Basic Mechanisms

CHAPTER 3 BASIC MECHANISMS



Allan I. Basbaum, PhD




1. What are nociceptors?


Nociceptors are neurons that respond to noxious thermal, mechanical, or chemical stimulation. The term is used for both peripheral and central neurons; however, because the receptor is located in the periphery, the term is best associated with small myelinated (A-delta) and unmyelinated (C) fiber primary afferent neurons. In the central nervous system, neurons that respond to noxious stimulation are considered nociresponsive. These are the “higher-order” neurons.



2. What properties characterize A-delta and C fibers?


A-delta fibers are small-diameter (1 to 6 μm), myelinated primary afferent fibers; C fibers are smaller-diameter (1.0 μm) unmyelinated primary afferents. The A-delta fibers conduct at velocities between 5 and 25 milliseconds; C fibers conduct at 1.0 μm/sec. A major component of the C fibers are polymodal nociceptors, which respond to thermal, mechanical, and chemical noxious stimulation. These express primary afferent nociceptors respond more selectively to noxious thermal or mechanical stimulation. It is unclear whether there are specific neurotransmitters associated with the modality subtypes of A-delta and C fibers.



3. Distinguish between first and second pain


First and second pain refers to the immediate and delayed pain responses to noxious stimulation. Other terms that denote these pains are fast and slow pain or sharp/pricking and dull/burning pain. The stimuli that generate first pain are transmitted by A-delta, small, myelinated afferents. Second pain results from activation of C fibers, which conduct impulses much more slowly, thus accounting for the time difference.



4. What are some of the molecules that are unique to the nociceptor?


All nociceptors use glutamate as their primary excitatory neurotransmitter. However, several other transmitters coexist with glutamate, and the differences in transmitters define the two major classes of nociceptors: The peptidergic class contains calcitonin gene–related peptide and substance P. The nonpeptide class is characterized by its binding of a unique lectin (IB4) and the fact that many of these neurons express the P2X3 purinergic receptor, which responds to adenosine triphosphate (ATP). Whether these classes mediate different types of pain remains to be determined; however, recent tracing studies indicate that the different subsets of nociceptors engage different circuits in the spinal cord and different ascending pathways.


A molecule that is present only in C-fiber nociceptors and that is relevant to the transmission of nociceptive messages is a possible therapeutic drug target. This is because the side-effect profile of such a drug would be limited by the fact that it is less likely to bind to unwanted sites in the central or peripheral nervous system. The cell bodies of small-diameter neurons in the dorsal root ganglion (which are the cell bodies of C fibers) contain several unique molecules, including the following:



image A tetrodotoxin-resistant Na channel (TTX-R)


image The vanilloid receptor (TRPV1), which is targeted by capsaicin, the active ingredient in hot peppers


image The P2X3 subtype of purinergic receptor, which is targeted by ATP


image A special type of dorsal root ganglion (D) specific acid-sensing ion channel (DRASIC)


Most recently, a class of G protein–linked receptors has been shown to be uniquely expressed in the dorsal root ganglion.



5. What are TRP channels?


TRP channels are a large family of transient receptor potential channels that allow ions to flow in response to a variety of stimuli, including temperature, many plant-derived compounds, and endogenous molecules. Different TRP channels cover the range of temperatures sensed by afferent fibers. For example, the threshold for TRPV1 is around 43-45° C, which is close to the threshold for evoking heat pain. TRPV2 has a higher threshold. TRPV3 responds to warm temperatures. TRPM8 responds to cooling.


Capsaicin is the exogenous stimulus that binds TRPV1. Camphor binds TRPV3; wasabi, mustard oil, garlic, and cinnamaldehyde bind TRPA1. With the exception of TRPV1, we still do not have information on the endogenous chemical ligands that activate these channels. However, there is considerable evidence that bradykinin, via an action at the B2 subtype of G protein–coupled receptor, regulates the properties of the TRPV1 and TRPA1 receptors.


Importantly, the properties of the channels are altered in the setting of injury. For example, TRPV1 not only responds to capsaicin and noxious heat but is regulated by pH. In the setting of tissue injury, where pH is lowered, the threshold for opening the channel is reduced sufficiently so that normally innocuous temperatures can evoke action potentials in nociceptors that express TRPV1. Studies in animals indicate that the pain of bone metastasis is significantly attenuated in animals in which TRPV1 is deleted genetically.



6. How are nociceptors altered by tissue injury?


When there is tissue injury (e.g., an arthritic joint), the nociceptor is exposed to an inflammatory “soup” containing a host of molecules that influence the properties of the nociceptor. These molecules include prostaglandin products of arachidonic acid metabolism, bradykinin, cytokines, serotonin, and growth factors (notably nerve growth factor [NGF]). This all occurs in the setting of lowered pH. Together these molecules contribute to peripheral sensitization, that process through which the threshold for firing of the nociceptor is lowered. The most direct way to treat peripheral sensitization is with nonsteroidal antiinflammatory drugs, which block the cyclooxygenase enzyme.



7. Where do nociceptive fibers enter the spinal cord?


Nociceptive primary afferent fibers have their cell bodies in dorsal root ganglia. The central branches of these afferents enter the spinal cord through the dorsal root and ascend or descend a few segments in the tract of Lissauer. The central branches terminate predominantly in the superficial laminae of the dorsal horn, including lamina I, the marginal zone, and lamina II, the substantia gelatinosa. Some A-delta primary afferent nociceptors also terminate more ventrally in the region of lamina V and around the central canal.


The fact that the level of analgesia observed following anterolateral cordotomy may be up to two segments below the segment at which the cordotomy was performed is presumed to reflect the anatomical course of axons in Lissauer’s tract. Some small-diameter primary afferents ascend the spinal cord one to two segments in the Lissauer’s tract, ipsilaterally, before entering the spinal cord and synapsing upon dorsal horn neurons, including cells at the origin of the spinothalamic and spinoreticular pathways.



8. Where is the first synapse in the spinal cord?


There is a differential projection of small-diameter and large-diameter primary afferent fibers to the spinal cord dorsal horn. The largest diameter Ia primary afferents arise from muscle spindles and make monosynaptic connection with motoneurons in the ventral horn. Large-diameter, nonnociceptive primary afferents synapse on neurons in lamina III and lamina IV that are at the origin of the spinocervical tract and on wide dynamic range neurons (see Question 7) in lamina V. Small-diameter nociceptive A-delta and C fibers arborize most densely in the superficial dorsal horn. The C fibers predominantly synapse with neurons in lamina I; they also synapse upon dorsally directed dendrites of neurons located more ventrally (e.g., in lamina V). In addition, there are connections with interneurons in the substantia gelatinosa. Many A-delta nociceptors terminate in lamina V.



9. What is meant by a second-order neuron?


Second-order refers to all of the spinal cord neurons that receive input from the primary afferent fibers, including interneurons and projection neurons. Second-order neurons are also located in the dorsal column nuclei; these receive input from large primary afferent fibers that ascend to the medulla via the dorsal and posterior columns. Note that many second-order neurons receive convergent input from small-diameter nociceptive primary afferents and from large-diameter nonnociceptive primary afferent fibers.



10. What is a wide dynamic range neuron?


Wide dynamic range refers to neurons in the spinal cord that respond to a broad range of intensity of stimulation. For example, there are neurons in lamina V that respond to nonnoxious brushing of the cell’s receptive field, as well as to intense mechanical stimulation and to noxious heat. Many wide dynamic range neurons also receive a visceral afferent input. By contrast, nociceptive-specific neurons respond exclusively to stimulus intensities in the noxious range.


Importantly, all primary afferent fibers are excitatory. Thus, any inhibitory effect that results from stimulation of large-diameter fibers (e.g., by vibration) results from an indirect mechanism involving inhibitory interneurons that influence the firing of the wide dynamic range neuron.



11. Describe the major ascending pathways that transmit nociceptive information

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Jun 14, 2016 | Posted by in PAIN MEDICINE | Comments Off on Basic Mechanisms

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