibers are nociceptors (cooling, petting)
49
A-delta fibers
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
50
Where in the SC do A-delta synapse?
Synapse in lamina I, V of spinal cord
51
Type I A-delta fibers
polymodal, mechanically sensitive afferents (MSAs), also activated via chemical stimulation
52
Type II A-delta fibers
mechanical insensitive afferents, MIAs (silent nociceptors), heat activated
53
Silent Nociceptors
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
54
A-beta fibers
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
55
B fibers: diameter
1-3uM
56
B fibers: myelin, conduction velocity
Myelin: +
3-15m/s
57
Location, function and order of blockade of B fibers
Post-ganglionic: SNS
Function: autonomaic
Order of blockade: 1
58
C fiber diameter
0.4-1.5uM, smallest
59
C fibers: myelin, conjunction velocity
No myeline
0.5-1.3m/s - fastest conduction
60
C fiber location, function, and order of blockade
Post ganglionic in SNS - autonomic, slow pain, temp
Order of blockade: 2 (with a-delta fibers)
61
A-delta fiber diameter
2-5uM
62
A-delta fiber: myelin, conduction
Myelin: +
5-25m/s
63
A-delta location, function, order of block
-Afferent sensory
-Fast pain, temp, touch
-Order of blockade: 2
64
A-gamma diameter
2-6uM
65
A-gamma myelin, conduction velocity
Myelin: ++, conduction velocity 5-15m/s
66
A-gamma: location, function, order of block
Location: efferent to m spindle
Function: muscle tone
Order of block: 3
67
A-beta fibers: diameter
3-6microM
68
A-beta fibers: myelin, conduction velocity
Myelin: ++
Conduction velocity: 30-70m/s
69
A-beta fibers: location, function, order of blockade
Location: efferent to m, afferent sensory
Fun: motor, sensory (touch, pressure)
Order of blockade: 4
70
A-alpha fibers diameter
15-20microM - largest
71
A-alpha fibers myelin, conduction
Myelin: +++ (most)
conduction (m/s) 30-120 - slowest
72
A-alpha location, function, order of blockade
Location: afferent/efferent to m/joints
Fxn: motor/proprioception
Order of blockade: 5
73
Chemical Nociceptors
Best understood
Acid-sensing ion channels ASICs, chemical irritants: TRPA1
Chemotransduction: tissue injury causes release of numerous chemicals
Also component of pathogenic organisms
74
Chemicals released during chemotransductinn
* 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
75
What cell types release chemical mediators during chemotransfuction
neurons, non-neuron cells including mast cells, macrophages/WBCs, platelets, Schwann cells, endothelial cells, keratinocytes, fibroblasts
76
Thermal Nociceptors
Primarily via transient receptor protein (TRP) channels
Heat: TRP vanilloid 1, TRPV1
Cold: TRP menthol-8 , TRPM8
77
Mechanical Nociceptors
Mechanotransduction: least understood, several different mechanoR involved
Based on stimulus type (pressure vs stretch), tissue
TRPA1, TRPV1, two pore potassium channels (TREK-1, TRAAK)
78
Peptidergic Nociceptors
C fibers release neuropeptides including substance P, CGRP
79
Nonpeptidergic Nociceptors
C fibers that express c-Ret neurotrophin R, targeted by glial-derived neurotrophic F
80
Ionotropic Transducers
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
81
Main Examples of Ionotrophic R
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
82
Metabotrophic Transducer/R
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
83
Main examples of Metabotrophic R
EP1-4 (grapriprant – EP4), B1/B2, H1, purinergic (P2Y2), endothelian A, protease-activated R (PAR-2)
84
Main examples of inflammatory mediator ligands
prostaglandins, bradykinin, histamine, ATP, endothelian-1, extracellular proteases
85
Neutrophin or Cytokine Transducers/R
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
86
Role of Cytokine R
recruit, separate protein kineases
o IL-1beta, TNF-alpha
87
Role of Neurotrophic R
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
88
Neutrotrophins
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
89
Nerve Growth Factors
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
90
Axon Reflex, Neurogenic Signaling
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)
91
Indirect Signaling
o Transducers present on non-neuronal cells
Bladder endothelium
GI epithelium
Airway epithelium
Keratinocytes
92
Indirect Signaling: Bladder Epithelium
* 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
93
3 components of pain
1. Sensory-discrimination component
2. Affective component
3. Evaluative component
94
Sensory-Discrimination Component of Pain
Temporal, spatial, thermal/mechanical
Discrimination of stimuli by intensity, location, etc
95
Affective Component of Pain
Subjective and emotional, describing associated fear, tension, autonomic responses)
JB: Motivational affective, negative emotional aspects
96
Evaluative Component of Pain
Magnitude of quality (ex: stabbing vs pounding; mild/severe)
JB: cognitive evaluative – evaluation of pain in terms of past experiences, context
97
SC DH, trigeminal ganglia
sites of termination of all nociceptive afferents
o Cell bodies in DRG, trigeminal ganglion
98
Visceral Nociceptors
nociceptive neurons from viscera travel into DH with autonomic neurons
o Most pass through autonomic ganglia
o Nociceptive neurons sparser in viscera
99
Laminae of Rexed
grey matter divided into 10 distinct laminae based on neuron size, density
100
Laminae I, II
I: marginal layer
II: substantia gelatinosa
Constitute superficial DH
Main target of nociceptive primary afferent neurons
101
Peptidergic C neurons expressing TRPV1
lamina I, outer lamina II (oII)
102
Nonpeptidergic C neurons
inner lamina II (iII)
103
A-delta neurons - laminae of rexed
lamina I, II, V
Overlap with projections of non-nociceptive mechanosensitive neurons in lamina III-V
Allows integration of nociceptive, non-nociceptive input
104
Four DH Neuron Types
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
105
Normal DH Transmission btw First, Second Order Neurons
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
106
Neuropeptides that are released as peptides during normal DH transmission
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
107
First Order Neuron Terminals
o Many R/ion channels: opioid R, a2 R, cannabinoid R, serotonin/NE R, GABA/glycine R, VG Na, Ca channels, VG K channels
108
Opioid R
Opioids, ketamine
Agonism: inhibition of NT release, hyper polarization
109
a2 R
Alpha 2 agonists, methadone
Agonism: inhibition of NT release, hyperpolarization
110
Cannabinoid R (CB1)
Cannabidiol (CBD)
Agonism: inhibition of NT release, hyperpolarization
111
Serotonin, NE R
Opioids, tramadol, ketamine, antidepressants
Agonism: inhibition of NT release
112
VG K Channels
Opioids
Stimulation: hyperpolarization
113
VG Ca Channels
Opioids, Gabapentin, pregabalin, ziconotide
Inhibition: inhibition of NT release
114
Cell Bodies of Second Order Neurons
o Many R/ion channels: opioid, serotonin/NE, adenosine (A1), GABAB, glycine
o Drugs that target them hyperpolarize second order neurons
115
Excitatory IN
o Release glutamate as NT – many other NTs released as well
o Involved in nociceptive reflex arcs
116
Inhibitory IN, Gate Theory
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
117
What are the two main ascending tracts?
1. Spinothalamic
- spine to thalamus
2. Spinomedullary
- spine to medulla
118
Spinothalamic Tract
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
119
Spinomedullary Tract
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
120
RAS
Reticular activating system
sends input from all afferent pathways to cortex
o Selective attention to stimuli, consciousness
121
Hypothalamus
o Input produces activity in SNS, pituitary gland
122
Limbic System
collection of structures in telencephalon, diencephaon (eg hippocampus, hypothalamus, amygdala)
o Responsible for motivation, emotion, learning, memory
o Ensures negative emotional reaction
123
Trigeminothalamic tract
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
124
Subcorticial way stations
Play Important role in:
--Autonomic functions
--Routing ascending signals to limbic (anterior cingulate cortex, amygdala, hippocampus), cortical regions
125
Spinocervicothalamic Tract
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
126
Role: Thalamus
Key neuroanatomical structure linking ascending input from spinothalamic tract to cortex
127
Role: Posterior Ventral Medial Nucleus
Targeted by subset of lamina I neurons that also target lateral thalamic nuclei
Projects to insular cortex (insula)
Medial, lateral nuclei
128
Lateral Nuclei of Ventral Posterior Nuclei
Sensory Discriminative
Targeted by lamina V WDR
Projects to somatosensory cortex (SI, SII) and motor cortex
Sinals related to SI, SII remain organized somatotopically
129
Medial Nuclei of Posterior Ventral Medial Nuclei
--Motivational-effective
Targeted by lamina I neurons
Projects to anterior cingulate cortex, ventral lateral orbital cortex
130
Somatosensory Cortex (SI)
Input from thalamus
Major structure underlying SD component of pain
Encodes location, time course, intensity, etc
131
Somatosensory Cortex (SII) (I think)
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
Insular Cortex (IC) Connections
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
Role of the Insular Cortex (IC)
Similar to SII
Connections btw IC, temporal lobe --> anticipation, elaboration of pain based on emotions, expectations, memory
134
Prefrontal Cortex: connections
Input from basal ganglia
135
Prefrontal Cortex - role
--Modulates attention to pain
--Implicated in placebo effect
--Produces reward-seeking, punishment aversive behaviors
--Adaptive strategies
136
Anterior Cingulate Cortex (ACC) Connections
Connected to amygdala, IC, PFC, pre motor cortex, basal gangliga
137
Anterior Cingulate Cortex Role
Modulates interconnected brain regions to mediate goal-directed/reward-based cognitive behaviors
Orchestration of motor responses
138
Basal Ganglia
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
Descending Pathways
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
Descending Pathways Assoc with PAG, RVM
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
What are the two populations of neurons in the RVM?
1. ON/facilitatory neurons
2. OFF/inhibitory neurons
Balance btw off, on determines nociceptive response
142
On/Facilitatory Neurons in RVM
o Pronociceptive
Express opioid R
o Inhibited directly by opioids/opioidergic neurons
143
Off/Inhibitory Neurons in RVM
--Antinociceptive
--Excited by PAG output: serotonin, NE
--Stimulate opioidergic IN
--Tonically inhibited via GABAergic neurons
144
What are the direct MOA in the DH?
* Presynaptic inhibition
* Postsynaptic inhibition
145
What are the indirect MOA in the DH?
* Inhibition or release of IN
* Non-synaptic release of mediators (volume transmission, capable of releasing mediators that diffuse t/o DH)
146
Hyperalgesia
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
Primary Hyperalgesia
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
Secondary Hyperalgesia
hyperalgesia in surrounding, uninjured skin
* Enhanced pain from mechanical stimuli only
* CNS, precedes long-term central sensitization
149
MOA Hyperalgesia
nociceptor sensitization --> lower threshold, increased threshold to suprathreshold stimuli, spontaneous activity, expansion of R field
150
Allodynia
decreased pain threshold, non-painful stimuli now painful
151
Some inflammatory mediators directly activate nociceptors, most change nociceptors
--Increases probability that given stimulus will activate R or generate AP
--Two MOA:
1) early post-translational changes
2) delayed transcription-dependent changes
152
Early Post-Translational Changes in Pain Signaling/Development of Hyperalgesia
* Phosphorylation of transducers or VG ion channels via second messenger pathways
* Altered receptor trafficking eg increased TRPV1 density
153
Delayed Transcription-dependent changes in Pain Signaling/Development of Hyperalgesia
* 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
Peripheral Sensitization
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
Changes that Occur as a result of Primary Sensitization
Lowered threshold of high threshold nociceptors to mechanical, thermal or chemical stimuli
--Ex: TRVP1 threshold from 42*C to 35*C
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
Maladaptive changes in ion channels
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
Challenges with nonspecific Na channel blockers when used as analgesics
restricted in applicability to pain management because inhibit multiple channel isoforms including those expressed in brain, heart - induce AEs
158
Which Nav channels are involved in inducing signals in peripheral nociceptors?
NaV 1.7, 1.8, 1.9: essential for inducing signals in peripheral nociceptors
not essential for function of CNS neurons or myocytes
159
Role of NaV 1.8
linked to peripheral neuropathies in humans, neuropathic pain studies in rats
160
Role of NaV 1.9
(NaN): in DRG, trigeminal ganglion – knockout mice display attenuated inflammatory pain behavior
161
Central Sensitization
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
Consequences of Central Sensitization
o Manifestation of pain hypersensitivity: tactile allodynia, secondary hyperalgesia, enhanced temporal stimulation
163
MOA Central Changes
1. NMDA R-mediated sensitization
2. Disinhibition
3. Glial-neuronal interactions
164
Disinhibition
“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
MOA of NMDA-R Sensitization
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
Details of NMDA R Activation
Repetitive, high frequency stimulus from C fibers --> increased glutamate release --> increased AMPA R binding --> Mg dislodges --> activation of normally silent NMDA R
167
Windup
* 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
Where do NMDA R antagonists bind?
NR2B in DH (substantial gelatinosa)
Ketamine, dextromethorphan, memantine
Required for descending inhibitory pathway of CNS as well as ascending
169
Translation changes in SC DH
Contribute to transition from persistent acute pain to chronic pain
170
Glial Cells
Microglia, astrocytes
* Resident macrophages in CNS, central role in pain
Astrocytes: enhance maintenance of central sensitization
171
Glial-Neuronal Interactions
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
Maintenance of Central Sensitization
1. Increased intracellular calcium
2. Changes in protein expression
173
Maintenance of central sensitization: increased IC calcium
* 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
Maintenance of Central Sensitization: changes in protein expression
* 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
Neuroplasticity
caused by prolonged or intense nociceptive activity resulting in peripheral, central sensitization
o Alterations in phenotype of DH neurons, other neurons in CNS
176
Targets of Transcriptional Changes in DH Neurons
1. Induction of COX-2
2. Endocannabinoids - derivatives of arachidonic acid
177
Targets of Transcriptional Changes in DH Neurons: induction of COX-2
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
Endocannabinoids
derivatives of arachidonic acid
Act on cannabinoid receptors (CB1 and CB2), expressed in all nociceptive neuroanatomic pathways of CNS, PNS
179
Activation of Endocannabinoids
reduces release of neurotransmitters (glutamate)
* Involved in descending supraspinal inhibitory modulation via PAG, RVM
180
Cannabinoids
antinociceptive properties for acute pain
* Antihyperalgesic, antiallodynic properties in models of neuropathic pain
181
Endogenous Ligands that are Endocannabinoids
1. anandamide
2. 2-arachidonoylglycerol (2-AG)
3. palmitoylthenolamdine
182
Endogenous ligand anandamide
activates CB1 and CB2
183
Endogenous ligand 2-arachidonoylglycerol (2-AG)
activates CB1, CB2
184
Endogenous ligand palmitoylthenolamide
activates CB2 R
185
Role of COX2 with endocannabinoids
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
Role of SNS
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
Role of LA
Block transmission, transduction
Block modulation via inhibition of substance P binding
Inhibit GABA uptake
Block NMDA R
Others
188
Role of Opioids
Centrally blunt pain perception in cortex, DH
Peripherally decrease NT release, decrease peripheral sensitization
189
Role of NSAIDS
Block COX leading to decreased inflammatory mediators peripherally
Centrally block hyperalgesia induced by activation of substance P, etc
190
Role of a2 agonists
centrally decrease AC --> decreased cAMP --> sedation, supra spinal analgesia
In DH: increase PLC, ITP, DAG, Ca leading to spinal analgesia
191
Role of NMDA Agonists
Non competitively block central sensitization
192
Medetomidine
racemic mixture of stereoisomers levomedetomidine, dexmedetomidine
o Levomedetomidine: inactive isomer
193
Evidence for a2 analgesic properties: xylazine
analgesic effects on GI pain in horses, lower cortisol/improved behavior in calves vs ket alone for disbudding, antinociception in llamas with telazol
194
a2 Site of Actions in CNS
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
a2a
voltage dependent, high concentration in dorsal horn of spinal cord
Synergism with a2a, a2c
196
α2a, α2b, α2c
Analgesic MOA mediated by Gi-protein activation of K+ channels of α2a and α2c
197
Cannabinoids + a2
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
Opioid R + a2
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
Local Anesthetics
Only analgesic drug that prevent nociceptive transmission, also inhibits transduction
200
MOA Antinociceptive Effect of LA
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
MAC Reduction Effects of Lidocaine
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
Anti-Inflammatory Effects of Lidocaine
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
Na Channels
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
Role of LA on Na Channels
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
Alternative R for LAs
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
Nodes of Ranvier
-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
Size of the Nerve and Block Order with LAs
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
NMDS R Structure
Hetero-tetrameric R (5 subunits): two each of NR1, NR2 subunits
Cation channels: permeable to Na, K, Ca
209
Role of Mg at NMDA R
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
MOA NMDA R Antagonists
**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
Ketamine: Somatic > Visceral Pain
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
Other Benefits of Ketamine
As an NMDA antagonist, may counter opioid-induces hyperalgesia
213
ROAs of Ketamine
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
Ketamine Sites of Action
peripheral in DH of SC, supraspinally in limbic, thalamoneocortical systems
o NMDA R in secondary afferent neurons (postsynaptically)
215
Ketamine at Opioid R
cannot exclude KOR effect
216
Ketamine at Monoaminergic R
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
Ketamine at VG Na Channels, L-type Ca Channels
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
Ketamine and ATP-Sensitive K Channels
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
Ketamine and Neutrophil, Cytokine Expression
suppresses neutrophil production by inflammatory mediators
o Reduction in cytokine production
o Alteration of inflammatory cell recruitment
220
Ketamine Metabolities
Rats: Norketamine = active metabolite with analgesic effects, not true in cattle
221
Amantadine, Memantine
Amantadine: PO NMDA antagonist, dopamine agonist
222
MOA Amantadaine
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
Amandatine Excretion
o Primarily renal excretion
224
AE Amandatine
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
Serotonin Syndrome
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
Drugs that Can Cause/Contribute to Serotonin Syndrome - antidepressants
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
Examples of SSRIs used in veterinary medicine
sertraline (Zoloft), fluoxetine (Prozac, Reconcile [PRN Pharmacal]), and citalopram (Celexa),
228
MOA Inhibitors Used in Veterinary Medicine
selegiline (Anipryl [Zoetis], Eldepryl), tranylcypromine, amitraz
229
Examples of TCAs used in vet med
trazodone, mirtazapine, amitriptyline
230
Opioids Known to Contribute to Serotonin Syndrome
-Buprenorphine
-Methadone
-Meperidine
-Tapentadol
-Tramadol
-Morphine (per Plumb's)
231
Antiemetics Known to Contribute to Serotonin Syndrome
-Ondansetron
-Granisetron
-Metoclopramidine
232
Anticonvulsants Known to Contribute to Serotonin Syndrome
--Carbamazepine, Valproic Acid (3rd or 4th line of anticonvulsant therapy, supposedly increases CNS levels of GABA/increases K+ conductance)
233
Tx Serotonine Sydrome
--decontamination
--Supportive Care: active cooling, BP support medications, anti seizure medications
234
Amantadine Other Effects
= local anesthetic
Mediated through sodium channel-blocking property with NMDA
Dogs with OA showed improvement with NSAID+amantidine use vs NSAID alone
235
NSAIDS
Long acting, non controlled PO or injectable drugs for pain management
o Inhibit transduction
236
NSAID MOA
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
NSAID Use
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
NSAIDS in Practice
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
COX 1 MOA
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
Leukotrienes, 5-Lopoxygenase (5-LOX)
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
Contraindications for NSAIDS
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
AEs NSAIDS
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
Opioids
Mimic action of endogenous opioids (enkephalins, endorphins, and dynorphins), bind their receptors where pain modulation occurs
244
Opioids MOA
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
Other Roles of Opioids
Inhibition of release of other excitatory NT (substance P)
o May occur through activation of peripheral opioid receptors
246
Opioids and Actual Analgesic Effects
* 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
Cellular Level MOA of Opioids
* 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
Opioid AEs
o AEs: hyperthermia in cats, dysphoria
Many AEs of opioids diminished when animal in pain
High safety margin, reversible if necessary
249
Opioids and Hypoalgesia
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
Opioid Sites of Action
o Peripherally, spinally, supraspinally at stereospecific opioid receptors
o Receptors: pre, post synaptic
251
Opioid R in Synovium
--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
Other Tissues than Can Generate Opioid R
Corneal tissue generates opioid receptors in several species
* Topically applied tramadol, morphine provide analgesia to cornea
253
Epidural Opioids
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
Supraspinal Effects of Morphine
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
Opioid R in Birds
more KOR expression
Few studies: MOR (hydro) may also be effective, increase thermal threshold in some species
256
Opioid R Classification
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
MOR Subtypes
M1, M2
258
DOR Subtypes
delta 1, delta 2
259
KOR Subtypes
Kappa 1, Kappa 2, Kappa 3
260
Opioids and Monoaminergic R
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
Opioids and Muscarinic R
Opioids can cause inhibition of ACh release from nerve endings (explains pupil changes / GI stasis)
262
Opioids and NMDA R
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
Nerve Growth Factor - mAB
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
Role of anti-NGF monoclonal antibodies (mABs)
o Bind to NGF, prevents interaction with R (TrkA)
o Interrupts NGF/TrkA signaling
o Decreases hyperalgesic response with OA
265
Corral et al 2021 (VAA)
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
Which mABs are used in dogs?
ranevetmab, bedinvetmab (Librela)
267
mAB Therapy in Cats
(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
AEs of Fruevetmab
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
Corticosteroids
Inhibit transduction
Anti-inflammatory drugs that reduce pain of inflammatory origin
270
Site of Action of Corticosteroids
Peripheral anti-inflamm effects
Some role of hypothalamic-pituitary-adrenocortical axis in pain modulation
271
AE Corticosteroids
Systemic AEs with long term high dose exogenous steroid administration
polyuria, polydipsia, GI ulceration, iatrogenic Cushing’s disease
272
Gabapentin, Pregabalin
o Most common for neuropathic pain
o Neuro-pharmaceutical compounds, structural analogs of GABA
o MOA does not appear from GABAergic
273
Gabapentin, Pregabalin Site of Action
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
NK-1 R Antagonists
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
NK1 R Antagonists Analgesic/MAC Sparing Effects
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
Transient R Potential Vanilloid Type 1 Antagonists
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
AEs of TRPV 1 Antagonists
Diarrhea, hyperthermia
278
Site of Action of TRPV 1 Antagonists
LG nonselective cation channel that contributes to regulation of intracellular calcium concentrations
279
Panoquell CA1 (Fluzapladib sodium)
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
SE of Panoquell CA1 (Fluzapladib sodium)
loss of appetite, digestive/resp tract disorders, liver dz/jaundice
281
Panoquell CA 1 MOA
leukocyte-function assoc antigen-1 (LFA-1) inhibitor
282
Amitriptyline, Nortripyline
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
MOA TCAs/SSRIs
increases synaptic levels of serotonin, NE
Other proposed MOAs for analgesia:
* Na channel blockade
* NMDA R antagonism
* Antihistamine activity
* NO OPIOID R ACTIVITY
284
Nortriptyline
active metabolite, available as Pamelor ®
285
Metabolism, Excretion of Ami/Nortriptyline
Hepatic metabolism in dogs, humans to produce active metabolite
Both are excreted unchanged in urine, caution in animals with renal insufficiency
286
Use of Ami/Notripyline in Animals
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
Most Common Use in Cats for Amitripyline
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
SE of Amitripyline in Cats
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
Amitripyline and Treatment of Pain Syndromes
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
ROA for Amitripyline
**PO**, transdermal application not effective at increasing plasma drug levels
Intrathecal admin --> marked spinal cord pathology
291
AE Amitripyline
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
Analgesic Effects of Cold
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
Effects of Heat
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
Shock Wave Therapy
* 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
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Peripheral Neuromodulation
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
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Spinal Neuromodulation
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
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Indirect Effect of Nutritional Support - omega 3s
EPA, DHA, a-linolenic acid (ALA)
o EPA, DHA: Precursors for anti-inflammatory lipid mediators
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Indirect Effect of Nutritional Support - omega 6s
* Omega 6s: linolenic acid, arachidonic acid (AA)
o AA: precursor for pro inflammatory lipid mediators
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Indirect Effect of Diets with High Polyunsaturated FAs
* 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
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Direct Effect of Diets high in PUFA
* Cartilage cell cultures treated with omega-3 PUFAs inhibit transcription of major enzymes, cytokines tied to matrix degradation
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Pulsed Signal Therapy
application of pulsed electromagnetic fields on joint, surrounding tissue
One study: subjective outcome measurements improved in OA dogs
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Laser Therapy
contributes to neuromodulation, neuroprotection
Stimulates metabolism, cellular respiration via light energy
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Muscle Spasm
* 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
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Myofascial Tension
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
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Methocarbamol
Centrally acting muscle relaxant: selectively inhibits spinal, supraspinal polysynaptic reflexes through action on interneurons without direct effects on skeletal m
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Methocarb use in Vet Med
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
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Methocarb Metabolism and Excretion
Extensive hepatic metabolism
Dealkylation, hydroxylation followed by conjugation
Urinary excretion of metabolites
Horses: guaifenesin = metabolite produced in low concentrations
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Dosing Methocarb
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
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Chronic Pain QOL Assessment
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
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Acute Pain in Dogs
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
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Acute Pain in Cats
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
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OA
* 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
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OA as a Disease
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
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Definition of OA via American Academy of Orthopedic Surgeons
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
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Pathophysiology of OA
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
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Why OA Painful
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
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Mainstays of OA Tx
WEDDS
Weight management, exercise/PT, diet modification, drugs, sx
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Radiosynoviorthesis
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
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Use/SE of Synovetin
* 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
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Other Requirements of Synovetin
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
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Benefits of Synovetin
* Pilot study: significant reduction in pain, lameness, no AEs
* Most efficacious with grade 1, 2 elbow dysplasia
