What are the types of pain? (2)
- pathologic (peripheral sensitization, central sensitization)
Physiologic pain is ________-mediated, meaning...
nociceptor; activation of high threshold peripheral pain receptors (nociceptors) by painful noxious (thermal, mechanical, chemical) stimuli
Nociceptor-mediated physiologic pain causes __________ tissue damage because it is...
minmal or no; a protective warning system.
Pathologic pain can be __________-mediated or it can be caused by... (3)
nociceptor; inflammation (tissue damage), neuropathic (nerve damage), or cancer pain
Describe inflammatory pain in the context of CNS plasticity and sustained noxious stimulation. [peripheral sensitization]
- damaged tissues, inflammatory, and tumor cells release chemical mediators (prostaglandinds, histamine, nerve growth factors), creating an "inflammatory sensitizing soup"
- this changes it from high-threshold to low threshold nociceptors and activates "silent" nociceptors, leading to peripheral sensitization and hypersensitvity to non-noxious, non-painful stimuli
Describe neuropathic pain.
damage (trauma, tumors) or dysfunction of the nervous system, leading to hypersensitivity and spontaneous activity in peripheral nerves to non-noxious, non-pain stimuli.
Describe non-nociceptor-mediated pathologic pain.
pain generated by impulse that would not normally produce pain; activity-dependent central sensitization (increased excitability of dorsal horn neurons d/t increased and cumulative effects of sensory inputs) or transcription-dependent central sensitization (enhanced gene and enzyme production and removal or inhibitory substances)
What are the 2 types of central sensitization in non-nociceptor-mediated pathologic pain, and how are they different?
- Activity-dependent: increased excitability of dorsal horn neurons d/t increased and cumulative effects of sensory inputs
- Transcription-dependent: enhanced gene and enzyme production and removal or inhibitory substances
Rewiring after peripheral nerve injury causes pathologic pain by...
nerve sprouting and connection with nociceptive neurons in the dorsal horn.
Describe the role of disinhibition in pathologic pain.
reduction of inhibitory neurotransmitters (GABA, glycine) and loss of inhibitory interneurons in the dorsal horn of the spinal cord
What is sickness syndrome?
biologic responses to stress in an attempt to cope with a disruption or threat to homeostasis, which can be behavioral, autonomic, neuroendocrine, and immunologic
How do we evaluate pain in animals?
- behavior (attitude, activity, appetite)
- physiology (HR, RR, BP)
- blood chemical (cortisol, catecholamines)
- response to manipulation (palpation, physical stimulation)
What is a basic pain scoring system based on? (4)
behavior, severity of pain, duration of pain, mechanism of pain
What are therapeutic approaches to pain? (4)
- pre-emptive therapy
- multi-modal therapy (balanced analgesia)
- mechanism based
Describe multi-modal analgesia. (4)
- Inhibit perception: anesthetics, opioids, alpha-2 agonists, benzos, phenothiazines
- Inhibit transmission: inhibit impulse conduction with local block or alpha-2 agonists
- Modulate spinal pathways: inhibit central sensitization with local anesthetics, opioids, alpha-2s, NSAIDs, ketamine, tricyclic antidepressants, anticonvulsants
- Inhibit transduction: inhibit peripheral sensitization of nociceptors with NSAIDs, opioids, locals, steroids
You can inhibit central sensitization by _____________ with... (7)
modulation of spinal pathways; local anesthetics, opioids, alpha-2s, NSAIDs, ketamine, tricyclic antidepressants, anticonvulsants
You can inhibit peripheral sensitization of nociceptors by ____________ with... (4)
inhibiting transduction; NSAIDs, opioids, locals, steroids
Opioids provide... (3)
analgesia, euphoria, and sedation
Alpha-2 agonists provide... (3)
sedation, muscle relaxation, and analgesia
How do local anesthetics work?
block nerve transmission by blocking Na+ inflow, blocking sensory functions (touch, pressure, pain) and motor functions
Short-lived pain, where no or minimal tissue injury occurs is ___________; pain that occurs following tissue injury is ___________.
physiologic pain; pathologic pain
Pathologic pain sensation in the absence of a noxious stimulus.
Pathologic pain sensation in response to a normally innocuous stimulus.
Pathologic pain sensation as an exaggerated response to a noxious stimulus.
Transduction of noxious stimuli (mechanical, chemical, and thermal) is mediated by __(2)__ peripherally.
A-delta (myelinated) and C fibers (unmyelinated)
The transformation of noxious stimuli into electrical signals, called action potentials.
Process by which sensory impulses are conducted to the spinal cord from the periphery.
Impulse amplification or suppression within the spinal cord.
Process by which impulses are transmitted to the brain from the spinal cord.
Integration, processing, and recognition of nociceptive information.
Describe the function of A-delta fibers.
- mediate the fast-onset sharp pain (first pain)
- high threshold (nociceptors to pain)
- low threshold (mechanoreceptors to pressure)
Describe the function of C fibers.
- mediate the longer-lsating burning pain (second pain)
- high threshold only (nociceptors for pain, thermoreceptors, mechanoreceptors)
Describe the physiologic process of nociception.
- 1. Painful stimulus
- 2. Transduction of painful stimuli from peripheral nociceptors to the spinal cord via primary afferent sensory nerve fibers
- 3. Impulse received in dorsal root ganglia of spinal nerves; transmission of impulses through sensory axons to synapse with neurons in the dorsal grey horn
- 4. Modulation of impulses occurs by amplification or suppression by excitatory or inhibitory interneurons
- 5. Projection of impulses from dorsal horn to the brain occurs via nerve tracts (spinothalamic, spinoreticular, spinohypothalamic tracts)
- 6. Perception is the integration and processing of nociceptive information in the brain to produce a response via descending tracts into the spinal cord--> inhibitory neurons to cope or disinhibition to increase pain
Sensory neurons in the dorsal horn are either...
wide-dynamic-range neurons that receive input from all sensory nerves and are sensitive to low- and high-threshold sensory input (A-delta) OR neurons that process high-threshold specific nociceptive information (C fibers)
Neurotransmitters that are important in the modulation step of nociception include... (5)
- glutamate, aspartate [amino acids]
- substance P, neurokinin A [peptides]
Where does the spinothalamic tract run?
brings ascending information from the spinal cord to thethalamus
Where does the spinoreticular tract run?
brings ascending information from the spinal cord to the reticular formation and thalamus
Where does the spinomesencephalic tract run?
brings ascending information from the spinal cord and terminates in the periaqueductal grey matter, limbic system, and hypothalamus of the midbrain
Where does the spinohypothalamic tract run?
brings ascending information from the spinal cord to the forebrain and hypothalamus
Pain causes sympathetic stimulation, which leads to...
vasoconstriction, increased myocardial work, and increased myocardial oxygen consumption--> skeletal muscle blood flow increases, whereas blood flow to the GI and urinary tract decreases (fight or flight)
Neurohormonal changes that occurs in response to pain can include...
This results in...
- release of ACTH, elevation in cortisol, NE, and Epi, and a decrease in insulin
- results in a catabolic state that is important for the immediate survival of the animal, but if left unchecked, can lead to immunosuppression, increased morbidity and mortality
Describe the physiologic pathway of "ouch pain", in which there is minimal to no tissue damage.
- 1. High-threshold painful stimulus
- 2. Transduction of electrical impulses through the C fibers
- 3. Transmission of pain impulses to dorsal grey horn of spinal cord through afferent peripheral nerves
- 4. Modulation of impulses by Mg++ binding NDMA receptor and glutamate from the C fiber enhances the impulse through excitatory interneurons
- 5. Projection of the impulse along spino-etc ascending pathways to the brain
- 6. Perception of the impulse and reaction to it
Describe the process of peripheral nerve terminal sensitization due to tissue damage, and how this is related to central sensitization.
- 1. Tissue damage, inflammation--> zone of primary hyperalgesia
- 2. Prostaglandins, heat, histamines (vasodilation), cytokines, nerve growth factor--> signaling molecules that stimulate the C fiber peripheral axon
- 3. "Sensitizing soup" increases the sensitivity of nociceptors (decreased threshold) [periph sensitization]
- 4. Dorsal horn neurons that are stimulated by constant nociceptive input (glutamate, substance P) become hyperexcitable to low intensity stimuli; occurs through unblocking of NDMA receptors and increased gene expression.
- 5. CNS plasticity and depressed inhibition--> sustained pain
Inflammation activates what enzymes? (4)
- phospholipase A2
- nuclear factor kappa beta
What are properties of NSAIDs? (3)
NSAIDs MOA is...
inhibit cyclooxygenase (better to inhibit just COX2)
What are the physiologic functions of COX1? (3)
- produces prostaglandins, which have vasodilatory effects in the kidneys
- produces prostacyclin, which are antithrombogenic when released by endothelium and cytoprotective to the GI tract when released from gastric mucosa
COX2 in the ___________ isoform, meaning...
- inducible (constitutive in repro tract and eye)
- it is induced by inflammatory stimuli (unlike COX-1, which is always constitutive)
The expression of COX-2 is blocked by _____________.
corticosteroids and NSAIDs
What are the physiologic functions of COX-2? (2)
- wound healing
- new blood vessel growth (angiogenesis)
Describe the role of COX-2 inhibition in centrally-mediated analgesia.
- peripheral tissue damage up-regulates CNS COX-2, increasing neuromodulatory prostanoids--> central nociceptive amplification by COX-2
- therefore, analgesic responses to NSAIDs cannot be accounted for solely by peripheral COX-2 inhibition
- COX-2 selective inhibitors exert analgesic effects by peripheral AND central inhibition of COX-2
What are the common therapeutic properties of NSAIDs? (3)
- alleviate swelling, redness, and pain of inflammation
- reduced fever
- relieve osteoarthritic pain
What are common side effects of NSAIDs? (5)
- gastric distress
- renal damage
- antithrombotic effect
- hypersensitivity reactions
- [dogs only- carprofen] hepatopathy
Compare the analgesic efficacy of opioids, locals, and NSAIDs after surgery.
- opioids have greatest analgesic effects immediately after surgery, but decreases fastest
- locals last longer than opioids
- NSAIDs provide lower analgesic effects but last much longer than the other two
Cox-1 inhibition leads to... (3)
COX-2 inhibition leads to... (6)
- anti-inflammatory (peripheral and central)
- antineoplastic (TCC- peroxicam)
What drugs are NDMA antagonists? (3)
- dissociatives (Ketamine- low dose)
Describe the MOA of Gabapentin.
- analgesia via central alpha-2 agonist activity
- (also an anticonvulsant)
What is the MOA of tricyclic antidepressants?
serotonin-NE reuptake inhibition
What is the MOA of tramadol? (4)
- weak Mu agonist
- selective serotonin reuptake inhibition
- NE reuptake inhibitor
- NDMA antagonist
Acepromazine has no ___________ but is used as an analgesic adjunct because it ___________.
intrinsic analgesic properties; affects perception