Nociception Flashcards
Recognize the pathways for processing of pain and temperature information and, describe where pain and temperature information is first detected, where the information first enters the central nervous system, and how the information gets to the brain
Pain and temperature are first detected at the free nerve ending in the skin and go down Adelta and C fibers to the dorsal root ganglion. Warm and cool receptors are found in the skin on the free nerve endings of
neurons that have cell bodies in the dorsal root (trunk and limbs) or trigeminal (head and neck) ganglia. Each primary sensory neuron has an axon that bifurcates; one branch (the receptor end) reaches the periphery (skin) while the other (the central axon) enters the central nervous system. Typically, cool receptors are associated with Aδ fibers, whereas warm receptors tend to be on C fibers. The message then goes to the dorsal horn of the spinal cord. The first synapse is made right away, then the second order neuron crosses and ascends in the anterolateral part. This then goes to the thalamus where inputs help localize the sensation to the somatosensory cortex (Spinothalamic tract). Spinoreticular tract conveys information via the reticular formation to the hypothalamus which helps with behavioral response to temperature. Stimulation of the periaqueductal gray region (PAG) in the midbrain produces a powerful analgesia.
Two other cortical regions are activated in humans when pain information is being processed. These regions are the cingulate gyrus and the insular cortex. The cingulate gyrus is part of the limbic system and contributes to
the emotional component of pain sensation. In contrast, the insular cortex processes information related to the autonomic component of pain
Pain (and temperature) inputs from head and neck are provided by trigeminal ganglion neurons. Their central axons enter the CNS at the level of the pons and descend to a caudal position before forming their first synapses. The site of the first synapse is in the spinal trigeminal nucleus, which is found in a region extending from the rostral spinal cord to caudal brain stem. The spinal trigeminal nucleus is functionally analogous to the dorsal horn of the spinal cord
Recognize the type of receptors that detect temperature information
Warm receptors: increase in temperature leads to increased frequency of action potential
Cool Receptors: decrease in temperature leads to increased frequency of action potential. 10x as many cool receptors as warm receptors
Describe how temperature receptors code their information.
For the cases of cool and warm receptor afferents, there is a transient change in action potential frequency followed by a steady-state change after a rapid stepchange in temperature (Figure 1). Information is thus provided about the absolute temperature (T, steady-state frequency during a prolonged exposure to a single temperature) and the rate of change of temperature (dT/dt, derived from the transient firing rate after a rapid change in T). At the thermo-neutral point of 33°C, cold and warm receptor afferents have similar firing rates.
Discuss the types of manipulations that distinguish first pain from second pain.
first pain (A-delta) is usually tolerable, alerts you, and is well-localized. Second pain (C) happens with a delay, is not well tolerated, and not very well localized- this is the aching and throbbing part of pain Pressure (as that applied by a super-inflated blood pressure cuff) can block conduction in peripheral fibers. This procedure will induce anoxia, and fibers with a high metabolic demand will be most vulnerable. As pressure is applied, the first fibers to become nonconductive are the most metabolically active ones, which are the larger diameter Aα and Aβ fibers. The individual would not sense touch, vibration or joint position/movement; the arm would be paralyzed. As pressure is increased, Aδ fibers would become blocked leaving only the sensation of burning pain. Finally at higher levels of pressure, C fibers would also be blocked. A similar sequence is observed when electrical stimulation is used to activate peripheral sensory nerves. A single electrical shock of low intensity can activate Aα and Aβ fibers, resulting in sensations of touch, vibration, and joint movement – all without pain. A shock of slightly higher intensity will evoke a sensation of pricking pain. Yet higher intensity and repetitive stimulation is required to elicit the sensation of burning pain. In contrast, anesthetics preferentially block small diameter fibers when applied at low concentrations. At low doses of anesthetics, burning pain is suppressed. Higher doses block pricking pain. Yet higher concentrations are required for block of touch afferents and motor axons (paralysis)
Discuss the stimuli that activate polymodal receptors
high intensity mechanical, chemical or thermal stimuli. C fibers.
Identify chemicals that act as pain activators and sensitizers.
Activator brings membrane to threshold. Sensitizer makes you more sensitive to a stimulus and makes it easier to get to threshold.
Activators: Bradykinin directly activates pain receptors of Aδ and C fibers. Potassium, acid and serotonin (5-HT) can also act as activators. Acids interact with several of the receptors mentioned previously, i.e., ASICs and VR-1.
Sensitizers: Substance P, Prostaglandins, 5HT
Substance P is contained in vesicles at both ends of the primary sensory neuron- released with repetitive stimulation.
ATP, acetylcholine and serotonin also can act singly or together as sensitizers
Identify the stimuli that activate the VR-1 receptor and where the VR-1 receptor is located.
Capsaicin receptor that is strongly activated by capsaicin and weakly activated by acids. It is also activated by moderate heat (43 celsius). Located on the polymodal nociceptors and opens a NSC channel when activated.
Discuss the type of pain information carried by C fiber afferents.
high intensity mechanical, chemical or thermal stimuli. Slower, because small diameter and unmyelinated.
Identify the location of the first synapse in the pain pathway and the neurotransmitters that operate at this synapse.
The major excitatory transmitter released by primary nociceptive sensory neurons at the site of the first synapse in the dorsal horn is glutamate. intense stimulation of C fibers leads to release of Substance P in the periphery from pain receptors. In addition, intense stimulation leads to release of Substance P from the C fiber’s presynaptic terminal in the dorsal horn – that is, at a central location. Consequently, glutamate and neuropeptides, such as Substance P, will be released
simultaneously in the CNS at the site of the first synapse in the pain pathway during periods of intense stimulation. Substance P binds to its receptor (also known as the neurokinin 1 receptor) and leads to closing of potassium channels and depolarization. Overall, Substance P’s effects lead to enhancement and prolongation of the actions of glutamate.
Describe the differences between and the properties of AMPA and NMDA receptors at the dorsal horn synapse.
AMPA receptors can bind to glutamate, but NMDA receptor requires glutamate and depolarization. As C fibers are stimulated, post-synaptic AMPA receptors will be stimulated first, as only glutamate is present. If C fiber stimulation is intense and persistent, both glutamate as well as post-synaptic depolarization will be present during the later periods of stimulation. Now, NMDA receptors will also be activated. Thus, repetitive firing of C fibers will lead to a progressively larger post-synaptic response. The NMDA receptor becomes phosphorylated by the action of protein kinase C (PKC) and tyrosine kinases.
Phosphorylation of the NMDA receptor removes the requirement for depolarization in order to activate it.
Discuss the basis for peripheral sensitization.
Sensitization of nociceptors is known as primary hyperalgesia, because the mechanism leading to the increased sensitivity to pain occurs at the first site of the pathway. When the sensitization is extreme enough to allow non-noxious stimuli to trigger a painful sensation, the term allodynia is used.
Discuss the basis for central sensitization (e.g., at the dorsal horn synapse).
With repetitive stimulation, Substance P binds to NK1 on the postsynaptic terminal and closes K channels, causing depolarization. This is an example of hyperalgesia
Describe the basis for the analgesic action of aspirin.
Bradykinin increases the synthesis of prostaglandins from neighboring cells, which then sensitize nociceptors.
Aspirins inhibit the enzyme, cyclooxygenase, which converts arachidonic acid to prostaglandin. By preventing the synthesis of prostaglandins, aspirin prevents nociceptor sensitization.
Describe the basis for the triple response.
Tissue damage leads to local production of bradykinin. In addition to being an activator, bradykinin acts as a vasodilator (leading to heat and redness) and increased permeability of capillary membranes. The latter effect will lead to fluid accumulation and swelling.
Bradykinin activates C fiber nociceptors, leading to depolarization and generation of action potentials. The action potentials initiated at these peripheral sites will propagate in 2 directions: one towards the cell body, and another, along collaterals towards yet more peripheral sites. The terminals of peripheral collaterals are distributed in neighboring skin regions. As action potentials invade the collateral terminals, substance P will be released in a region surrounding the site of the wound. Substance P produces vasodilation but typically to a lesser extent than does bradykinin. (The peptide CGRP may also be involved in the response.) The milder vasodilation produces
Identify the location of action and describe the effects of Substance P.
Substance P is released both at the synapse as well as in the periphery from the axon. Substance P is a classic example of a sensitizer and will reduce the threshold for activation of nociceptors with collaterals in the exposed region. Substance P produces vasodilation but typically to a lesser extent than does bradykinin.
