unit 10 - opioids Flashcards
pain is multifaceted
(slide 1 for chart)
- Opioids are most closely associated with the management of pain and with rewarding processes associated with drug abuse and addiction. Therefore understanding the mechanisms of pain is important.
- Pain is not a simple sensation and the behavioral responses to it are the result of processing of pain sensory input by multiple types of neural systems.
- The peripheral input is some kind of painful stimulus. There is significant processing and modulation of the pain signal at the level of the spinal cord. Pain also affects mood and has an affective component not found with many other sensory modes. Therefore, there is significant descending input from cognitive and motivational systems that affect sensations of pain. These cognitive processes and are especially important for chronic pain perception.
pain involves multiple neural networks
- amygdala - fear, anxiety, associations, depression
- nocireceptors - injury, disease
- other cortical networks - attention, memories, interpretations, expectations
- PAG, dorsal horn, cortical pain receptors
(see slide 3 for chart)
pain and information processing in the nervous system
chart on slide 4
- Pain and other somatosensory input travel in separate neural pathways, but they interact. We’ll discuss this in the context of the “gate control” theory of pain. Together with the descending influences, there are multiple factors involved in how we perceive pain.
acute pain
can be mild and last just a moment, or it might be severe and last for weeks or months.
chronic pain
is pain that is ongoing and usually lasts longer than six months.
first (fast) pain
is felt within about 0.1 second after a pain stimulus is applied.
- use different afferent fiber types then slow pain
second slow pain
begins only after 1 second or more and then increases slowly over many seconds and sometimes even minutes.
- uses different afferent fiber type than fast
somatic and psychological characteristics of acute pain
- tachycardia (increase in HR)
- increased cardiac output
- increased blood pressure
- pupillary dilation
- palmar sweating
- hyperventilation
- hypermobility
- escape behavior
- anxiety state
fight-flight response
somatic and psychological characteristics of chronic pain
- sleep disturbance
- irritability, aggression
- appetite disturbance
- constipation
- psychomotor slow
- lowered pain tolerance
- social withdrawal
- abnormal illness behavior
depression
thermal or mechanical nociceptors
- Free nerve endings
- Small diameter nerve fibers
- Thinly myelinated
- A fibers
- 5-30 m/s
polymodal nociceptors
- Free nerve endings
- Activated by high-intensity mechanical, chemical and hot (>45°C) or cold
- Small diameter unmyelinated
- C-fibers
- 0.5-2 m/s
nociceptors
- sensory neurons that respond to damaging or potentially damaging stimuli.
- responsive to multiple types of physiological and chemical stimuli.
- do not have specialized endings - have free nerve endings
-pressure = mechanical pressure
-chemical = tissue damage, releases bradykinin and prostaglandins
-heat
A fibers
fast, sharp pain
- responsible for localization of the pain
- uses glutamate as neurotransmitter
- responsible for withdrawal reflex
- important: pain is adaptive, it keeps you from using a damaged part of the body so it can repair
C-fibers
“slow pain”
- burning pain, aching pain
- responsible for perceptual discomfort
- use substance P and glutamate as neurotransmitters
- most affected by opioids
chemical mediators that can activate and/or sensitize nociceptors
Here, are some important chemical mediators of pain:
1) Injury or tissue damage releases bradykinin, serotonin, prostaglandins, ATP and hydrogen ions, which activate or sensitize nociceptors.
Activation of nociceptors leads to the release of substance P and CGRP (calcitonin gene related peptide).
Substance P acts on mast cells in the vicinity of sensory endings to evoke degranulation and the release of histamine, which directly excites nociceptors. Substance P produces plasma extravasation (leakage of fluid) and CGRP produces dilation of peripheral blood vessels; the resultant edema causes additional liberation of bradykinin.
Collectively these effects lead to tissue inflammation which also involves activation of the immune system.
So,
Substance P -> mast cells -> histamine -> excites nociceptors!
Substance P+CGRP -> dilation -> edema -> more bradykinin!
inflammation
The four cardinal signs of inflammation—redness (Latin rubor), heat (calor), swelling (tumor), and pain (dolor)
acute inflammation
short onset and duration, change in hemodynamics, production of exudate, granular leukocytes
chronic inflammation
long onset and duration, presence of non-granular leukocytes and extensive scar tissue
first pain vs second pain
Subjectively, we often become aware of pain in 2 waves (i.e., with different latencies).
Respectively, these are referred to as first pain (or fast pain) and second pain (or slow pain). Each of these types of pain has been associated with a specific type of nociceptive afferent neuron. First pain is mediated by myelinated A fibers and second pain is mediated by unmyelinated C-fibers.
First pain (fast pain), A fibers - notice something has happened, and can localize it because the pathway and information goes to the somatosensory cortex.
Second pain (slow pain), C-fibers - the pain that stays with you
Propagation of action potentials in sensory fibers results in the perception of pain.
This electrical recording from a whole nerve shows a compound action potential representing the summated action potentials of all the component axons in the nerve. Even though the nerve contains mostly nonmyelinated axons, the major voltage deflections are produced by the relatively small number of myelinated axons. This is because action potentials in the population of more slowly conducting axons are dispersed in time, and the extracellular current generated by an action potential in a nonmyelinated axon is smaller than the current generated in myelinated axons.
B. First and second pain are carried by two different primary afferent axons. First pain is abolished by selective blockade of A myelinated axons (middle) and second pain by blocking C fibers (bottom).
substance P localization and mechanisms in pain
- Location of substance P containing neurons and fibers in the spinal cord, skin, and intestine. SP positive cells and fibers are shown as filled circles and solid lines, respectively. Non-SP cells and fibers are depicted with open circles and shaded lines.
- A diagrammatic representation of laminae in the gray matter of the human cervical spinal cord. Neurons in laminae I and II project to cells in laminae V and VI that form the lateral spinothalamic tract. This pathway then ascends, mostly contralaterally, to higher centers in the brain stem.
nociceptive afferent terminals
highly organized.
Projection neurons in lamina I receive direct input from myelinated (A) nociceptive afferent fibers and indirect input from unmyelinated (C) nociceptive afferent fibers via stalk cell interneurons in lamina II. Lamina V neurons receive low-threshold input from the large diameter myelinated fibers (A) of mechanoreceptors as well as both direct and indirect input from nociceptive afferent fibers (A and C).
The anatomy and interplay between these different fiber types can give an account for how pain can be “gated”.
Details:
Projection neurons in lamina I receive direct input from myelinated (A) nociceptive afferent fibers and indirect input from unmyelinated (C) nociceptive afferent fibers via stalk cell interneurons in lamina II. Lamina V neurons are predominately of the wide dynamic-range type. They receive low-threshold input from the large diameter myelinated fibers (A) of mechanoreceptors as well as both direct and indirect input from nociceptive afferent fibers (A and C). In this figure the lamina V neuron sends a dendrite up through lamina IV, where it is contacted by the terminal of an A primary afferent. A dendrite in lamina III arising from a cell in lamina V is contacted by the axon terminal of a lamina II interneuron.
gate control theory of pain perception
the nonnociceptive, large-diameter sensory fiber (orange) is more active than the nociceptive small-diameter fiber (blue), therefore the net input to the inhibitory interneuron (red) is net positive. The inhibitory interneuron provides presynaptic inhibition to both the nociceptive and nonnociceptive neurons, reducing the excitation of the transmission cells. In the bottom panel, an open “gate” (free-flowing information from afferents to the transmission cells) is pictured. This occurs when there is more activity in the nociceptive small-diameter fibers (blue) than the nonnociceptive large-diameter fibers (orange). In this situation, the inhibitory interneuron is silenced, which relieves inhibition of the transmission cells. This “open gate” allows for transmission cells to be excited, and thus pain to be sensed
types of neurons in dorsal horn - gate control theory
Unmyelinated pain fibers (C)
Myelinated nociceptive afferents (A)
Myelinated non-nociceptive afferents (A)
Projection neurons
Inhibitory interneurons (spontaneously active)
opiate-induced inhibition of substance P release
According to this model of opiate-mediated analgesia in the spinal cord, opiate receptors are located on the presynaptic terminals of primary afferent (nociceptive) axons containing SP. Local inhibitory neurons release enkephalin onto these terminals, thereby reducing SP release and attenuating the transmission of pain information to the brain.
Main Point:
- Activation of local neurons which release the opioid, enkephalin, produces an inhibition of substance P release from a primary afferent nociceptive neuron. This is an example of presynaptic inhibition. This presynaptic opioid receptor site is one of several probable CNS sites where opioid analgesics such as morphine exert their effects.
