Pain Physiology Flashcards
Excitatory Pain Modulating Transmitters
Substance P, Neurokinin A, Glutamate, Aspartate
Inhibitory Pain Modulating Neurotransmitters
Glycine and GABA by intrinsic spinal neurons. Enkephalins, Serotonin, and Norepi released in dorsal horn from descending efferent neuronal pathways.
Substance P Receptor
Neurokinin -1 (NK1) and Neurokinin-2 (NK2)
Glutamate receptors
NMDA, AMPA, kainite
Enkephalin receptors
Mu and delta
Serotonin receptors
5-HT
Where do A-delta fibers terminate?
In Rexed lamina I and V
Where do C-fibers terminate?
In Rexed lamina II and III
Specificity Theory
Specific pain receptors transmit signals to a “pain center” in the brain that produces the perception of pain. Does not account for psychological factors that affect our perception of pain
Pattern Theory
Pain signals are sent to the brain only when stimuli sum together to produce a specific combination or pattern. Does not posit specialized pain receptors nor does it see the brain as having control over the perception of pain. Set the stage for Gate Control Theory.
Gate Control Theory
Best accepted pain theory. Accounts for both “top-down” brain influences on brain perception as well as other effects of tactile stimulation (rubbing banged knee) in appearing to reduce the perception of pain. There is a gate through which all info regarding pain must pass. An “open gate” means that transmission cells (T-cells) can carry signals to the brain where pain is perceived. A “closed gate” stops t-cells from firing and no pain signal is sent to the brain.
- Where is the proposed “gate” or control system according to the Gate Control Theory?
- What controls whether the gate is opened or closed?
- The dorsal horn of the spinal cord
2. The Substantia gelatinosa in the dorsal horn.
What are the four elements of pain processing?
1) transduction 2) transmission 3) modulation 4) perception
An event where noxious stimuli are converted into an action potential
Transduction
Conduction of action potential via first, second, and third-order neurons
Transmission
Most common site for modulation of pain
Dorsal horn of spinal cord
What is the modulation of pain?
The altering of afferent neural transmission along the pain pathway. Can involve either inhibition or augmentation of pain signals.
These receptors are sodium-dependent channels and are essential for fast synaptic afferent input.
AMPA and kainate
MOA between NMDA and Substance P
NMDA receptor is calcium channel-dependent and is activated by prolonged depolarization of second-order neurons. Release of substance P into spinal cord will remove magnesium block on the channel of NMDA receptor, giving glutamate free access to NMDA.
What is the surgical stress response?
Activation of the SNS, neuroendocrine response, and immune system modulation with the release of cytokines.
The neuroendocrine response increases the secretion of which catabolic hormones?
cortisol, glucagon, growth hormone, and catecholamines
The neuroendocrine response decreases the secretion of which anabolic hormones?
insulin and testosterone
What are the consequences of the neuroendocrine response?
Hyperglycemia and negative nitrogen balance. This results in poor wound healing, muscle wasting, fatigue, and impaired immunocompetency.
What are the 3 primary mechanisms of action for opioid analgesia?
1) inhibition of calcium influx PRESYNAPTICALLY, preventing depolarization of cell and release of NT substance P and glutamate
2) Enhanced potassium efflux and hyperpolarization of POSTSYNAPTIC cells, decreasing pain transmission
3) activation of descending inhibitory pain circuit via inhibition of GABAergic transmission in the brainstem,
Allodynia
Perception of normally nonnoxious stimuli as pain
Anesthesia Dolorosa
Pain in an area that lacks sensation
Dysesthesia
Unpleasant or abnormal sensation with or without a stimulus
hyperalgesia
increased response to noxious stimuli
Allodynia is usually associated with which type of pain?
Neuropathic pain
Discuss the role of NMDA receptors in chronic pain states.
Under normal conditions, NMDA receptors remain inactive because of magnesium stability. In chronic pain, magnesium is displaced and NMDA receptors are easily accessible to glutamate which allows calcium ions to enter cells, causing an exaggerated release of substance P and excitatory amino acids.
Which type of receptors are known to play a significant role in chronic pain wind up?
NMDA receptors. They do not participate significantly in primary nociceptive transmission, they have a bigger role in spinal or central sensitization.
Radiculopathy
Functional abnormality of one or more nerve roots.
Explain NMDA receptor role in preventive analgesia.
Prevention of NMDA receptor activation in the dorsal horn prevents wind up, facilitation, central sensitization, and long term potentiation.
A-delta fibers
fast, myelinated. “first pain.” sharp or stinging. well localized.
C-fibers
slow, unmyelinated. “second pain.” diffuse. Associated with affective and motivational aspects of pain.
Types of nociceptors
Mechanoreceptors: pinch, pinprick sensation
Silent nociceptors: activated only in presence of inflammation
Polymodal mechano-heat nociceptors: response to excess pressure, temp extremes, and pain-producing substances (alogens) such as substance P, histamine, serotonin, and PGEs. You A-delta and C fibers are polymodal.
two types of second-order neurons
nociceptive-specific: located in lamina I, respond only to noxious stimuli, involved in sensory-discriminative aspects of pain.
wide dynamic range (WDR): Laminae IV, V, VI. Respond to both nonnoxious and noxious stimuli. involved in the affective-motivational component of pain.
where are the cell bodies of first, second, and third-order neurons located?
dorsal root ganglion, dorsal horn, and thalamus, respectively.
What causes “wind up” aka central sensitization?
Repetitive C-fiber stimulation of WDR neurons in the dorsal horn.
What is the perception of pain?
Integration of painful input into the somatosensory and limbic cortices.
A-alpha fibers
Heavily myelinated. Motor function.
What analgesics affect the PERCEPTION of pain?
PARENTERAL opioids, alpha 2 agonist, and general anesthetics.
What drugs inhibit the TRANSMISSION of pain?
Local anesthetics.
alpha 2 agonists affect which elements of pain processing?
Modulation and perception.
NSAIDS affect which elements of pain processing?
Transduction and modulation.
3 critical principles for successful preventative analgesia
- Depth of analgesia must be adequate enough to block all nociceptive input during surgery.
- Analgesic technique must be extensive enough to include entire surgical field.
- Duration of analgesia must include both the surgical and postsurgical periods.
Neuropathic pain responds best to which drugs? Which are first line drugs?
NMDA receptor antagonists, alpha 2 agonists, and alpha2-delta subunit calcium channel ligands, SNRIs, TCAs. SNRIs are considered first line.
Neuropathic pain is the result of…
accidental nerve injury secondary to cutting, traction, compression, or entrapment.
Surgical procedures that are high risk for neuropathic pain.
limb amputations, thoracotomy, breast surgery, gallbladder surgery, and inguinal hernia repair.
Two prodrugs that require metabolism by CYP2D6 enzyme to active analgesic form.
Codeine and tramadol.
Where do first-order neurons primarily synapse with second-order neurons in the dorsal horn?
In laminas I, II, and V.
What 3 areas are opioid receptors located?
- the periphery, following inflammation
- the spinal cord dorsal horn, primarily Rexed lamina II of substantia gelatinosa
- supraspinally in the brainstem (PAG), thalamus, amygdala, and limbic cortex.
Where are mu type opioid receptors found along the descending inhibitory pathway?
In the periaqueductal gray, the nucleus raphe magnus, and the rostral ventral medulla.
Which area in the dorsal horn is the major site of action for opioids?
Lamina II substantia gelatinosa. It contains many interneurons responsible for processing and modulating nociceptive input
Lamina V responds to…
both noxious and nonnoxious stimuli and receives both somatic and visceral inputs.
Lamina I responds to…
Nociceptive stimuli from cutaneous and deep somatic tissues
What category of receptors are opioids?
GPCR
What laminae make up the dorsal horn?
Laminae I - VI, which represents the primary sensory component of the spinal cord.
What laminae make up the ventral horn?
laminae VII-IX and X, involved in somatic motor and autonomic functions, respectively.
Where do SOMATIC C fibers primarily terminate? What abour VISCERAL C fibers?
Laminae I and II of the same and/or one or two adjacent spinal segments from which they entered. Visceral C fibers have a wider branching pattern, can terminate in ipsilateral laminae I, II, V, and X and also contralateral V and X (they are less localizable). They may terminate in the dorsal horn more than five segments rostrally or caudally.
Pain fibers originating from the head are carried by which nerves?
trigeminal V, facial VII, glossopharyngeal IX, and vagal X
spinalreticular pain pathway
arousal and autonomic responses to pain. The reticular formation is associated with changes in LOC in response to pain.
spinalmesencephalic pathway
antinociceptive descending pathways because of its projection in the PAG. Plays a role in the control and inhibition of pain. Neurons in the PAG activate our natural pain suppression system that involve the release of endogenous opioids.
muscle tendon, bone, and fascia have ____ nociceptors
somatic
Visceral organs have ____ nociceptors
silent
Factor VII allows the release of what?
Bradykinin
Role of COX enzyme
converts arachidonic acid to prostacyclin and PGE2 which potentiates edema from bradykinin
Phospholipase A2
Produces PGEs and forms arachidonic acid
Lipoxygenase pathway and arachidonic acid
Produces leukotrienes
What do ASA and NSAIDS inhibit?
COX enzyme
What do corticosteroids inhibit?
They inhibit the production of PGEs by blocking phospholipase A2 activation.
Receptor field expansion
Dorsal horn neurons increase their receptive fields to become more sensitive to stimuli whether noxious or not
What is the goal of preemptive analgesia?
To prevent central sensitization to pain, reducing postoperative analgesic requirements. It occurs by preventative NMDA receptor activation in the dorsal horn that is associated with wind up, facilitation, central sensitization, and long term potentiation.
What is acute pain?
It is usually less than one-month duration, self-limiting and resolves with healing of injury. Nearly always NOCICEPTIVE. Poorly controlled acute pain can lead to chronic pain.
What is chronic pain?
1-6 months duration and persists beyond usual course of disease or healing. Maybe nociceptive, neuropathic, or both. Usually have attenuated neuroendocrine response.
4 predictors of acute postoperative pain after elective surgery.
1) Presence of preoperative pain
2) Patient’s fear regarding outcome of surgery
3) Patients who catastrophize pain
4) Expected postoperative pain
Factors that contribute to the surgical stress response.
Extent of surgical field. Number of pain receptors involved in the area. Bleeding, infection, anxiety, and presence of coexisting disease. The older the patient, the worse the surgical stress response.
What role do steroids play in regional blocks?
They prolong the duration.
What 3 major pathways make up the anterolateral system?
The spinothalamic, spinoreticular, and spinomesencephalic tracts.
The “triad” of the descending pain inhibition system
PAG, rostral ventral medulla, and dorsolateral pontine tegmentum
What contributes to primary hyperalgesia (exaggerated response to pain at the site of injury)?
Peripheral sensitization of polymodal C fibers and high threshold mechanoreceptors by chemical mediators of pain.
What is secondary hyperalgesia?
Increased pain response evoked by stimuli outside the area of injury caused by central sensitization.
What are the two aspects of gabapentin’s MOA?
Modulation of the calcium-induced release of glutamate centrally in the dorsal horn, and activation of descending noradrenergic pathways in the spinal cord and brain.
Substance P
Released from peripheral afferent nociceptor C fibers and is involved in slow, chronic pain.
Glutamate
Release from A-delta and C primary afferent fibers. Effects are instantaneous, producing initial, fast, sharp pain.
Acetaminophen MOA
Works centrally. Reduces PGE synthesis by uncertain mechanism (but may be by COX enzyme).
How are nerve fibers classified?
By their anatomy, rate of transmission, and sensory modality transduced.
true visceral pain
dull, diffuse and midline. autonomic responses to pain such N/V, BP and HR changes
true parietal pain
sharp localized
referred parietal pain
referred to the chest and upper abdominal wall
referred visceral pain
referred to neck and shoulder
How do parenteral opioids work?
by initiating action potentials in the descending dorsal lateral funiculus
The affective component to the perception of noxious stimuli and autonomic responses such as increased BP and HR are mediated by….
the spinohypothalamic and spinoamygdalar pathways. Ascending axonal projections of these pathways arise from the spinal cord lamina I and X.
Name 4 blocks that are done for cancer pain
lumbar sympathetic block, splanchnic nerve block, celiac plexus block, hypogastric plexus block.
What block must be done under fluoroscopy to minimize the risk of aortic dissection?
The celiac plexus block.
Allodynia is mediated by which type of fibers?
large diameter A-beta fibers.
