C-fibers responsive to noxious heat (C-H; ~10% of C-nociceptors) play a key role in heat sensation. A-fiber nociceptors are predominately heat- and or mechanosensitive (A-MH, A-H, A-M); however, sensitivity to noxious cold is also observed. Determining the contribution of each of these fiber types to pain perception requires an understanding of the molecular mechanisms underlying the detection of particular stimulus modalities and nociceptor connectivity in central circuits. Noxious stimuli are transduced into electrical signals in free “unencapsulated” nerve endings that have branched from the main axon and terminate in the wall of arterioles and surrounding connective tissue and may innervate distinct regions in the dermis and epidermis. The endings are ensheathed by Schwann cells except at the end bulb and mitochondria- and vesicle-rich varicosities. Fibers lose their myelin sheath, and the unmyelinated A-fiber branches cluster in separated small spots within a small area, the anatomical substrate for their receptive field. C-fiber branches are generally more broadly distributed, precluding precise localization of the stimulus. In contrast, specialized nonneuronal structures conferring high sensitivity to light touch, stretch, vibration, and hair movement are innervated by low threshold A-fibers (Neto et al., 2022). Nociceptive endings are in the vicinity of keratinocytes, mast cells, and Langerhans cells, indicating the capacity of peripheral sensory endings to monitor the status of the skin. Nociceptors, like other primary somatosensory neurons, are pseudounipolar: A single process emanates from the cell body in the dorsal root ganglion (DRG) or trigeminal ganglion (TG) and bifurcates, sending a peripheral axon to innervate the skin and a central axon to synapse on second-order neurons in the dorsal horn of the spinal cord or the trigeminal subnucleus caudalis (Vc), respectively. In this way, propagating electrical signals between the periphery and spinal cord (or brainstem) follow a direct axonal pathway, thus reducing the risk of conduction failure. Nociceptors are excitatory neurons and release glutamate as their primary neurotransmitter as well as other components including peptides (e.g., substance P, calcitonin gene-related peptide [CGRP], somatostatin) important in both central synaptic signaling and efferent signaling in the skin. Invasion of action potentials into the nociceptor soma via the short stem axon can lead to biochemical changes (e.g., phosphorylation and activation of the MAPK superfamily of signaling pathways) that ultimately alter gene expression and functional phenotype. Although it is thought that direct communication between the soma of primary sensory neurons does not occur, vesicle exocytosis is observed in dissociated soma and may influence associated Schwann cells and possibly nearby neurons.
The central axon of DRG neurons enters the spinal cord via the dorsal root and sprouts branches that innervate multiple spinal segments in the rostral and caudal direction as well as the segment associated with the particular DRG and dorsal column nuclei of the caudal medulla. They terminate predominantly in laminae I, II, and V of the dorsal horn on relay neurons and local interneurons important for signal modification. The relay neurons project to the medulla, mesencephalon, and thalamus, which in turn project to somatosensory and anterior cingulate cortices to drive sensory-discriminative and affective-cognitive aspects of pain, respectively (Robayo et al., 2022). Local inhibitory and excitatory interneurons in the dorsal horn as well as descending inhibitory and facilitatory pathways originating in the brain modulate the transmission of nociceptive signals, thus contributing to the prioritization of pain perception relative to other competing behavioral needs and homeostatic demands. The cell body (soma) has served as an extremely useful model to study molecules and modulatory mechanisms mediating the transduction of noxious stimuli, the transmission of electrical signals to the CNS, and the release of neurotransmitters and neuropeptides at central and peripheral terminals. The soma expresses many molecular entities that are expressed in free nerve endings, central terminals, and axons. However, data from whole-cell soma recordings have been shown in a few cases to be at odds with behavioral or peripheral physiological data (e.g., heat transduction, and proton responsiveness). Although the underlying differences in these cases may be due to the differential distribution of transduction molecules, it is also possible that nonneuronal peripheral components are required in vivo and lacking in dissociated neuronal cultures (Barkai et al., 2020). This underscores the importance of corroborating results from cultured neurons with behavior and/or acute preparations retaining intact terminal fields. Labeling with retrograde dyes injected into the target tissue has enabled the characterization of functional attributes of the soma of nociceptors innervating those tissues. The heterogeneity of functional phenotypes observed in isolated sensory cell bodies appears to reflect the variability observed in cutaneous nociceptor fiber types observed in studies in which recordings from fiber or soma during receptive field stimulation are combined with subsequent nociceptor labeling to identify terminal morphology (Wank et al., 2022) and the expression of nocisensors, markers, and peptides. Nociceptors differentially express a variety of anatomical and biochemical markers (e.g., the expression of versican, the binding partner for the isolectin), however, the functional significance of these markers, especially given striking species differences, is unknown. Here, we will address how the functional heterogeneity of the nociceptor has an impact on the perception of pain.
THE PHYSIOLOGY OF PAIN
A comprehensive understanding of the physiology of pain involves a close examination of the nociceptive pathway signals responsible for the transmission of pain stimulus from the periphery to the brain. This course examines this pathway with an emphasis on the integration and modulation of the nociceptive signal at different regions of the central nervous system. Mechanical, chemical, or thermal nociceptive stimulation will recruit peripheral nociceptors that conduct the nociceptive signal in the primary somatosensory neuron to the dorsal horn of the spinal cord. In the dorsal horn, the primary neuron will make synaptic contact with the secondary or projection neuron. Secondary neurons forming the spinothalamic (lateral) and spinoreticular (medial) tracts will immediately cross into the spinal cord and send afferent projections to higher centers (Lee & Neumeister, 2020). A large proportion of afferents will make a second synapse in the lateral and medial nuclei of the thalamus, which subsequently make synaptic contact with tertiary neurons. It is important to emphasize that the secondary neurons may also synapse
with neurons in different nuclei of the brainstem, including the periaqueductal gray (PAG) and nucleus raphe magnus (NRM), areas involved in descending endogenous pain modulation. An injury that causes a potential risk for the organism will activate free nerve endings that respond to nociceptive stimulation. Most of these fibers are polymodal and will respond to different modalities, including mechanical, thermal, and chemical stimulation. A nociceptive stimulation will initiate a cascade of events. Pronociceptive inflammatory molecules will be released into the periphery and will produce peripheral hyperalgesia. These pronociceptive inflammatory molecules originate in various blood cells (mastocytes, polymorphonuclear cells, and platelets) and include bradykinins, prostaglandins, histamine, serotonin, adenosine triphosphate, and also from immune cells which produce interleukins, interferon, and tumor necrosis factors. Substance P and calcitonin gene-related protein (CGRP), which act as neurotransmitters in the CNS, are also released into the periphery and act as proinflammatory factors in the periphery, favoring neurogenic inflammation (Zasler et al., 2022).
Book Code: PYFL4024
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